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Tablet

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What is a tablet ?
Submitted by on Sun, 11/15/2009 - 22:55 What will you gain? 1.1 Why do we need to convert an active pharmaceutical ingredient into a suitable dosage form? 1.2 What is a tablet? 1.3 Advantages and disadvantages of tablet as a dosage form

1.1 Why do we need to convert an active pharmaceutical ingredient into a suitable dosage form? (1-5)
Active pharmaceutical compounds (drugs) are used for the treatment of a disease or for prophylactic purpose. An Active Pharmaceutical Ingredient (API) may exist in solid, liquid or semisolid form. They are rarely prescribed to the patients as such i.e. without adding excipients, since the desired effect may not be obtained. Earlier, it was thought that excipients are inert in nature but, in recent time it is well known that excipients can greatly modify the intended effect of a drug. The API and excipients are suitably processed in pharmaceutical industry to convert them into dosage forms such as tablet, capsule, suspension, solution, etc. The selection of excipients and processing of drug excipients mixture is as important as API itself. Patient acceptability can be improved by controlling the organoleptic properties. Dosage form provides desired therapeutic level of a drug.

1.2 What is a tablet? (1-5)
It is a solid dosage form each containing a unit dose of one or more medicament/s. Tablets are solid, flat or biconvex discs prepared by compressing a drug or a mixture of drugs with or without suitable excipients. Tablets may be swallowed whole or being chewed. Some are dissolved or dispersed in water before administration. Some are put in oral cavity, where the active ingredient is liberated at a predetermined rate. Implants or passeries may also be presented in form of tablet.

Tablet may vary in shape and differ greatly in size and weight depending on the amount of medicinal substance and the intended mode of administration.

1.3 Advantages and disadvantages of tablet as a dosage form. (1-5)
The advantages are listed below: I.Large scale manufacturing is feasible in comparison to other dosage forms. Therefore, economy can be achieved. II.Accuracy of dose is maintained since tablet is a solid unit dosage form. III. Tailor made release profile can be achieved. IV. Longer expiry period and minimum microbial spillage owing to lower moisture content. V. As tablet is not a sterile dosage form, stringent environmental conditions are not required in the tablet department. VI. Ease of packaging (blister or strip) and easy handling over liquid dosage form. VII. Easy to transport in bulk. Emergency supply supplies can be carried by patients. VIII.Organoleptic properties (taste, appearance and odour) are best improved by coating of tablet. IX. Product identification is easy and markings done with the help of grooved punches and printing with edible ink. X. Different types of tablets are available like buccal, floating, colon targeting, effervescent, dispersible, soluble, and chewable, etc. XI. In composition to parenterals dosage form, a doctor or a nurse is not required for administration. I.e. self administration is possible. XII. In comparison to capsules, tablets are more tamperproof. The disadvantages are listed below:

I.It is difficult to convert a high dose poorly compressible API into a tablet of suitable size for human use. II.Difficult to formulate a drug with poor wettability, slow dissolution into a tablet. III. Slow onset of action as compared to parenterals, liquid orals and capsules. IV. The amount of liquid drug (e.g. Vitamin E, Simethicone) that can be trapped into a tablet is very less. V. Difficult to swallow for kids, terminally ill and geriatric patients. VI. Patients undergoing radiotherapy cannot swallow tablet. Key Phrases Ø Reasons to go for dosage form i) To control organoleptic properties ii) Achieve desired therapeutic level of drug Ø The most widely used dosage form is tablet Ø Advantages i) Accurate dose ii) Tailor made release profiles iii) Longer expiry period iv) Stringent environmental condition is NOT required v) Easy handling Ø Disadvantages i) Slow onset of action ii) Large amount of liquid cannot be incorporated iii) Difficulty in swallowing especially for geriatric and pediatric patients

Types of tablets
Submitted by on Sun, 12/06/2009 - 19:49

1.4 Types of Tablets
What will you gain? 1.4.1 Oral tablets for ingestion 1.4.2 Tablets used in the oral cavity 1.4.3 Tablets administered by other routes 1.4.4 Tablets used to prepare solution With advancement in technology and increase in awareness towards modification in standard tablet to achieve better acceptability as well as bioavailability, newer and more efficient tablet dosage forms are being developed. The main reasons behind formulation of different types of tablets are to create a delivery system that is relatively simple and inexpensive to manufacture, provide the dosage form that is convenient from patient’s perspective and utilize an approach that is unlikely to add complexity during regulatory approval process. To understand each dosage form, tablets here are classified by their route of administration and by the type of drug delivery system they represent within that route. Table.1. Various Types Of Tablets 1.4.1 ORAL TABLETS FOR INGESTION 1.4.1.1 Standard compressed tablets 1.4.1.2 Multiple compressed tablets I. Compression coated tablet II. Layered tablet III. Inlay tablet 1.4.1.3 Modified Release tablet

1.4.1.4 Delayed action tablet 1.4.1.5 Targeted tablet I. Floating tablet II. Colon targeting tablet 1.4.1.6 Chewable tablet 1.4.1.7 Dispersible tablet 1.4.2.1 Lozenges and troches 1.4.2.2 Sublingual tablet 1.4.2.3 Buccal tablet 1.4.2.4 Dental cones 1.4.2.5 Mouth dissolved tablet 1.4.3.1 Vaginal tablet 1.4.3.2 Implants 1.4.4.1 Effervescent tablet 1.4.4.2 Hypodermic tablet 1.4.4.3 Soluble tablet 1.4.1 Oral tablets for ingestion (1-3) These tablets are meant to be swallowed intact along with a sufficient quantity of potable water. Exception is chewable tablet. Over 90% of the tablets manufactured today are ingested orally. This shows that this class of formulation is the most popular world wide and the major attention of the researcher is towards this direction.
1.4.1.1 Standard compressed tablets

1.4.2

TABLETS USED IN THE ORAL CAVITY

1.4.3

1.4.4

TABLETS ADMINISTERED BY OTHER ROUTES TABLETS USED TO PREPARE SOLUTION

These are the standard uncoated tablets made by either direct compression or wet granulation or dry granulation or double compaction.

1) Figure.1. Standard Compressed Tablet They may be used for local action in gastro-intestinal tract or systemic action. When the tablet exert local action, they are formulated as more water insoluble by means of selecting slow dissolving excipients and thus provides local action for long time period. e.g., antacids and adsorbents. The drugs that produce systemic action have some aqueous solubility and designed to disintegrate and dissolve quickly so that the drug can be quickly absorbed and produce systemic action. Generally, an API exhibits bioavailability depending upon Biopharmaceutical Class, which is based on water solubility and gastro-intestinal membrane permeability criteria. But, it can be altered by appropriate selection of excipients and processing technology.
1.4.1.2 Multiple compressed tablets

The tablets in this category are prepared for two reasons: to separate physically or chemically incompatible ingredients and to produce repeat action/ prolonged action tablet. The tablet manufacturing machine is generally operated at relatively lower speed than for standard compression tablet. There are three categories under this class: I.Layered tablets – two to three component system. II.Compression coated tablets – tablet within a tablet. III.Inlay tablet – coat partially surrounding the core. The layered tablet is preferred over compression coated tablet as the surface contact is less and the production is simple and more rapid. I. Multilayered tablets When two or more active pharmaceutical ingredients are needed to be administered simultaneously and they are incompatible, the best option for the formulation pharmacist would be to formulate multilayered tablet. It consists of several different granulations that are compressed to form a single tablet composed of two or more layers and usually each layer is of different colour to produce a distinctive looking tablet. Each layer is fed from separate feed frame with individual weight control. Dust extraction is essential during compression to avoid contamination. Therefore, each layer undergoes light compression as each component is laid down. This avoids granules intermixing if the machine vibrates. For example, admixture containing Phenylephedrin HCL and Ascorbic Acid with Paracetamol. Paracetamol + phenylephedrine Hydrochloride → one layer

Paracetamol + ascorbic acid → another layer.

Figure.2. Multilayered Tablet 2) II. Compression coated tablets This type of tablet has two parts, internal core and surrounding coat. The core is small porous tablet and prepared on one turret. For preparing final tablet, a bigger die cavity in another turret is used in which first the coat material is filled to half and then core tablet is mechanically transferred, again the remaining space is filled with coat material and finally compression force is applied. This tablet readily lend itself in to a repeat action tablet as the outer layer provides the initial dose while the inner core release the drug later on. But, when the core quickly releases the drug, entirely different blood level is achieved with the risk of over dose toxicity. To avoid immediate release of both the layers, the core tablet is coated with enteric polymer so that it will not release the drug in stomach while, the first dose is added in outer sugar coating. Even so, coating operation requires interpretation while manufacturing and dawdling the manufacturing process. Sometimes, inner core may be of liquid formulation to provide immediate release of core after the coat gets dissolved.

Figure.3. Compression Coated Tablet III. Inlay tablets (4) A type of layered tablet in which instead the core tablet being completely surrounded by coating, top surface is completely exposed. While preparation, only the bottom of the die cavity is filled with coating material and core is placed upon it. When compression force is applied, some coating material is displaced to form the sides and compress the whole tablet. It has some advantages over compression coated tablets: i)Less coating material is required. ii)Core is visible, so coreless tablets can be easily detected. iii)Reduction in coating forms a thinner tablet and thus freedom from capping of top coating.

Figure.4. Inlay Tablets
1.4.1.3 Modified Release tablets

The main aim behind formulation of this dosage form is to release the medicament slowly for long time duration after administration of a single tablet.

Figure.5. Graphical Comparison Of Blood Concentration V/S Time A widespread use of this type of tablet is seen in present scenario, as well as many researchers have concentrated their attention in this direction. This is mainly because of improvement in patient’s compliance as the dosage frequency is reduced, patient can take an undisturbed sleep at night, it’s also beneficial for psychiatric patients who forget to take their tablets regularly and the dose related side effects and toxicities are reduced. Any adjuvant that can alter water uptake rate, swelling and gelling characteristics of Matrixing agents can alter the release rate of API e.g., electrolytes in HPMC matrix tablet. It’s also possible to achieve pulsed drug release. Weakly basic drugs exhibit good solubility at low pH while less soluble at high pH conditions, which can result in incomplete drug release for sustained release formulations. The drug release can be modified by providing suitable micro environmental pH in the tablet e.g., acidic polymer, succinic acid, etc. Similarly, inclusion of alkaline polymers results in desirable drug release of acidic drugs. On the other hand, formulation of this type of dosage form presents challenge for the formulator: increases the cost of manufacturing, chances of burst drug release and drop in drug release rate in terminal phase and thus incomplete release on API. In case of accidental poisoning, the doctor has to deal with special treatment problems. Due to large size, patient may feel difficulties in swallowing as the matrixing agent to drug ratio is high. Classic approaches are usually based on adaptation of either film coated or multiparticulate technologies or those involving slow release matrices. Coating technology (6)

It combines semi permeable coatings and osmotic tablet cores to produce “zero order release” technology. Attention is also focused to trigger drug release at critical time point e.g., to achieve drug release 1 -2 hours before the patient awakens. Alza’s prolific research activities have yielded a technology called “Ringcap” which is based on a tablet, preferentially film coated, partially coated with a series of rings whose respective thickness provides the means of moderating the rate at which the drug is released from final dosage form.

Figure.6. Ringcap (Coated) Tablet Matrix technology Classically matrix products exhibit first order (or perhaps square-root-of-time) drug release characteristics. In order to achieve zero order release characteristics, it’s necessary to employ specially designed materials or strategies that seek to manipulate tablet structure or geometry. Combination of conventional HPMC matrix technology with upper and lower layer. This helps to moderate drug release by increase in surface area with concomitant reduction in drug concentration within the device.

Figure.7. Matrix Tablet Release of medicament can follow various mechanisms (2) i) Diffusion is rate limiting Diffusion is driving force where the movement of drug molecules occurs from high concentration in the tablet to lower concentration in gastro intestinal fluids. This movement depends on surface area exposed to gastric fluid, diffusion pathway, drug concentration gradient and diffusion coefficient of the system.

Figure.8. Diffusion Release Pattern

In practice, we can follow either of the two methods, 1.The drug is formulated in an insoluble matrix; the gastric fluid penetrates the dosage form and dissolves the medicament and release the drug through diffusion. 2.The drug particles are coated with polymer of defined thickness so as the portion of drug slowly diffuse through the polymer to maintain constant drug level in blood. ii) Dissolution is rate limiting The drugs with poor water solubility (BCS class 2 and 4) are inherently sustained release forms. While for water soluble drugs, it’s possible to incorporate a water insoluble carrier to reduce dissolution of the drug particles are coated with this type of materials e.g. Polyethylene Glycol. One may skip the use of disintegrating agent to promote delayed release. iii) Osmotic pressure is rate limiting Osmosis is a phenomenon in which the flow of liquid occurs from lower concentration to higher concentration through a semi permeable membrane which allows transfer of liquid only. The whole drug is coated with a semi permeable membrane with a hole on one end of tablet made by a laser beam. The gastric fluid penetrates through the membrane, solubilizes the drug and increases the internal pressure which pumps the drug solution out of the aperture and releases the drug in gastric environment. The delivery rate is constant provided that the excess of drug present inside the tablet. But, it declines to zero once the concentration drops below saturation.

Figure.9. Osmotic Release Pattern iv) Release is controlled by ion exchange Ion exchangers are water insoluble resinous materials containing salt forming anionic or cationic groups. While manufacturing, the drug solution is mixed with resin and dried to form beads which are tableted. The drug release depends upon high concentration of charged ions in gastro intestinal tract where, the drug molecules are exchanged and diffused out of

the resin into the surrounding fluid. This mechanism relies upon the ionic environment of resin and not pH or enzyme on absorption site.
1.4.1.4 Delayed action tablets

Enteric coated tablet is such an example of delayed action tablet. This formulation is preferred when, i)The API irritates gastric mucosa e.g., aspirin or strong electrolytes ii)Drugs that produce nausea and vomiting. iii)API is sensitive to low pH e.g., erythromycin iv)When it’s necessary to release the drug undiluted. e.g., intestinal antibacterial, antiseptic agents, intestinal vermifuge, etc. The commonly used coating agents are: Cellulose acetate phthalate, Hydroxy methyl propyl phthalate, polyvinyl acetate phthalate, Eudragit®, etc. This dosage form is intended to hydrate and begin to dissolve in duodenum (pH 4 to 6) or in small intestine where pH increases to 7 to 8. The presence of esterases or bile salts like surface active agents plays a role in drug release.
1.4.1.5 Targeted tablets

When we need to release the API at a specific site in the elementary tract, targeted drug delivery is a preferred option. Depending upon the composition and release mechanism of a tablet, the drug is delivered to a particular region. Under this category, we have two types of tablet: I. Gastro retentive Tablet This type of dosage form is to be opted when API release is desired in stomach (Antacids, APIs used against H.pylori infection) or site of absorption is either stomach or upper part of small intestine.

Figure.10. Floating Tablet To retain the drug for longer time period in stomach, following approaches can be used:

i) Low density tablet (effervescent or non effervescent) ii) Tablets that can expand in gastric environment (swelling or by unfolding) and thus increasing the size so that it cannot cross the pyloric sphincter. iii) Using mucoadhesive polymers that stick to mucosa of stomach and provide slow drug release. Supine position is to be avoided and also high level of fluid is necessary or if the swelling formulation leaves stomach before it swells it’s ineffective. Drugs like Diazepam, Levodopa, Benserazide, and Ciprofloxacin are successfully marketed in this formulation. II. Colonic tablets (7,8) When the aim is to deliver the drug into colon without dilution in other regions of gastrointestinal tract or the drug has poor absorption in stomach or small intestine, colonic drug delivery is an answer of choice. The pH in this region varies from 6.4 - 7 and presence of microbial flora plays as important role in drug release especially in this region. Various mechanisms are adopted for drug release in this area are coating with pH sensitive polymer e.g., Eudragit®S100, Eudragit® L100, biodegradable polymer like polymers which are sensitive to colonic bacteria, bioadhesive polymers which selectively sticks to colonic mucosa e.g., polycarbophils or polyethans, redox sensitive polymers that respond to redox potential in colon which expresses the total metabolic and bacterial action.
1.4.1.6 Chewable tablets

The patients who have difficulty in swallowing tablets whole or for children who have not yet learnt to swallow a tablet, chewable tablet serves as an attractive alternative. The added advantage of this medication is that it can be taken at any time or when water is not available. Mannitol is normally used as a base due to low hygroscopy and more importantly, it gives pleasant, cooling sensation. Antacid tablets are invariably prepared as chewable to obtain quick ingestion relief as well as the antacid dose is too large to swallow and the activity is related to particle size. Another example is multivitamin tablet which a patient can take as a daily dose.
1.4.1.7 Dispersible tablet (9)

These tablets disintegrate either rapidly in water, to form a stabilized suspension, or disperse instantaneously in the mouth to be swallowed without the aid of water. So, it’s preferred for pediatric patients who cannot swallow a solid dosage form and the API is unstable if formulated in liquid formulation. Also helpful for patients having prolonged illness who are

prone to nauseatic sensations if they have to swallow a tablet. The added advantage of this formulation is faster onset of action as compared to standard compressed tablet. The properties of the water dispersible tablet, such as porosity, hardness, disintegration time and increase in viscosity after dispersion are necessary to investigate during manufacturing which decides the product performance. The common examples of API formulated in this dosage form are analgesics e.g., aspirin, ibuprofen, etc. 1.4.2 Tablets used in the oral cavity (1-3) The tablets under this group are aimed release API in oral cavity or to provide local action in this region. The tablets under this category avoids first-pass metabolism, decomposition in gastric environment, nauseatic sensations and gives rapid onset of action. The tablets formulated for this region are designed to fit in proper region of oral cavity.
1.4.2.1 Lozenges and troches

The tablet is a flat faced at least about 18mm in diameter and meant to suck and dissolves in the mouth. The compressed tablet is called troches and the tablets produced by fusion or candy molding process are called lozenges. Flavours and sweeteners are added to make tablets palatable. The tablet generally contains sucrose or lactose and gelatin solution to impart smooth taste. Lozenges for local action in mouth/ throat are: antiseptics, antibiotics, demulcents, antitussive agents or astringents. To produce systemic action: multivitamin tablet.
1.4.2.2 Sublingual tablets

They are to be placed under the tongue and produce immediate systemic effect by enabling the drug absorbed directly through mucosal lining of the mouth beneath the tongue.

Figure.11. Sublingual Tablets The drug absorbed from stomach goes to mesenteric circulation which connects to stomach via portal vein. Thus, absorption through oral cavity avoids first-pass metabolism. The tablets are usually small and flat, compressed lightly to keep them soft. The tablet must dissolve quickly allowing the API to be absorbed quickly. It’s designed to dissolve in small quantity of saliva. After the tablet is placed in the mouth below the tongue, the patient should avoid eating, drinking, smoking and possibly talking in

order to keep the tablet in place. Swallowing of saliva should also be avoided since the saliva may contain dissolved drug. Bland excipients are used to avoid salivary stimulation. Due to inconvenience in administration, this dosage form is prepared only for those API(s) for which the only satisfactory nonparenteral method is this route. For example, Glyceryl trinitrate (vasodilator) and Isoprinosine sulphate (bronchodilator).
1.4.2.3 Buccal tablets

Completeness of drug absorption is desired but fast drug absorption is not intended. The tablets are designed not to disintegrate. They are flat elliptical or capsule shaped tablets as it can be easily held between gum and cheek. It’s placed near the opening of parotid duct to provide the medium to dissolve the tablet.

Figure.12. Buccal Tablets Since this tablet is to be kept for 30-60 minutes in oral cavity, care should be taken to see that all the ingredients are finely divided to avoid gritty or irritating sensation. This tablet is most often used when replacement hormonal therapy is to be administered. Antifungal drugs are preferred to be administered by this route. e.g., Miconazole – under preclinical trial – still not in market.
1.4.2.4 Dental cones

These tables are designed to be loosely packed in the empty socket remaining following a tooth extraction.

Figure.13. Dental Cones Main purpose behind the use of this tablet is either to prevent multiplication of bacteria in the socket by employing a slow releasing antibacterial compound or to reduce bleeding by an astringent or coagulant containing tablet. It’s formulated to dissolve or erode slowly in presence of a small volume of serum or fluid over 20-40 minutes period.
1.4.2.5 Mouth Dissolved tablets/ Rapidly Dissolving tablets (10)

Known to the FDA as orally disintegrating tablets, they are also called mouth-dissolving, fast-dissolving, rapid-melt, porous, orodispersible, quick dissolving. These kinds of tablets are preferred when fast action or relief is desired. Most commonly used drugs under this formulation are the agents active against Migraine. The tablets are designed to disintegrate as well as dissolve within one minute or some within 10 seconds of oral administration in limited quantity of saliva. They liquefy on tongue and patient swallows the liquid, without the need of water. A number of techniques are used to prepare these tablets, including lyophilization, soft direct compression. Matrices having an API and high porosity are also being prepared using sublimation process. Urea, urethane, ammonium carbonate, ammonium bicarbonate, hexamethylene, benzoic acid, naphthalene and camphor are commonly used for sublimation processing as they they volatize rapidly. After removal by sublimation, these inert volatile substances leave the matrices with a high porosity. Disintegrants and sugar based excipients, such as sodium starch glycolate, cross carmellose sodium, mannitol, xylitol, dextrose, fructose, maltose and polydextrose have been incorporated in almost all the orally disintegrating dosage forms (ODDFs). Loading of drug is made by preparing a blank and drug is post loaded. Generally the drug in solution is added after which the solvent evaporates. Taste masking poses numerous challenges since the drug product dissolves in mouth, any taste of drug must be covered, either by flavoring technique or by micro encapsulation or nanoencapsulation. A major drawback of most of these systems is that the packaging system needs a higher degree of protection due to the lower hardness and more friability of the porous nature of tablets, except the DuraSolv technology of CIMA Labs, which are suitable for rigors of bulk bottle packaging. Keep the orally disintegrating tablet in the blister pack inside the outer foil pouch until the patient is ready to take the medicine. Make sure that operator’s hands are dry and peel open the blister to remove the tablet. Place the tablet on tongue and let it dissolve. These dosage forms have become a delivery system of choice for most patients as they provide comfort for administration throughout the day. Pharmaceutical companies, on the other hand, benefit from value addition in terms of product life-cycle management in today’s market. 1.4.3 Tablets administered by other routes (1-3) These tablets are administered by other route except for the oral cavity and so the drugs are avoided from passing through gastro intestinal tract. These tablets may be inserted into other body cavities or directly placed below the skin to be absorbed into systemic circulation from the site of application.
1.4.3.1 Vaginal tablets

This tablet undergoes slow dissolution and drug release in vaginal cavity of women. The shape is kept ovoid or pear shaped to facilitate retention in vagina. The tablet should be made compatible with plastic tube inserters which are designed to place the tablet in the upper region of vaginal tract. These tablets generally release antibacterial,

antiseptics or astringents to treat vaginal infections or release steroids for systemic absorption.
1.4.3.2 Implants

These tablets are inserted into subcutaneous tissue by surgical procedures where they are very slowly absorbed over a period of a month or a year. A special injector with a hollow needle and plunger is used to administer the rod shaped tablet for other shapes, surgery is required. The tablets may be pellet, cylindrical or rosette shaped with diameter not more than 8mm. They are sterile formulation without excipients and made hard with large particle size to achieve gradual drug release. The tablets are produced by a sterile single punch hand operated machine in which the die cavity is filled with hand since the material does not normally flow well. Mainly, these tablets are prepared to deliver growth hormones to food producing animals and ear is the preferred site for administration of the drug. 1.4.4 Tablets used to prepare solution The tablets under this category are required to be dissolved first in water or other solvents before administration or application. This solution may be for ingestion or parenteral application or for topical use depending upon type of medicament used.
1.4.4.1 Effervescent tablets (11)

The oral dosage forms are the most popular way of taking medication despite having some disadvantages like slow absorption and thus onset of action is prolong. This can be overcome by administrating the drug in liquid from but, many APIs have limited level of stability in liquid form. So, effervescent tablets acts as an alternative dosage form. The tablet is added into a glass of water just before administration and the drug solution or dispersion is to be drunk immediately. The tablet is quickly broken apart by internal liberation of CO2 in water due to interaction between tartaric acid and citric acid with alkali metal carbonates or bicarbonates in presence of water.

Figure.14. Effervescent Tablets Due to liberation in CO2 gas, the dissolution of API in water as well as taste masking effect is enhanced. The advantages of effervescent tablets compared with other oral dosage forms

includes an opportunity for formulator to improve taste, a more gentle action on patient’s stomach and marketing aspects. To manufacture these tablets, either wet fusion or heat fusion is adopted. The tablets are compressed soft enough to produce an effervescent reaction that is adequately rapid. Water soluble lubricants are used to prevent an insoluble scum formation on water surface. To add sweetness to the formulation, saccharin is added since sucrose is hygroscopic and add too much of bulk to the tablet. The manufacturing shall be done under controlled climatic condition to avoid effervescent reaction. The packaging is done under 25% RH at 25ºC. Hands of the consumers and atmospheric moisture after opening the container can also result in loss of product quality. The most commonly used effervescent tablet today is aspirin tablet.
1.4.4.2 Hypodermic tablets

These tablets contain one or more readily water soluble ingredients and are intended to be added in water for injection of sterile water to form a clear solution which is to be injected parenterally. They were widely used by rural physician due to its portability. One bottle of sterile water was carried by the doctor to prepare many types of injectables. It can be used for medicaments whose stability in water is very poor.
1.4.4.3 Soluble tablets (12)

Tablets are pre-formed solids of uniform shape and dimensions, usually circular, with either flat or convex faces, the distance between faces being less than the diameter. Water soluble tablets are intended for application after dissolution in water and contain an active ingredient should be totally soluble in water at used concentrations. All the excipients used to formulate these tablets are required to be completely soluble in water including the glidants, binders, etc. So, manufacturing of this kind of tablets are challenge for the formulator. Companies manufacturing these tablets have patented them.

Figure.15. Soluble Tablets Key Phrases Ø When two or more active pharmaceutical ingredients are needed to be administered simultaneously and they are incompatible, the best option for the formulation

pharmacist would be to formulate multilayered tablet. Ø When we need to release the medicament slowly for long time duration after administration of a single tablet we go for modified release formulation. Ø When we need to release the API at a specific site in the elementary tract, targeted drug delivery is a preferred option. Ø Dispersible tablets disintegrate either rapidly in water, to form a stabilized suspension, or disperse instantaneously in the mouth to be swallowed without the aid of water Ø Sublingual tablet is designed to dissolve in small quantity of saliva and used when immediate action within few minutes is desired. Ø Buccal tablet is most often used when replacement hormonal therapy is to be administered. Ø Implants are inserted into subcutaneous tissue by surgical procedures where they are very slowly absorbed over a period of a month or a year.

Formulation of tablets
Submitted by on Sun, 12/06/2009 - 19:50

1.5 Formulation
Ø What will you gain? 1.5.1 Excipient and their functionalities 1.5.2 Diluents 1.5.3 Binders 1.5.4 Disintegrants 1.5.5 Antifrictional Agents 1.5.6 Miscellaneous Excipients

1.5.1 Excipient and their functionalities (13-15) Excipient means any component other than the active pharmaceutical ingredient(s) intentionally added to the formulation of a dosage form. Many guidelines exist to aid in selection of non toxic excipients such as IIG (Inactive Ingredient Guide), GRAS (Generally Regarded As Safe), Handbook of Pharmaceutical Excipients and others. While selecting excipients for any formulation following things should be considered wherever possible: keep the excipients to a minimum in number minimize the quantity of each excipients and multifunctional excipients may be given preference over unifunctional excipients. Excipients play a crucial role in design of the delivery system, determining its quality and performance. Excipients though usually regarded as nontoxic there are examples of known excipient induced toxicities which include renal failure and death from diethylene glycol, osmotic diarrhoea caused by ingested mannitol, hypersensitivity reactions from lanolin and cardiotoxicity induced by propylene glycol. Excipients are chosen in tablet formulation to perform a variety of functions like i) For providing essential manufacturing technology functions (binders, glidants, lubricants may be added), ii) For enhancing patient acceptance (flavors, colourants may be added), iii) For providing aid in product identification (colourants may be added), iv) For Optimizing or modifying drug release (disintegrants, hydrophilic polymers, wetting agents, biodegradable polymers may be added), v) For enhancing stability (antioxidant, UV absorbers may be added) Various excipients used in tablet formulation and their functionalities.
(1, 4, 16)

Table.2. Excipient With Their Functions In Tablet Formulation EXCIPIENT Diluents or Fillers FUNCTION Diluents make the required bulk of the tablet when the drug dosage itself is inadequate to produce tablets of adequate weight and size. Binders are added to tablet formulations to add cohesiveness to powders, thus

Binders or Granulating agents or Adhesives

Disintegrants

Lubricants

Antiadherents

Glidants

Wetting agents

Dissolution retardants

Dissolution enhancers

Adsorbents

Buffers

Antioxidants

providing the necessary bonding to form granules, which under compaction form a cohesive mass or a compact which is referred to as a tablet. A disintegrant is added to most tablet formulations to facilitate a breakup or disintegration of the tablet when placed in an aqueous environment. Antifrictional Agents Lubricants are intended to reduce the friction during tablet formation in a die and also during ejection from die cavity. Antiadherents are added to reduce sticking or adhesion of any of the tablet granulation or powder to the faces of the punches or to the die wall. Glidants are intended to promote the flow of tablet granulation or powder mixture from hopper to the die cavity by reducing friction between the particles. MISCELLANEOUS Wetting agents are added to tablet formulation to aid water uptake during disintegration and assist drug dissolution. Dissolution retardants as the name suggest, retards the dissolution of active pharmaceutical ingredient(s). Dissolution enhancers as the name suggest, enhance the dissolution rate of active pharmaceutical ingredient(s). Adsorbents are capable of retaining large quantities of liquids without becoming wet; this property of absorbent allows many oils, fluid extracts and eutectic melts to be incorporated into tablets. Buffers are added to provide suitable micro environmental pH to get improved stability and / or bioavailability. Antioxidants are added to maintain product stability, they act by being

Chelating agents

Preservatives

Colours

Flavours

Sweeteners

preferentially oxidized and gradually consumed over shelf life of the product. Chelating agents are added to protect against autoxidation; they act by forming complexes with the heavy metal ions which are often required to initiate oxidative reactions. Preservatives are added to tablet formulation in order to prevent the growth of micro-organisms. Colours are added to tablet formulation for following purposes: to disguise off colour drugs, product identification and for production of more elegant product. Flavours are added to tablet formulation in order to make them palatable enough in case of chewable tablet by improving the taste. Sweeteners are added to tablet formulation to improve the taste of chewable tablets.

Ø Key Phrases Ø Tablet formulations are usually designed to satisfy following criteriaPatient acceptability; accuracy and uniformity of drug content; manufacturability; optimal drug dissolution and stability. Ø Excipients are any component other than active pharmaceutical ingredient(s) intentionally added to the formulation of a dosage form. Ø Excipients play a crucial role in design of the delivery system, determining its quality and performance. Ø Various excipients used in tablet formulation are diluents, binders, disintegrants, lubricants, antiadherents, glidants, wetting agents, dissolution retardants, dissolution enhancers, absorbents, buffers, antioxidants, chelating agents, preservatives, colours, flavours, sweeteners, etc. 1.5.2 Diluents (Fillers)

What will you gain? 1.5.2.1 Introduction 1.5.2.2 Classification of diluents 1.5.2.2.1 Organic diluents 1.5.2.2.2 Inorganic diluents 1.5.2.2.3 Co-processed diluents
1.5.2.1 Introduction (1, 17)

In order to facilitate tablet handling during manufacture and to achieve targeted content uniformity, the tablet size should be kept above 2-3 mm and weight of tablet above 50 mg. Many potent drugs have low dose (for e.g. diazepam, clonidine hydrochloride) in such cases diluents provide the required bulk of the tablet when the drug dosage itself is inadequate to produce tablets of adequate weight and size. Usually the range of diluent may vary from 5-80%. Diluents are also synonymously known as fillers. Diluents are often added to tablet formulations for secondary reasons like to provide better tablet properties such as: i)To provide improved cohesion ii)To allow direct compression manufacturing iii)To enhance flow iv)To adjust weight of tablet as per die capacity No matter for what purpose they (diluents) are added they must meet certain basic criteria for satisfactory performance in tablet dosage form. They are as follows: Diluent should not react with the drug substance and moreover it should not have any effect on the functions of other excipients, it should not have any physiological or pharmacological activity of its own, it should have consistent physical and chemical characteristics, it should neither promote nor contribute to segregation of the granulation or powder blend to which they are added, it should be able to be milled (size reduced) if necessary in order to match the particle size distribution of the active pharmaceutical ingredient, it should neither support microbiological growth in the dosage form nor contribute to any microbiological load, it should neither adversely affect the dissolution of the product nor interfere with the bioavailability of active pharmaceutical ingredient, it should preferably be colourless or nearly so.

1.5.2.2 Classification of diluents (16,17)

Tablet diluents or fillers can be divided into following categories: i)Organic materials - Carbohydrate and modified carbohydrates. ii)Inorganic materials – Calcium phosphates and others. iii)Co-processed Diluents. Carbohydrate substances such as sugars, starches and celluloses may also function as binders during wet granulation process. Whereas when used in direct compression system, they serve as the diluent. The inorganic diluents, do not exhibit binding properties when used in wet granulation and direct compression. Tablet diluent or filler may also be classified on the basis of their solubility in water as soluble and insoluble. Table.3. Classification Of Diluents Based On Their Solubility INSOLUBLE TABLET FILLERS OR SOLUBLE TABLET FILLERS OR DILUENTS DILUENTS Starch Lactose Powdered cellulose Microcrystalline cellulose Calcium phosphates, etc. Selection of diluent should be done after considering properties of diluent such as: Compactibility, flowability, solubility, disintegration qualities, hygroscopicity, lubricity and stability.
1.5.2.2.1 Organic diluents (1,17-20)

Sucrose Mannitol Sorbitol, etc.

Carbohydrates Sugar and Sugar alcohols Lactose α-lactose monohydrate, spray dried lactose and anhydrous lactose are widely used as diluent.

Characteristics of α -Lactose monohydrate (hydrous) Lactose monohydrate is not directly compressible and therefore it is suitable for use in wet granulation. It has poor flow properties. α-lactose monohydrate is water soluble. It produces a hard tablet and the tablet hardness increases on storage. Disintegrant is usually needed in lactose containing tablets. Drug release rate is usually not affected. It is usually unreactive, except for discoloration when formulated with amines and alkaline materials (i.e. browning or maillard reaction). It contains approximately 5% moisture and hence is a potential source of instability especially with moisture sensitive drugs. It is inexpensive. It is commercially available under the trade name of: PharmatoseÒ and Respitose® manufactured by DMV International. Characteristics of Lactose spray dried It is directly compressible diluent. It exhibits free flowing characteristics. It needs high compression pressures in order to produce hard tablets. Its compressibility is adversely affected if dried below 3% moisture.

It has high dilution potential. It is more prone to darkening in the presence of excess moisture, amines and other compounds due to the presence of a furaldehyde. Usually, neutral or acid lubricant should be used when spray dried lactose is employed. Expensive compared to anhydrous and hydrous lactose. It is commercially available as Spray Process 315® manufactured by Foremost Farms USA. Characteristics of Lactose anhydrous Lactose anhydrous is a directly compressible diluent. It does not exhibit free flowing property. It can pick up moisture at elevated humidity as a result of which changes in tablet dimensions may occur. It does not undergo a maillard reaction to the extent shown by spray dried lactose, although this may occur in some cases to a slight degree. It is inexpensive. It is commercially available as Pharmatose® DCL 21 manufactured by DMV Pharma. Starch Characteristics of Compressible Starch (Pregelatinized) It is a directly compressible diluent. It has better flow compared to unmodified starch. It

also shows high compressibility as the aggregated granules undergo plastic deformation on compression. It possesses good binding properties. It also possesses disintegrant activity. It requires high pressure in order to produce a hard tablet. For good flow, it requires a flow promoter. It is prone to softening when combined with large amounts of magnesium stearate. It is commercially available under the trade name of Starch 1500 LMÒ manufactured by Colorcon. Sucrose Characteristics of Sucrose or sugar It requires high machine pressures, especially in cases with over wetted granulations. It is water soluble. It possesses good binding properties. It is slightly hygroscopic. It is inexpensive. It produces gritty mouth feel (i.e., it is not free from grittiness). It is a calorie contributor and is cariogenic. Mannitol

Characteristics of Mannitol Mannitol a sugar alcohol is an optical isomer of Sorbitol. It exhibits poor flow properties. It requires high lubricant content. It is probably the most expensive sugar used as a tablet diluent and is water soluble. It is widely used in chewable tablets because of its negative heat of solution, its slow solubility and its mild cooling sensation in mouth. It can be used in vitamin formulation, where moisture sensitivity may create a problem. It is comparatively non hygroscopic. It is free from grittiness. It possesses low caloric value and is noncariogenic. It is commercially available under the brand name ParteckÒM manufactured by EMD Chemicals .Other commercial products are PearlitolÒ and MannogemÒ. Sorbitol Characteristics of Sorbitol Sorbitol is often combined with mannitol formulations in order to reduce diluent cost. It is highly compressible diluent and is water soluble. It is hygroscopic in nature. It has good mouth feel and

sweet cooling taste. It is free from grittiness. It possesses low caloric value and is noncariogenic. It is commercially available as SorbifinÒ and NeosorbÒ . Poorly absorbed sugar alcohols such as Sorbitol and mannitol can decrease small intestinal transit time. Therefore absorption may be altered for the drugs that are preferentially absorbed from this region. Celluloses (1,17,
21)

Powdered cellulose Characteristics of Powdered cellulose Powdered cellulose products consist of finely divided amorphous and crystalline α-cellulose particles. Powdered cellulose may be used alone or together with other fillers such as lactose, calcium phosphates, dextrans and others. It possesses poor compressibility and exhibits poor flow properties. It has poor binding properties and low dilution potential. It is water insoluble. It possesses some degree of inherent lubricity. It is inexpensive. It is commercially available under the trade name of ElcemaÒG-250 manufactured by Degussa Corporation.

Microcrystalline cellulose Characteristics of Microcrystalline cellulose Microcrystalline cellulose (MCC) is highly compressible and is perhaps the most widely used direct-compression tablet diluent. Hard tablets, at low compression pressures, are usually obtained when MCC is used as tablet diluent. It undergoes plastic deformation on compression and hence it is more sensitive to lubricants. It exhibits fair flowability. It exhibits binding properties. It also possesses disintegrant activity and thus promotes fast tablet disintegration. It is water insoluble. MCC is expensive. Silicified MCC (SMCCProsolvÒ) provides increased compactibility, enhanced flow and improved uniformity compared to MCC (AvicelÒ manufactured by FMC Biopolymer) SMCC is more suitable for cohesive poorly compressible ingredients in direct compression formulation. Other commercial product is EmcocelÒ manufactured by Penwest Pharmaceutical Co.
1.5.2.2.2 Inorganic diluents (17,22)

Calcium phosphates The calcium phosphates, here includes, the dihydrate and anhydrous form of dibasic calcium phosphate and tribasic calcium phosphate. They are granular insoluble materials. They are widely used both as wet granulation and direct compression diluents in tablet formulation. Bulk density of calcium phosphates is higher than that of organic fillers. They are used extensively in vitamin and mineral preparations. Dibasic calcium phosphate dihydrate is also commonly known as

dicalcium phosphate, calcium hydrogen phosphate dihydrate and secondary calcium phosphate dihydrate. Dibasic calcium phosphate is available commercially under the trade name Di-TabÒ (manufactured by Rhone-Poulenc) and EmcompressÒ (Manufactured by E.Mendell Co.).An anhydrous form of dibasic calcium phosphate is available commercially under the trade name A-TabÒ (manufactured by Rhone-Poulenc). Fujicalin®, a novel commercially available free flowing spherically granulated dicalcium phosphate anhydrous (SGDCPA) for direct tableting was compared with directly compressible dicalcium phosphate dihydrate (DCPD) and it was found that SGDCPA exhibited same good flowability and better compactibility. Whereas in contrast to DCPD, SGDCPA exhibited significant uptake of moisture when exposed to relative humidity exceeding 70 %.Tribasic calcium phosphate is also commonly referred as tricalcium phosphate, tricalcium orthophosphate and hydroxyapatite. Tribasic calcium phosphate is available under the trade name Tri-TabÒ. Characteristic of Calcium Phosphates They are directly compressible and are characterized by brittle fracture on compression during tableting process. Hard tablets are produced when calcium phosphates are used as diluents. They exhibit good flow properties. They are non hygroscopic. They are inexpensive. They are abrasive in nature and hence can cause wear of tablet tooling. Sometimes their alkalinity is a major source of drug instability.
1.5.2.2.3 Co-processed diluents (17,23)

Co-processing means combining two or more materials by an appropriate process. The products so formed are physically modified in such a special way that they do not loose their chemical structure and stability. Now a days direct compression technique has been one of the well-accepted methods of tablet manufacture. An extensive range of materials from various sources have been developed and marketed as directly compressible diluents such as lactose, starch, cellulose derivatives, inorganic substance, polyalcohols, and sugar-based materials. In addition to the development of directly compressible excipients by modifying just a single substance,

co-processing of two or more components has been applied to produce composite particles or co-processed excipients. The composite particles or co-processed excipients are introduced in order to provide better tableting properties than a single substance or the physical mixture. Table.4. List Of Co-Processed Excipients Used To Achieve Better Tableting Properties TRADE NAME Fast Flo lactose® MANUFACTURER DESCRIPTION Foremost Whey It is spray processed Products lactose which is a mixture of crystalline α-lactose monohydrate and amorphous lactose. 75% lactose and 25% MCC (MicroCrystalline Cellulose) 93% α-lactose monohydrate, 3.5% polyvinylpyrrolidone, and 3.5% crospovidone. Ingredient Technology Sucrose 95-97%, invert sugar 3-4% and magnesium stearate 0.5% Amstar Corp. Sucrose 97% and modified dextrins 3% E.Mendell Co. Inc. Sucrose 90-93% and invert sugar 7-10%.

Microcellac®

Ludipress®

Nu-Tab®

Di-Pac®

Sugartab®

Emdex® Cal-Tab®

E.Mendell Co. Inc.

Dextrose 93-99% and maltose 1-7% Ingredient Technology Calcium sulfate 93% and vegetable gum 7% Ingredient Technology Calcium carbonate 95% and maltodextrins 5% Ingredient Technology Calcium carbonate (minimum) 90% and Starch, NF (maximum) 9%

Cal-Carb®

Calcium 90®

Key Phrases Ø Diluents make the required bulk of the tablet when the drug dosage itself is inadequate to produce tablets of adequate weight and size.

Ø Diluents are often added to tablet formulations for secondary reasons like to provide better tableting properties. Ø Tablet diluents or fillers can be divided into following categories: i) Organic materials ii) Inorganic materials iii) Co-processed diluents Ø Tablet diluents or fillers may also be classified on the basis of their solubility in water as soluble diluent and insoluble diluent. Ø Microcrystalline cellulose (MCC) is perhaps the most widely used directcompression tablet filler. Ø Co-processing means combining two or more materials by an appropriate process. Ø The composite particles or co-processed excipients are introduced to provide better tableting properties than a single substance or the physical mixture. 1.5.3 Binders ( Adhesives, Granulating agent) What will you gain? 1.5.3.1 Why to go for Granulation? 1.5.3.2 Granulation Processes 1.5.3.3 Types of Binders 1.5.3.4 Direct compression (DC) Binders 1.5.3.5 Mechanism of granule formation 1.5.3.6 Near Infrared (NIR) spectroscopy : A tool for granulation end point measurement 1.5.3.7 Factors to

be considered in Granulation 1.5.3.8 Evaluation tests for Binders/Granules Binder is one of an important excipient to be added in tablet formulation. In simpler words, binders or adhesives are the substances that promotes cohesiveness. It is utilized for converting powder into granules through a process known as Granulation. Granulation is the unit operation by which small powdery particles are agglomerated into larger entities called granules.
1.5.3.1 Why to go for Granulation? (24)

Powders/Granules intended for compression into tablets must possess two essential properties : flow property and compressibility. Flow property/Fluidity is required to produce tablets of a consistent weight and uniform strength. Compressibility is required to form a stable, intact compact mass when pressure is applied. These two objectives are obtained by adding binder to tablet formulation and then proceeding for granulation process. Granules so formed should possess acceptable flow property and compressibility. Some drugs exhibit poor fluidity and compressibility. In such cases binders have to be added

for improving flow property and compressibility. Other reasons for Granulation process are to improve appearance, mixing properties, to avoid dustiness, to densify material, to reduce segregation, in general to either eliminate undesirable properties or to improve the physical and chemical properties of fine powders.
1.5.3.2 Granulation Processes (24)

The standard methods frequently used today in tablet manufacturing are granulation and direct compression. Granulation technique includes wet granulation and dry granulation/slugging methods wherein binders are added in solution/suspension form and in dry form respectively. In Direct Compression, binders possessing direct compressibility characteristics are used. Binder when used in liquid form gives better binding action as compared to when used in dry form.
1.5.3.3 Types of Binders (18,25-28)

Table.5. Classification Of Binders Sugars Sucrose Liquid glucose Natural Binders Acacia Tragacanth Gelatin Starch Paste Pregelatinized Starch Alginic Acid Cellulose Synthetic/Semisynthetic Polymer Methyl Cellulose Ethyl Cellulose Hydroxy Propyl Methyl Cellulose ( HPMC) Hydroxy Propyl Cellulose Sodium Carboxy Methyl Cellulose Polyvinyl Pyrrolidone (PVP) Polyethylene Glycol (PEG) Polyvinyl Alcohols Polymethacrylates

Table.6. Commonly Used Binders

BINDER Starch 1500Ò MethocelÒ

CATEGORY Partially Pregelatinized Maize Starch Hydroxy Propyl Methyl Cellulose Hydroxy Propyl Methyl Cellulose Polyvinylpyrrolidone Polyvinylpyrrolidone Polyvinylcaprolactam

MANUFACTURER Colorcon Dow Chemicals Wolff-Cellulosics

WalocelÒHM LuvitecÒ LuvicrossÒ LuvicaprolactamÒ

Natural Starch and Chemical Company BASF Company BASF Company BASF Company

Table.7. Characteristics Of Commonly Used Binder BINDER Starch Paste SPECIFIED CONCENTRATION 5-25%w/w - Freshly prepared starch paste is used as a binder.

COMMENTS

Pregelatinized Starch (PGS)

5-10%w/w

(Direct Compression) [Partially and Fully PGS] 5-75%w/w (Wet Granulation )

- Its method of preparation is very crucial. - It is starch that have been processed chemically and/or mechanically to rupture all or part of the granules in the presence of water and subsequently dried. It contains 5% free amylose, 15% free amylopectin and 80% unmodified starch. - Obtained from maize, potato or rice starch. - It is multifunctional excipient used as a tablet binder, diluent, disintegrant and flow aid.

- They enhance both flow and compressibility and can be used as binders in Direct Compression as well as Wet Granulation. - High purity PGS allow simplified processing as they swell in cold water and therefore reduce time/costs compared with traditional starch paste preparation. - Comparable to Methyl Cellulose. - Used as a binder in either wet or dry granulation processes. - Soluble in both water and alcohol. - Used in wet granulation process. - It is also added to powder blends in the dry form and granulated in situ by the addition of water, alcohol or hydroalcoholic solution. - Valuable binder for chewable tablets. - The drug release is not altered on storage. - Used as a meltable binder. - Anhydrous granulating agent where water or alcohol cannot be used . - It may prolong disintegration time

Hydroxypropyl Methyl Cellulose (HPMC)

2-5%w/w

Polyvinyl 0.5-5%w/w Pyrrolidone (PVP)

Polyethylene 10-15%w/w Glycol (PEG) 6000

when concentration is 5% or higher - It improves the plasticity of other binders.
1.5.3.4 Direct compression (DC) Binders (29)

Due to ease of manufacture, product stability and high efficiency, the use of Direct Compression for tableting has increased. For Direct Compression, directly compressible binders are required which should exhibit adequate powder compressibility and flowability. Direct Compression binders should be selected on the basis of compression behavior, volume reduction under applied pressure and flow behavior in order to have optimum binding performance. The choice and selection of binders is extremely critical for Direct Compression tablets. Table.8. Commonly Used Dc Binders Dc Binder AvicelÒ (PH 101) SMCCÒ (50) UNI-PUREÒ(DW) Class MCC SMCCb Partially PGSc
a

Manufacturer FMC Corporation Penwest Pharmaceutical National Starch

UNI-PURE (LD) DC LactoseÒ DI TABÒ

Ò

& Chemical Low density starch National Starch & Chemica DC lactose anhydrous Quest International Group DC-DCPDd Rhodi

a – Microcrystalline Cellulose, b – Silicified Microcrystalline Cellulose, c – Pregelatinized Starch, d – Dibasic Calcium Phosphate Dihydrate Table.9. Characteristics Of Dc Binders Flow Behavior Compressibility DI TABÒ> SMCCÒ(50) > DC LactoseÒ , UNI PUREÒ(DW) > AvicelÒ (PH 101) > UNI PUREÒ(LD) UNI PUREÒ(LD) > SMCCÒ(50) , AvicelÒ(PH 101) > UNI PUREÒ(DW) , DC LactoseÒ > DI TABÒ UNI PUREÒ(LD) > SMCCÒ(50) > UNI PUREÒ(DW) > AvicelÒ(PH 101) > DC LactoseÒ > DI TABÒ

Crushing Strength

1.5.3.5 Mechanism of granule formation (30) Granules are formed in three stages: Nucleation: Here, the particles adhere due to liquid bridges which are the initiation step of Granulation. These adhered particles play a role of nucleus for further enlargement of granules. Transition: Enlargement of nucleus takes place by two possible mechanisms. Individual particle adhere to the nucleus or two or more nuclei combine among themselves. Ball growth or enlargement of the granule: Ball growth occurs either by Coalescence or Breakage or Abrasion Transfer or Layering. In Coalescence a larger granule is formed when two or more granules are united. In Breakage granules break and the fragments of granule adhere to other granules. This forms a layer of material over intact granules. In Abrasion Transfer granule material are abraded through attrition by the agitation of granule bed and abraded material adheres to other granules resulting into enlarged granules. In layering particles adheres to the already formed granules increasing their size. 1.5.3.6 Near Infrared (NIR) spectroscopy : A tool for granulation end point measurement (31) NIR Spectroscopy is applicable for monitoring of wet granulation process when impeller torque method cannot be applied. Watano et al determined the granulation end point using agitated fluidized bed where in IR moisture sensor was installed. The properties of the wet mass obtained from NIR are independent of granulator equipment variables such as impeller design. Even the powder blending efficiency in the dry mixing phase can be monitored inline by NIR. NIR spectroscopy could be an excellent tool in wet granulation measurement.
1.5.3.7 Factors to be considered in Granulation (24,30,32)

Compatibility The primary criteria is the compatibility of binder with the API & other tablet components. This is traditionally found by choosing appropriate stability study design. Currently Differential Scanning Calorimetry (DSC) is used to ascertain compatibility.

Characteristics of drugs and other excipients The drugs characteristics like its compressibility, particle size, surface area, porosity, hydrophobicity, solubility in binder are important while fixing a granulation process. The drug that exhibits poor compressibility requires the use of a strong binder (liquid glucose, sucrose, etc.) while the drugs that exhibit good compressibility can be successfully handled using a weak binder ( starch paste etc.,). Fine and porous particles requires higher amount of liquid binder as compared to coarse particles. Hydrophilic drug/excipients exhibiting absorption characteristics require higher volume of binder as compared to hydrophobic drug/excipients. The granule quality (size , friability) is governed by the solubility of the drug in the granulation solution. Spreading of Binder Spreading of binder/granulation solution on the powder blend is of paramount importance in successful granulation. A binder that spreads easily on particles is superior as compared to that which shows poor wetting quality. HPMC is a superior binder for

paracetamol as compared to PVP. Type and quantity of Binder The uniformity of the particle size, hardness, disintegration and compressibility of the granulation depends on type and quantity of binder added to formulation. As for example hard granulations results due to stronger binder or a highly concentrated binder solution which require excessive compression force during tableting. On the other hand, fragile granulations results due to insufficient quantity of binder which segregates easily. Larger quantities of granulating liquid produce a narrower particle size range and coarser and hard granules i.e. The proportion of fine granulates particle decreases. Therefore the optimum quantity of liquid needed to get a given particle size should be known in order to keep a batch to batch variations to a minimum. Temperature and Viscosity The temperature and viscosity of binder is also important. Fluid (less viscous) binder exhibit good spreading behavior. Method of Addition of Binder The method of addition of binder is also important. PVP can be used as solution as a binder or it may be dry blended with powders and later activated

by adding water. Distribution of binder is favored if it is dispersed instead of pouring it. Mixing Time The mixing time also determines quality of granules. If the wet massing time is higher (resulting into hard granules), the tablets may fail the dissolution test in certain cases since drug release from hard granules is altered. Material of Construction of Granulator The material of construction of granulator determines the volume of binder required as well as granule size distribution. Any vessel wall which are wetted easily by binder demands the need of higher volume of binder. As for example vessel wall made up of Stainless Steel require higher volume of binder as compared to vessel made up of plastics (PMMA – Polymethylmethacrylate and PTFE – Polytetrafluoroethylene i.e. Teflon). In case of PMMA and PTFE due to high contact angle, all granulating liquid is forced immediately into

the powder bed and gives narrow particle size distribution. While in case of steel, due to less contact angle liquid layer formed on the wall surface which in turn causes inhomogeneous distribution of liquid over the powder bed resulting into broader granule size. Type of Granulator Fluidized Bed Granulator produces porous granules as compared to High Shear Granulators. Process Variables Higher degree of densification of the granules results due to higher impeller speed as well as longer wet massing time. And also there is tendency of agglomeration since liquid saturation increases. Consequently, impeller speed and wet massing time affect the granule size. Apparatus Variables The apparatus variables in High Shear Mixer have a larger effect on granule growth than in Fluidized Bed Granulators because the shear forces are dependent on the mixer construction. The size and shape of the mixing chamber, impeller and chopper vary in

different High Shear Mixers. Impeller Movement Adhesion of wetted mass to the vessel is less if impeller movement is helical. This gives a narrower granule size and few lumps. In case of High Shear Mixers, adhesion of wetted mass to the vessel is a problem which can be reduced by proper construction of the impeller or by coating the vessel with Polytetrafluoroethylene i.e. Teflon.
1.5.3.8 Evaluation tests for Binders/Granules (1)

Compactness, physical and chemical stability, rapid production capability, efficacy are some of the characteristics that make tablet a ruling dosage form. These characteristics depend on the quality of granules from which it is made. The characteristics of granules produced are affected by formulation and process variables. So it becomes essential to evaluate the granule characteristics to monitor its suitability for tableting. Particle Size and Particle Size Distribution The particle size of granules affect the average tablet weight, tablet weight variation, disintegration time, granule friability, granulation flowability and the drying rate kinetics of wet granulations. Therefore the effects of granule size and size distribution on the quality of tablet should be determined by formulator. The methods usually adopted for measurement of particle size and particle size distribution includes Microscopy, Sieving, Conductivity test. Surface Area Surface area of the drug effects upon dissolution rate especially

in cases where drug have limited water solubility. The two most common methods for surface area determination are Gas Adsorption and Air Permeability. Density Granule density, True Density, Bulk Density may influence compressibility, tablet porosity, flow property, dissolution and other properties. Higher compression load is required in case of dense and hard granules which in turn increases the tablet disintegration and drug dissolution times. Density is usually determined by pycnometer. % Compressibility Compressibility is the ability of powder to decrease in volume under pressure. Compressibility is a measure that is obtained from density determinations. % Compressibility = (Tapped density – Bulk density/Tapped density)*100 Compressibility measures gives idea about flow property of the granules as per CARR’S Index which is as follows : Table.10. Carr’s Index % Compressibility 5 – 15 12 – 16 18 – 21 23 – 28 28 – 35 35 – 38 Flow Description Excellent Good Fair Poor Poor Very Poor

> 40 Flow Properties

Extremely Poor

It is very important parameter to be measured since it affects the mass of uniformity of the dose. It is usually predicted from Hausner Ratio and Angle Of Repose Measurement. Hausner Ratio = Tapped Density / Bulk Density Table.11. Hausner Ratio HAUSNER RATIO Less than 1.25 1.25 – 1.5 More than 1.5 Good Flow Moderate Poor Flow TYPE OF FLOW

Angle of Repose (Φ) is the maximum angle between the surface of a pile of powder and horizontal plane. It is usually determined by Fixed Funnel Method and is the measure of the flowability of powder/granules. Φ = tan-1 (h / r) where, h = height of heap of pile r = radius of base of pile Table.12.Angle Of Repose (Φ) ANGLE TYPE

OF REPOSE < 25 25 – 30 30 – 40 > 40

OF FLOW Excellent Good Passable Very Poor

Friability Friability is important since it affects in particle size distribution of granules affecting compressibility into tablet, tablet weight variation, granule flowability. Friability is determined carrying out Tumbler Test or using Friability Tester ( Roche Friabilator ) and % loss is determined. Moisture Content It affects the granule flowability, compressibility as well as the stability of moisture sensitive drug and therefore should be determined to evaluate the quality of granule.

Key Phrases ØBinders are added in tablet formulation to have required flow property and compressibility of powders. ØWet Granulation, Dry Granulation/Slugging, Direct Compression are major granule manufacturing methods. ØDirect Compression Binders are more efficient than conventional binders. ØPregelatinized Starch is used as multifunctional excipient: tablet binder (wet granulating agent as well as direct compression binder), diluent, disintegrant and flow aid. ØPolyethylene Glycol used as meltable binder. ØGranules are formed in three stages: Nucleation, Transition and Ball Growth. ØNIR a tool for granulation end point measurement and is better than torque impeller method. ØCompatibility of binder with API and other excipients, characteristics of binder, process variables, and apparatus variables affects the quality of granules. ØGranules have to be evaluated in order to measure its suitability for tableting. 1.5.4 Disintegrants What will you gain? 1.5.4.1 Introduction 1.5.4.2 Mechanism of tablet disintegrants 1.5.4.3 Methods of addition of disintegrants

1.5.4.4 Types of disintegrants 1.5.4.5 Factors affecting disintegration
1.5.4.1 Introduction

Bioavailability of a drug depends in absorption of the drug, which is affected by solubility of the drug in gastrointestinal fluid and permeability of the drug across gastrointestinal membrane. The drugs solubility mainly depends on physical – chemical characteristics of the drug. However, the rate of drug dissolution is greatly influenced by disintegration of the tablet. The drug will dissolve at a slower rate from a nondisintegrating tablet due to exposure of limited surface area to the fluid. The disintegration test is an official test and hence a batch of tablet must meet the stated requirements of disintegration. Disintegrants, an important excipient of the tablet formulation, are always added to tablet to induce breakup of tablet when it comes in contact with aqueous fluid and this process of desegregation of constituent particles before the drug dissolution occurs, is known as disintegration process and excipients which induce this process are known as disintegrants. The objectives behind addition of disintegrants are to increase surface area of the tablet fragments and to overcome cohesive forces that keep particles together in a tablet.

Figure.16. Schematic Representation Of Tablet Disintegration And Subsequent Drug Dissolution

1.5.4.2 Mechanism of tablet disintegrants (16,29,33-39)

The tablet breaks to primary particles by one or more of the mechanisms listed below:I.By capillary action II.By swelling III.Because of heat of wetting IV.Due to disintegrating particle/particle repulsive forces V.Due to deformation VI.Due to release of gases VII.By enzymatic action By Capillary Action Disintegration by capillary action is always the first step. When we put the tablet into suitable aqueous medium, the medium penetrates into the tablet and replaces the air adsorbed on the particles, which weakens the intermolecular bond and breaks the tablet into fine particles. Water uptake by tablet depends upon hydrophilicity of the drug /excipient and on tableting conditions. For these types of disintegrants maintenance of porous structure and low interfacial tension towards aqueous fluid is necessary which helps in disintegration by creating a hydrophilic network around the drug particles. By Swelling Perhaps the most widely accepted general mechanism of action for tablet disintegration is swelling Tablets with high porosity show poor disintegration due to lack of adequate swelling force. On the other hand, sufficient swelling force is exerted in the tablet with low porosity. It is worthwhile to note that if the packing fraction is very high, fluid is unable to penetrate in the tablet and disintegration is again slows down.

Figure.17. Disintegration Of Tablet By Wicking And Swelling Because of heat of wetting (air expansion) When disintegrants with exothermic properties gets wetted, localized stress is generated due to capillary air expansion, which helps in disintegration of tablet. This explanation, however, is limited to only a few types of disintegrants and can not describe the action of most modern disintegrating agents. Due to disintegrating particle/particle repulsive forces Another mechanism of disintegration attempts to explain the swelling of tablet made with ‘non-swellable’ disintegrants. Guyot-Hermann has proposed a particle repulsion theory based on the observation that nonswelling particle also cause disintegration of tablets. the electric repulsive forces between particles are the mechanism of disintegration and water is required for it. Researchers found that repulsion is secondary to wicking. Due to deformation Hess had proved that during tablet compression, disintegranted particles get deformed and these deformed particles get into their normal structure when they come in contact with aqueous media or water. Occasionally, the swelling capacity of starch was improved when granules were extensively deformed during

compression. This increase in size of the deformed particles produces a break up of the tablet. This may be a mechanism of starch and has only recently begun to be studied

Figure.18. Disintegration By Deformation And Repulsion Due to release of gases Carbon dioxide released within tablets on wetting due to interaction between bicarbonate and carbonate with citric acid or tartaric acid. The tablet disintegrates due to generation of pressure within the tablet. This effervescent mixture is used when pharmacist needs to formulate very rapidly dissolving tablets or fast disintegrating tablet. As these disintegrants are highly sensitive to small changes in humidity level and temperature, strict control of environment is required during manufacturing of the tablets. The effervescent blend is either added immediately prior to compression or can be added in to two separate fraction of formulation. By enzymatic reaction Here, enzymes presents in the body act as disintegrants. These enzymes destroy the binding action of binder and helps in disintegration Table.13. Disintegrating Enzymes ENZYMES BINDER Amylase Starch Protease Gelatin Cellulase Cellulose and it’s derivatives Invertase Sucrose

1.5.4.3 Methods of addition of disintegrants The method of addition of disintegrants is also a crucial part. Disintegrating agent can be added either prior to granulation (intragranular) or prior to compression (after granulation i.e. extragranular) or at the both processing steps. Extragranular fraction of disintegrant (usually, 50% of total disintegrant requires) facilitates breakup of tablets to granules and the intragranular addition of disintegrants produces further erosion of the granules to fine particles.
1.5.4.4 Types of disintegrants (34,40-42)

Starch Starch was the first disintegrating agent widely used in tablet manufacturing. Before 1906 potato starch and corn starch were used as disintegrants in tablet formulation. However, native starches have certain limitations and have been replaced by certain modified starches with specialized characteristics. The mechanism of action of starch is wicking and restoration of deformed starch particles on contact with aqueous fluid and in doing so release of certain amount of stress which is responsible for disruption of hydrogen bonding formed during compression. Lowenthal & Wood proved that the rupture of the surface of a tablet employing starch as disintegrant occurs where starch agglomerates were found. The conditions best suited for rapid tablet disintegration are sufficient number of starch agglomerates, low compressive pressure and the presence of water. The concentration of starch used is also very crucial part. If it is below the optimum concentration then there are insufficient channels for capillary action and if it is above optimum concentration then it will be difficult to compress the tablet. Pregelatinized starch Pregelatinized starch is produced by the hydrolyzing and rupturing of the starch grain. It is a directly compressible disintegrants and its optimum concentration is 5-10%. The main mechanism of action of Pregelatinized starch is through swelling. Modified starch To have a high swelling properties and faster disintegration, starch is modified

by carboxy methylation followed by cross linking, which is available in market as cross linked starch. One of them is SODIUM STARCH GLYCOLATE. Even low substituted carboxymethyl starches are also marketed as ExplotabÒ and Primojel®. Mechanism of action of this modified starches are rapid and extensive swelling with minimum gelling. And its optimum concentration is 4-6 %. If it goes beyond its limit, then it produces viscous and gelatinous mass which increases the disintegration time by resisting the breakup of tablet. They are highly efficient at low concentration because of their greater swelling capacity. Table.14. List Of Disintegrants CONCENTRATION SPECIAL COMMENTS IN GRANULES (%W/W) Starch USP 5-20 Higher amount is required, poorly compressible Starch 1500 5-15 ® Avicel (PH 101, 10-20 Lubricant properties and PH 102) directly compressible ® Solka floc 5-15 Purified wood cellulose Alginic acid 1-5 Acts by swelling Na alginate 2.5-10 Acts by swelling ® Explotab 2-8 Sodium starch glycolate, superdisintegrant. ® Polyplasdone (XL) 0.5-5 Crosslinked PVP ® Amberlite (IPR 88) 0.5-5 Ion exchange resin Methyl cellulose, Na CMC, 5-10 HPMC AC-Di-Sol® 1-3 Direct compression 2-4 Wet granulation Carbon dioxide _ Created insitu in effervescent tablet Cellulose and its derivatives Sodium carboxy methylcellulose (NaCMC and CARMELLOSE sodium) has highly hydrophilic structure and is soluble in water. But when it is modified by internally crosslinking we get modified crosslinked cellulose i.e. Crosscarmellose sodium which is nearly water insoluble due to cross linking. It rapidly swells to 4-8 times its original volume when it comes in contact with water. Microcrystalline cellulose (MCC) DISINTEGRANTS

MCC exhibit very good disintegrating properties because MCC is insoluble and act by wicking action. The moisture breaks the hydrogen bonding between adjacent bundles of MCC. It also serves as an excellent binder and has a tendency to develop static charges in the presence of excessive moisture content. Therefore, sometimes it causes separation in granulation. This can be partially overcome by drying the cellulose to remove the moisture. Alginates Alginates are hydrophilic colloidal substances which has high sorption capacity. Chemically, they are alginic acid and salts of alginic acid. Alginic acid is insoluble in water, slightly acidic in reaction. Hence, it should be used in only acidic or neutral granulation. Unlike starch and MCC, alginates do not retard flow and can be successfully used with ascorbic acid, multivitamin formulations and acid salts of organic bases. Ion-exchange resin Ion exchange resin (AmbreliteÒ IPR-88) has highest water uptake capacity than other disintegrating agents like starch and Sodium CMC. It has tendency to adsorb certain drugs. Miscellaneous This miscellaneous category includes disintegrants like surfactants, gas producing disintegrants and hydrous aluminium silicate. Gas producing disintegrating agents is used in soluble tablet, dispersible tablet and effervescent tablet. PolyplasdoneÒXL and PolyplasdoneÒXL10 act by wicking, swelling and possibly some deformation recovery. Polyplasdone®XL do not reduce tablet hardness, provide rapid disintegration and improved dissolution. Polyplasdone® as disintegrating agent has small particle size distribution that impart a smooth mouth feel to dissolve quickly. Chewable tablet does not require addition of disintegrant. Superdisintegrants As day’s passes, demand for faster disintegrating formulation is increased. So, pharmacist needs to formulate disintegrants i.e. Superdisintegrants which are effective at low concentration and have greater disintegrating efficiency and they are more effective intragranularly. But have one drawback that it is hygroscopic therefore not used with moisture sensitive drugs.

And this superdisintegrants act by swelling and due to swelling pressure exerted in the outer direction or radial direction, it causes tablet to burst or the accelerated absorption of water leading to an enormous increase in the volume of granules to promote disintegration.

Figure.19. Mechanism of superdisintegrants by swelling Table.15. List Of Superdisintegrants SUPERDISINTEGRANTS EXAMPLE OF MECHANISM OF ACTION ® Crosscarmellose Crosslinked -Swells 4-8 folds cellulose in < 10 seconds. Ac-Di-Sol® -Swelling and wicking both. SPECIAL COMMENT -Swells in two dimensions. -Direct compression or granulation

Nymce ZSX® Primellose® Solutab® -Starch free Vivasol® Crosspovidone Crosspovidon M® Kollidon® Polyplasdone® Sodium starch glycolate Explotab® Primogel® Alginic acid NF

Crosslinked PVP -Swells very little and returns to original size after compression but act by capillary action Crosslinked starch

-Water insoluble and spongy in nature so get porous tablet

Crosslinked

-Swells 7-12 folds -Swells in three in <30 dimensions and seconds high level serve as sustain release matrix -Rapid swelling in -Promote

alginic acid Satialgine® Soy polysaccharides Emcosoy®

Natural super disintegrant

Calcium silicate

aqueous medium disintegration in or wicking action both dry or wet granulation -Does not contain any starch or sugar. Used in nutritional products. -Wicking action -Highly porous, -light weight -optimum concentration is between 20-40%

1.5.4.5 Factors affecting disintegration

Effect of fillers (43,44) The solubility and compression characteristics of fillers affect both rate and mechanism of disintegration of tablet. If soluble fillers are used then it may cause increase in viscosity of the penetrating fluid which tends to reduce effectiveness of strongly swelling disintegrating agents and as they are water soluble, they are likely to dissolve rather than disintegrate. Insoluble diluents produce rapid disintegration with adequate amount of disintegrants. Chebli and cartilier proved that tablets made with spray dried lactose (water soluble filler) disintegrate more slowly due to its amorphous character and has no solid planes on which the disintegrating forces can be exerted than the tablet made with crystalline lactose monohydrate. Effect of binder As binding capacity of the binder increases, disintegrating time of tablet increases and this counteract the rapid disintegration. Even the concentration of the binder can also affect the disintegration time of tablet. Effect of lubricants(16,34) Mostly lubricants are hydrophobic and they are usually used in smaller size than any other ingredient in the tablet formulation. When the mixture is mixed, lubricant particles may adhere to the surface of the other particles. This hydrophobic coating inhibits the wetting and consequently tablet disintegration.

Lubricant has a strong negative effect on the water uptake if tablet contains no disintegrants or even high concentration of slightly swelling disintegrants. On the contrary, the disintegration time is hardly affected if there is some strongly swelling disintegrants are present in the tablet. But there is one exception like sodium starch glycolate whose effect remains unaffected in the presence of hydrophobic lubricant unlike other disintegrants. Effect of surfactants Table.16. The Effects Of Various Surfactants Surfactant Sodium lauryl sulfate Remarks Good-various drugs Poor - various drugs Good Poor Good Poor Poor

Polysorbate 20 Polysorbate 40 & 60 Polysorbate 80 Tweens Poly ethylene glycol

(Good – decrease in disintegration time, Poor – increase in disintegration time) Sodium lauryl sulphate increased absorption of water by starch or had a variable effect on water penetration in tablets. Surfactants are only effective within certain concentration ranges. Surfactants are recommended to decrease the hydrophobicity of the drugs because the more hydrophobic the tablet the greater the disintegration time. Aoki and fukuda claimed that disintegration time of granules of water-soluble drugs did not seem to be greatly improved by the addition of nonionic surfactant during granulation , but the desired effect of a surfactant appeared when granule were made of slightly soluble drugs. The speed of water penetration was increased by the addition of a surfactant. Key Phrases Ø Disintegrants are added to tablet to induce breakup when it comes in contact with aqueous fluid. Ø Disintegration

by capillary action or by swelling is the major mechanism for disintegrants. Ø Disintegrant can be added intragranular or extragranular or at both stages. Ø Superdisintegrants have greater efficiency at low concentration and hence, their demand is increasing day by day. 1.5.5 Antifrictional Agents What will you gain? 1.5.5.1 Lubricants 1.5.5.1.1 Classification of lubricants 1.5.5.1.1.1 Water Insoluble Lubricants 1.5.5.1.1.2 Water Soluble Lubricants 1.5.5.2 Antiadherents 1.5.5.3 Glidants
1.5.5.1 Lubricants(4,16)

Lubricants are the agents that act by reducing friction by interposing an intermediate layer between the tablet constituents and the die wall during compression and ejection. Solid lubricants, act by boundary mechanism, results from the adherence of the polar portions of molecules with long carbon chains to the metal surfaces to the die wall. Magnesium stearate is an example of boundary lubricant. Other is hydrodynamic mechanism i.e. fluid lubrication where two moving surfaces are separated by a finite and continuous layer of fluid lubricant. Since adherence of solid lubricants to the die wall is more than that of fluid lubricants, solid lubricants are more effective and more frequently used. Since primarily lubricants are required to act at the tooling or material interface, lubricants should be incorporated in the final mixing step, after granulation is complete. When hydrophobic

lubricants are added to a granulation, they form a coat around the individual particles (granules), which may cause an increase in the disintegration time and a decrease in the drug dissolution rate. Presence of lubricants may results in a less cohesive and mechanically weaker tablet because it may interfere with the particle – particle bonding. Surface area is important parameter for deciding lubricant efficiency. Lubricants with high surface area are more sensitive to changes in mixing time than lubricant with low surface area. Therefore lubricant mixing time should be kept minimum. Tooling used to compress the tablet is important for deciding type and level of lubricant used. Additional lubricant is often added to the tablet formulations that are to be compressed with curved face punches. Further, the amount of lubricant increases as the particle size of the granulation decreases but its concentration should not exceed to 1% for producing maximum flow rate. Lack of adequate lubrication produces binding which can results in tablet machine strain and can lead to damage of lower punch heads, lower cam track, die seats and the tooling itself. And it may also yield tablets with scratched edges and are often fractured at the top edges. With excessive binding the tablet may be cracked and fragmented by ejection.
1.5.5.1.1 Classification of lubricants

Lubricant are classified according to their water solubility i.e. water insoluble and water soluble. Selection of lubricant is depends partly on mode of administration, type of tablet, desired disintegration and dissolution properties, physicochemical properties of granules or powder and cost.
1.5.5.1.1.1 Water Insoluble Lubricants

Water insoluble lubricants are most effective and used at reduced concentration than water soluble lubricants. Since these lubricants function by coating , their effectiveness is related with their surface area, extent of particle size reduction, time, procedure of addition and length of mixing. Table.17. List Of Insoluble Lubricants INSOLUBLE CONCENTRATION COMMENTS

LUBRICANTS Stearates(Magnesium Stearate, Calcium Stearate, Sodium stearate) Talc Sterotex Waxes Stearowet Glyceryl behapate(Compritol®888) Liquid paraffin

0.25 -1 1 -2 0.25 – 1 1-5 1-5 1-5 Up to 5

Reduce tablet strength; prolong disintegration; widely used. Insoluble but not hydrophobic; moderately effective. Both lubricant and binder; Dispersion problem; inferior to stearates

1.5.5.1.1.2 Water Soluble Lubricants

Water Soluble Lubricants are used when a tablet is completely soluble or when unique disintegration and dissolution characteristics are required. Tablet containing soluble lubricant shows higher dissolution rate than tablet with insoluble lubricants. Physical mixture of this lubricant i.e. SLS or MLS with stearates can lead to the best compromise in terms of lubricity, tablet strength and disintegration. Table.18. List Of Soluble Lubricants WATER SOLUBLE LUBRICANTS Boric acid Sodium benzoate Sodium oleate Sodium acetate Sodium Lauryl sulfate (SLS) Magnesium lauryl sulfate (MLS)
1.5.5.2 Antiadherents (4, 16)

CONCENTRATION RANGE (%W/W) 1 5 5 5 1–5 1-2

Some material have strong adhesive properties towards the metal of punches and dies or the tablet formulation containing excessive moisture which has tendency to result in picking and sticking problem. Therefore antiadherents are added, which prevent sticking to punches and die walls. Talc, magnesium stearate and corn starch have excellent antiadherent properties. Vegan had suggested that silicon oil can be used as antiadherent.

Table.19. List Of Antiadherents ANTIADHERENT RANGE(%W/W) Talc Cornstarch 1–5 3 – 10 COMMENT Lubricant with excellent antiadherents properties Lubricant with excellent antiadherents properties Does not give satisfactory results due to small surface area. Cab-O-Sil® and Syloid® Water soluble lubricant; excellent antiadherents properties Antiadherents with water soluble lubricant Antiadherents with water insoluble lubricant

Colloidal silica

0.1 – 0.5

DL-Leucine Sodium lauryl sulfate Stearates
1.5.5.3 Glidants (4, 16)

3 – 10 <1 <1

GLIDANTS are added to the formulation to improve the flow properties of the material which is to be fed into the die cavity and aid in particle rearrangement within the die during the early stages of compression. If the flow properties are extremely poor then glidants are ineffective and consideration of force free mechanisms may be necessary. Starch is a popular glidant because it has additional value of disintegrant. Concentration of starch is common up to 10%, but should be limited otherwise it will worsen the flow of material. Talc is a glidant which is superior to starch; its concentration should be limited because it has retardant effect on dissolution-disintegration profile. Silaceous material like colloidal silica i.e. syloid, pyrogenic silica (0.25%), hydrated sodium silioaluminate (0.75%) are also successfully used to induce flow. Glidants act by interposing their particles between those of material and lower the overall interparticulate friction of the system by virtue of their reduced adhesive tendencies. Similar to lubricants, they are required at the surface of feed particles and they should be in fine state of division and appropriately incorporated in the mixture. Key Phrases Ø Lubricants are

added to reduce the friction during compression. Ø Antiadherents avoid sticking to die walls and picking by punches. Ø Glidants improve the flow property of material/granules. 1.5.6 Miscellaneous Excipients What will you gain? 1.5.6.1 Wetting Agents 1.5.6.2 Dissolution Retardants 1.5.6.3 Dissolution Enhancers 1.5.6.4 Adsorbents 1.5.6.5 Buffers 1.5.6.6 Antioxidants 1.5.6.7 Chelating Agents 1.5.6.8 Preservatives 1.5.6.9 Colourants 1.5.6.10 Flavours 1.5.6.11 Sweeteners
1.5.6.1 Wetting Agents

Wetting Agents in tablet formulation aid water uptake and thereby enhancing disintegration and assisting in drug dissolution. Incorporation of anionic surfactant like Sodium Lauryl Sulphate (SLS) is known to enhance the dissolution.It has been established that SLS improves permeation of drug through biological membrane since it destroys the path through which drug has to pass and thus minimizing the path length for the drug to travel. Wetting agents are mainly added when hydrophobic drug is to be formulated into tablet. SLS, Sodium diisobutyl sulfosuccinate are used as wetting agent in tablet formulation.

1.5.6.2 Dissolution Retardants

Dissolution Retardants are incorporated into tablet formulation only when controlled release of drug is required. Waxy materials like stearic acid and their esters can be used as dissolution retardants.
1.5.6.3 Dissolution Enhancers

They are the agents that alter the molecular forces between ingredients to enhance the dissolution of solute in the solvent. Fructose, Povidone, Surfactants are used as dissolution enhancer.
1.5.6.4 Adsorbents (4)

Adsorbents are the agents that can retain large quantities of liquids. Therefore liquids like Vitamin E can be incorporated into tablets by addition of adsorbents .Most commonly used adsorbents in pharmaceuticals are anhydrous calcium phosphate, starch, magnesium carbonate, bentonite, kaolin, magnesium silicate, magnesium oxide and silicon dioxide. Generally the liquid to be adsorbed is first mixed with the adsorbent prior to incorporation into the formulation. Silicon dioxide when added can play as both glidant and an adsorbent role in the formula.
1.5.6.5 Buffers

Buffers are added to maintain a required pH since a change in pH may cause significant alteration in stability. Most commonly used buffering agent in tablet formulation includes sodium bicarbonate, calcium carbonate, and sodium citrate.
1.5.6.6 Antioxidants

Antioxidants are added in tablet formulation to protect drug from undergoing oxidation. Antioxidants undergo oxidation in place of drug or they block the oxidation reaction or they act as synergists to other antioxidants. Chelators may also act as antioxidant. Most commonly used antioxidants include ascorbic acid and their esters , alpha-tocopherol , ethylene diamine tetra acetic acid , sodium metabisulfite , sodium bisulfite , Butylated Hydroxy Toluene (BHT) , Butylated Hydroxy Anisole (BHA) , citric acid , and tartaric acid .
1.5.6.7 Chelating Agents

Chelating agents tend to form complexes with trace amount of heavy metal ions inactivating their catalytic activity in the oxidation of medicaments. Ethylenediamine tetracetic acid and its salts, Dihydroxy Ethyl Glycine, Citric Acid and Tartaric Acid are most commonly used chelators.

1.5.6.8 Preservatives

Preservatives may be a part of tablet formulation in order to prevent the growth of microorganisms in tablet formulation. Parabens like methyl, propyl, benzyl, butyl p-hydroxy benzoate are used as preservatives.
1.5.6.9 Colourants(1, 4,16)

Colourants neither contribute to therapeutic activity nor do they improve product bioavailability or stability but are incorporated into tablets for purposes like to facilitate identification of similar looking products with in a product line to avoid mix ups, to facilitate identification of products of similar appearance that exist in the lines of different manufacturers, to overcome colour change on aging, disguising of off-colour drugs, for brand image in the market, to enhance the aesthetic appearance of the product to have better patient acceptance. Most widely used colourants are dyes and lakes which are FD & C and D & C approved. Dyes are generally applied as solution especially in the granulating agent. Lakes are usually employed as dry powders for colouring. In general, direct compression tablets are coloured with lakes because no granulation step is used. Natural colourants can be used and generally they do not require the FDA certification before use in drug products. One of the important advantage in using lakes is reduced risk of interaction between the drug and other ingredients as well as colour development is rapid which reduces processing time .While employing wet granulation , care should be taken to prevent colour migration during drying . In any coloured tablet, the formulation should be checked for resistance to colour changes on exposure to light. Reflectance Spectrophotometry, Tristimulus Colourimetric Measurements and Microreflectance Photometer used to measure the colour uniformity and gloss on a tablet surface. Table.20. Some Commonly Used Pharmaceutical Colourants (Synthetic) FD & C COLOUR Red 3 Red 40 Yellow 5 Yellow 6 Blue 1 Blue 2 Green 3
1.5.6.10 Flavours(1,4)

COMMON NAME Erythrosine Allura red AC Tartrazine Sunset Yellow Brilliant Blue Indigotine Fast Green

Flavors are commonly used to improve the taste of chewable tablets as well as mouth dissolved tablets. Flavors are

incorporated either as solids (spray dried flavors) or oils or aqueous (water soluble) flavors. Solids that is dry flavors are easier to handle and generally more stable than oils. Oil is usually added at the lubrication step because of its sensitivity to moisture and their tendency to volatilize when heated during drying. It may also be adsorbed onto an excipient and added during the lubrication process. The maximum amount of oil that can be added to granulation without affecting tableting characteristics is 0.5 to 0.75 %w/w. aqueous flavors are less used because of its instability on aging.
1.5.6.11 Sweeteners(1,4,45)

Sweeteners are added primarily to chewable tablets. Table.21. Some Of The Sweeteners Used In Tablet Formulation NATURAL SWEETENERS Mannitol Lactose Cyclamate Sucrose Aspartame Dextrose Saccharin is 500 times sweeter than sucrose. Its major disadvantages are that it has a bitter aftertaste and is carcinogenic. Even cyclamate is carcinogenic .Aspartame is about 180 times sweeter than sucrose. The primary disadvantage of aspartame is its lack of stability in the presence of moisture. When aspartame is used with hygroscopic components, it will be necessary to determine its stability under conditions in which the product can adsorb atmospheric moisture. Aspartame is available in market under the brand NutrasweetÒ manufactured and marketed by Nutrasweet Company. Key Phrases ØOnly FD&C and D&C approved colourants can be incorporated into tablet formulation. ØFlavours and Sweeteners are one of the important ingredients of chewable and mouth dissolving tablet formulation. ARTIFICIAL SWEETENERS Saccharin

Ideal properties of API for formulating tablets

Submitted by on Sun, 12/06/2009 - 19:52 1.6 Ideal Properties of API for formulating tablets (46) What will you gain? The desirable properties of API for formulating tablets : 1.6.1 High purity 1.6.2 High stability 1.6.3 Good compatibility with excipients 1.6.4 Optimum bulk powder properties 1.6.5 Optimum and uniform particle size – particle size distribution 1.6.6 Spherical shape 1.6.7 Good flowability 1.6.8 Optimum moisture content 1.6.9 Good compressibility 1.6.10 Absence of static charge on surface 1.6.11 Good organoleptic properties 1.6.12 Miscellaneous 1.6.1 High Purity API has to be in pure form otherwise impurities can catalyze series of chemical reactions, e.g. in case of hydrocortisone impurity of cupric ion causes oxidation of ketone functional group.

API should meet specifications given in the respective Pharmacopoeia. 1.6.2 High stability The API should be stable against photolysis, oxidation, hydrolysis, etc. to keep the formulation a simple one. Sensitive particles require careful handling during manufacturing. 1.6.3 Good compatibility with excipients (47) In order to formulate a tablet one need to add excipient along with API. There should not be any kind of interaction between excipient and API. Excipients have to be inert in nature. However there are some reported examples of API-excipient interactions like Lisinopril reacts with lactose and undergoes browning reaction leading to darkening on storage. So, avoid the use of lactose and use other fillers for API containing primary amine. To ascertain drug and excipient interaction, 1:1 mixture is prepared and stored under accelerated/ICH conditions. The amount of drug degraded shall be determined to select the most suitable excipient. 1.6.4 Optimum bulk powder properties Bulk powder properties have to be optimum to: i) Prevent segregation. ii) Have optimum size tablet particularly for low potency-low density API. iii) Have good flow. 1.6.5 Optimum and Uniform particle size-particle size distribution API should have uniform particle size and close particle size distribution because it has pronounce effect on uniformity of content, uniformity of weight, disintegration time, granule friability, drying rate kinetics of wet granulation, flowability, compressibility, stability, dissolution, bioavailability, etc. The flow and compression characteristics are important from the viewpoint of industrial

pharmacist. Strong tablets are obtained if fine particles are used due to increase in surface area and surface energy. 1.6.6 Spherical shape The shape of particles decides flowability. Spherical shaped particles exhibit good flow as compared to needle shaped particles. Particles with irregular shape may exhibit hindered flow due to interlocking between particles. This point is very important since it is directly related with weight of tablet and uniformity. 1.6.7 Good flowability (48-50) Flow is important for having uniformity of weight and uniformity of drug content. It can be measured using angle of repose, Carr’s index and Hausner ratio. The methods used to improve flow are summarized below i)Addition of glidants ii) Addition of fines: Addition of fines up to certain extent improves flow. This is because of filling of void space and decrease in surface roughness. iii) By wet granulation: Wet granulation gives regular sphere shaped granules and removes static charge if present on particle surface. Thus, flow property improved. iv) By densification with help of slugging. 1.6.8 Optimum moisture content (51-53) Moisture content has to be optimum because of the following reasons: i)Total lack of moisture results into brittle tablet. ii) Moisture affects flow, which in turn affects uniformity of content. iii)High amount of moisture gives stickiness, which will affect compaction. iv)Picking/sticking may be observed. Moisture content can be controlled by:

i)Use of anhydrous salts. ii)Use of non-aqueous solvent. iii) Optimum drying time. iv) Addition of finely powdered adsorbent like magnesium oxide. 1.6.9 Good compressibility (1,2,4,5,54) API should exhibit good compressibility. However this depends upon its intrinsic nature like:
(A) Elasticity:

The particles deform under the effect of pressure in a die but they revert back to original state on removal of applied pressure i.e. on ejection. Such tablets may exhibit capping and or lamination. The intrinsic nature of particle can be changed by: i)Wet massing ii)Pre-compression iii)Plastic tabulating matrix (micro crystalline cellulose) Elastic material is less suitable for direct compression.
(B)Plasticity:

Plastic material gets bonded after viscoelastic deformation. Viscoelastic deformation is time dependent. Hence, the crushing strength is dependent on the time that tablet spends in a die. Changing the turret speed can change dwell time. Plastic materials may exhibit viscoelastic deformaiton.
(C) Brittle fracture:

A particle fractures into small particles on application of pressure in a die. Brittle fracture also promotes tableting. Brittle materials are less lubricant sensitive as compared to plastic materials. A blend of lactose and MCC is widely used in industry to get advantages of brittle materials and plastic materials.

1.6.10 Absence of static charge on surface (55) It is important because of the following reasons: i)Affects uniformity of dose and weight variation (flow worsen if attractive forces generated). ii) During mixing it may cause segregation and lead to non-uniformity of content if API and excipients are charged. iii) Charged API may adhere to feed frame and result into serious damage to tablet equipment. In order to remove charge certain treatments can be given like granulation, addition of diluents or lubricant, surface coating with help of colloidal silica, etc. 1.6.11 Good organoleptic properties Many API are unpalatable and unattractive in their natural form. In such cases, tablet formulation require certain care. API has to be checked for colour and taste.
I. Colour

Ideally API should be colourless. For coloured API, the following steps shall be considered: i)Select appropriate excipient to avoid mottling. ii)Incorporate API in smallest particle size. iii)Incorporate colour in dry form along with binder and activate mixture by addition of water or other activator. iv)Coating can be applied to conceal non-uniform colour (sugar coated multivitamin tablet).
II. Taste

It is very important for tablets because they come in contact with taste buds. Ideally API should have no taste. But sometimes it might have unpleasant taste like bitter e.g. Chloramphenicol, Clindamycin, etc. The following taste masking options can be tried:

i)Use of prodrug to decrease API solubility in saliva or to reduce affinity for taste receptor e.g. Chloramphenicol Palmitate. ii)Sugar coating or film coating. iii)Addition of sweeteners like mannitol in cause of fast dissolving tablet or chewable tablet. iv) Use of drug-ion exchange adsorbent in formulation. v)Drug β-cyclodextrin complex may exhibit good taste profile and good compressibility as well. 1.6.12 Miscellaneous points i)API should not exhibit sublime characteristics ii)Liquid APIs are less suitable for tablet formulation. One of the options is conversion of liquid in pseudosolid (mix liquid API with adsorbents). A combination of Valproic acid and Sodium Valproate is a typical example of converting a liquid into pseudosolid. iii)BCS class IV drugs are difficult to formulate if dissolution and bioavailability requirements are to meet as per regulatory agencies. Key Phrases ØHigh Purity to avoid contamination and degradation. ØHigh stability against photolysis, oxidation, hydrolysis, etc. ØGood compatibility with excipients. For example, avoid use of lactose with drugs with primary amine functional group. ØOptimum bulk powder properties to prevent segregation and to have good flow. ØOptimum particle size and size distribution to have uniformity of weight, uniformity of content, good flow and compressibility. ØSpherical shape to avoid interlocking between the particles and thus to aid flow.

ØGood flow to have uniformity of weight and uniformity of drug content ØOptimum amount of moisture to avoid problems like brittle tablet, picking/sticking, etc. ØGood compressibility to have nicely bonded tablet. ØAbsence of static charge on the surface to prevent demixing and damage to tableting equipment by adhering to feed frame. ØGood organoleptic properties to have better patient acceptance. ØMiscellaneous: Convert liquid API to pseudosolid e.g. Valproic acid and Sodium valproate, etc.

Operations involved in tablet manufacturing
Submitted by on Sun, 12/06/2009 - 19:52

1.7 Operations involved in tablet manufacturing(1-3)
What will you gain? 1.7.1 Introduction 1.7.2 Dispensing (weighing and measuring) 1.7.3 Sizing 1.7.4 Powder blending 1.7.5 Granulation 1.7.6 Drying 1.7.7 Tablet compression 1.7.8 Auxillary equipments 1.7.9 Packaging 1.7.1 Introduction The manufacture of oral solid dosage forms such as tablets is a complex multi-stage process under which the starting

materials change their physical characteristics a number of times before the final dosage form is produced. Traditionally, tablets have been made by granulation, a process that imparts two primary requisites to formulate: compactibility and fluidity. Both wet granulation and dry granulation (slugging and roll compaction) are used. Regardless of weather tablets are made by direct compression or granulation, the first step, milling and mixing, is the same; subsequent step differ. Numerous unit processes are involved in making tablets, including particle size reduction and sizing, blending, granulation, drying, compaction, and (frequently) coating. Various factors associated with these processes can seriously affect content uniformity, bioavailability, or stability.

Figure.20. Various Unit Operation Sequences In Tablet Manufacturing

Figure.21. Typical Manufacturing Process Of Tablet Table.22. Typical Unit Operation Involved In Wet Granulation, Dry Granulation And Direct Compression(13) WET GRANULATION 1. Milling and mixing of drugs and excipients 2. Preparation of binder solution 3. Wet massing by addition of binder solution or granulating solvent 4. Screening of wet mass 5. Drying of the wet granules DRY GRANULATION DIRECT COMPRESSION 1. Milling and mixing of drugs and excipients

1. Milling and mixing of drugs and excipients 2. 2. Compression Compression of tablet into slugs or roll compaction 3. Milling and screening of slugs and compacted powder 4. Mixing with lubricant and disintegrant 5. Compression of tablet

6. Screening of dry granules 7. Blending with lubricant and disintegrant to produce “running powder” 8. Compression of tablet

1.7.2 Dispensing (weighing and measuring) Dispensing is the first step in any pharmaceutical manufacturing process. Dispensing is one of the most critical steps in pharmaceutical manufacturing; as during this step, the weight of each ingredient in the mixture is determined according to dose. Dispensing may be done by purely manual by hand scooping from primary containers and weighing each ingredient by hand on a weigh scale, manual weighing with material lifting assistance like Vacuum transfer and Bag lifters, manual or assisted transfer with automated weighing on weigh table, manual or assisted filling of loss-in weight dispensing system, automated dispensaries with mechanical devices such as vacuum loading system and screw feed system. Issues like weighing accuracy, dust control (laminar air flow booths, glove boxes), during manual handling, lot control of each ingredient, material movement into and out of dispensary should be considered during dispensing. 1.7.3 Sizing The sizing (size reduction, milling, crushing, grinding, pulverization) is an impotent step (unit operation) involved in the tablet manufacturing. In manufacturing of compressed tablet, the mixing or blending of several solid ingredients of pharmaceuticals is easier and more uniform if the ingredients are approximately of same size. This provides a greater uniformity of dose. A fine particle size is essential in case of lubricant mixing with granules for its proper function. Advantages associated with size reduction in tablet manufacture are as follows: i) It increases surface area, which may enhance an active ingredient’s dissolution rate and hence bioavailability.

ii)Improved the tablet-to-tablet content uniformity by virtue of the increased number of particles per unit weight. iii)Controlled particle size distribution of dry granulation or mix to promote better flow of mixture in tablet machine. iv)Improved flow properties of raw materials. v)Improved colour and/or active ingredient dispersion in tablet excipients. vi)Uniformly sized wet granulation to promote uniform drying. There are also certain disadvantages associated with this unit operation if not controlled properly. They are as follows: i)A possible change in polymorphic form of the active ingredient, rendering it less or totally inactive, or unstable. ii) A decrease in bulk density of active compound and/or excipients, which may cause flow problem and segregation in the mix. iii)An increase in surface area from size reduction may promote the adsorption of air, which may inhibit wettability of the drug to the extent that it becomes the limiting factor in dissolution rate. A number of different types of machine may be used for the dry sizing or milling process depending on whether gentle screening or particle milling is needed. The ranges of equipment employed for this process includes Fluid energy mill, Colloidal mill, Ball mill, Hammer mill, Cutting mill, Roller mill, Conical mill, etc. 1.7.4 Powder blending The successful mixing of powder is acknowledged to be more difficult unit operation because, unlike the situation with liquid, perfect homogeneity is practically unattainable. In practice, problems also arise because of the inherent cohesiveness and resistance to movement between the individual particles. The process is further complicated in many system, by the presence of substantial segregation influencing the powder mix. They arise because of difference in size, shape, and density of the component particles. The powder/granules blending are involved at stage of pre granulation and/or post granulation stage of

tablet manufacturing. Each process of mixing has optimum mixing time and so prolonged mixing may result in an undesired product. So, the optimum mixing time and mixing speed are to be evaluated. Blending step prior to compression is normally achieved in a simple tumble blender. The Blender may be a fixed blender into which the powders are charged, blended and discharged. It is now common to use a bin blender which blends. In special cases of mixing a lubricant, over mixing should be particularly monitered. The various blenders used include “V” blender, Oblicone blender, Container blender, Tumbling blender, Agitated powder blender, etc. But now a days to optimize the manufacturing process particularly in wet granulation the various improved equipments which combines several of processing steps (mixing, granulation and/or drying) are used. They are “Mixer granulator” or “High shear mixing machine”. 1.7.5 Granulation Following particle size reduction and blending, the formulation may be granulated, which provides homogeneity of drug distribution in blend. 1.7.6 Drying Drying is a most important step in the formulation and development of pharmaceutical product. It is important to keep the residual moisture low enough to prevent product deterioration and ensure free flowing properties. The commonly used dryer includes Fluidized – bed dryer, Vacuum tray dryer, Microwave dryer, Spray dryer, Freeze dryer, Turbo - tray dryer, Pan dryer, etc. 1.7.7 Tablet compression After the preparation of granules (in case of wet granulation) or sized slugs (in case of dry granulation) or mixing of ingredients (in case of direct compression), they are compressed to get final product. The compression is done either by single punch machine (stamping press) or by multi station machine (rotary press). The tablet press is a high-speed mechanical device. It 'squeezes' the ingredients into the required tablet shape with extreme precision. It can make the tablet in many shapes, although they are usually round or oval. Also, it can press the name of the manufacturer or the product into the top of the tablet.

Each tablet is made by pressing the granules inside a die, made up of hardened steel. The die is a disc shape with a hole cut through its centre. The powder is compressed in the centre of the die by two hardened steel punches that fit into the top and bottom of the die. The punches and dies are fixed to a turret that spins round. As it spins, the punches are driven together by two fixed cams - an upper cam and lower cam. The top of the upper punch (the punch head) sits on the upper cam edge .The bottom of the lower punch sits on the lower cam edge. The shapes of the two cams determine the sequence of movements of the two punches. This sequence is repeated over and over because the turret is spinning round. The force exerted on the ingredients in the dies is very carefully controlled. This ensures that each tablet is perfectly formed. Because of the high speeds, they need very sophisticated lubrication systems. The lubricating oil is recycled and filtered to ensure a continuous supply. Common stages occurring during compression Stage 1: Top punch is withdrawn from the die by the upper cam Bottom punch is low in the die so powder falls in through the hole and fills the die Stage 2: Bottom punch moves up to adjust the powder weight-it raises and expels some powder Stage 3: Top punch is driven into the die by upper cam Bottom punch is raised by lower cam Both punch heads pass between heavy rollers to compress the powder Stage 4: Top punch is withdraw by the upper cam Lower punch is pushed up and expels the tablet Tablet is removed from the die surface by surface plate Stage 5: Return to stage 1

Figure.22. Stage Occurring During Compression 1.7.8 Auxiliary Equipments (1)
I. Granulation Feeding Device:

In many cases, speed of die table is such that the time of die under feed frame is too short to allow adequate or consistent gravity filling of die with granules, resulting in weight variation and content uniformity. These also seen with poorly flowing granules. To avoid these problems, mechanized feeder can employ to force granules into die cavity.
II.Tablet weight monitoring devices:-

High rate of tablet output with modern press requires continuous tablet weight monitoring with electronic monitoring devices like Thomas Tablet Sentinel, Pharmakontroll and Killan control System-MC. They monitors force at each compression station by starin gage technology which is then correlated with tablet weight.
III. Tablet Deduster : -

In almost all cases, tablets coming out of a tablet machine bear excess powder on its surface and are run through the tablet deduster to remove that excess powder.

IV. Fette machine

Fette machine is device that chills the compression components to allow the compression of low melting point substance such as waxes and thereby making it possible to compress product with low meting points. 1.7.9 Packaging Pharmaceutical manufacturers have to pack their medicines before they can be sent out for distribution. The type of packaging will depend on the formulation of the medicine. 'Blister packs' are a common form of packaging used for a wide variety of products. They are safe and easy to use and they allow the consumer to see the contents without opening the pack. Many pharmaceutical companies use a standard size of blister pack. This saves the cost of different tools and to change the production machinery between products. Sometimes the pack may be perforated so that individual tablets can be detached. This means that the expiry date and the name of the product have to be printed on each part of the package. The blister pack itself must remain absolutely flat as it travels through the packaging processes, especially when it is inserted into a carton. This poses interesting problems for the designers. Extra ribs are added to the blister pack to improve its stiffness. Key Phrases The manufacturing of tablet involves numerous unit processes including ØParticle size reduction and sizing ØBlending ØGranulation ØDrying,compaction ØCoating.

Manufacturing methods of tablets
Submitted by on Sun, 12/06/2009 - 19:53

1.8 Manufacturing methods

1.8.1 Direct compression(1-3,5,17) What will you gain? 1.8.1.1 Introduction. 1.8.1.2 The events that motivates the industry people to use direct compression technique. 1.8.1.3 Merits 1.8.1.4 Merits over wet granulation process 1.8.1.5 Demerits 1.8.1.6 Manufacturing steps for direct compression 1.8.1.7 Direct compression Excipients 1.8.1.7.1 An ideal direct compression excipient should possess the following attributes. 1.8.1.7.2 Major excipients required in direct compression.
1.8.1.1 Introduction

In early days, most of the tablets require granulation of the powdered Active Pharmaceutical Ingredient (API) and Excipients. At the availability of new excipients or modified form of old excipients and the invention of new tablet machinery or modification of old tablet machinery provides an ease in manufacturing of tablets by simple procedure of direct compression. Amongst the techniques used to prepare tablets, direct compression is the most advanced technology. It involves only blending and compression. Thus offering advantage particularly in terms of speedy production. Because it requires fewer unit operations, less machinery, reduced number of personnel and considerably less processing time along with increased product stability. Definition: The term “direct compression” is defined as the process by which tablets are compressed directly from powder mixture of API and suitable excipients. No pretreatment of the powder blend by wet or dry granulation procedure is required.
1.8.1.2 The events that motivates the industry people to use direct compression technique

I.Commercial availability of the directly compressible excipients possessing both good compressibility and good flowability. For example, Spray dried lactose, Anhydrous lactose, Starch-1500, microcrystalline cellulose, Di-PacÒ, Sorbitol II.Major advances in tablet compression machinery: i)Improved positive die feeding, ii)Precompression of powder blend.
1.8.1.3 Merits

i)Direct compression is more efficient and economical process as compared to other processes, because it involves only dry blending and compaction of API and necessary excipients. ii)The most important advantage of direct compression is economical process. Reduced processing time, reduced labor costs, fewer manufacturing steps, and less number of equipments are required, less process validation, reduced consumption of power. iii)Elimination of heat and moisture, thus increasing not only the stability but also the suitability of the process for thermolabile and moisture sensitive API’s. iv)Particle size uniformity. v)Prime particle dissolution. In case of directly compressed tablets after disintegration, each primary drug particle is liberated. While in the case of tablets prepared by compression of granules, small drug particles with a larger surface area adhere together into larger agglomerates; thus decreasing the surface area available for dissolution. vi)The chances of batch-to-batch variation are negligible, because the unit operations required for manufacturing processes is fewer. vii)Chemical stability problems for API and excipient would be avoided. viii)Provides stability against the effect of aging which affects the dissolution rates.

1.8.1.4 Merits over wet granulation process

The variables faced in the processing of the granules can lead to significant tableting problems. Properties of granules formed can be affected by viscosity of granulating solution, the rate of addition of granulating solution, type of mixer used and duration of mixing, method and rate of dry and wet blending. The above variables can change the density and the particle size of the resulting granules and may have a major influence on fill weight and compaction qualities. Drying can lead to unblending as soluble API migrates to the surface of the drying granules.
1.8.1.5 Demerits

Excipient Related i)Problems in the uniform distribution of low dose drugs. ii)High dose drugs having high bulk volume, poor compressibility and poor flowability are not suitable for direct compression. For example, Aluminium Hydroxide, Magnesium Hydroxide iii) The choice of excipients for direct compression is extremely critical. Direct compression diluents and binders must possess both good compressibility and good flowability. iv) Many active ingredients are not compressible either in crystalline or amorphous forms. v) Direct compression blends may lead to unblending because of difference in particle size or density of drug and excipients. Similarly the lack of moisture may give rise to static charges, which may lead to unblending. vi) Non-uniform distribution of colour, especially in tablets of deep colours. Process Related i)Capping, lamination, splitting, or layering of tablets is sometimes related to air entrapment during direct compression. When air is trapped, the resulting tablets expand when the pressure of tablet is released, resulting in splits or layers in the tablet. ii)In some cases require greater sophistication in blending and compression equipments. iii) Direct compression equipments are expensive.

1.8.1.6 Manufacturing steps for direct compression

Direct compression involves comparatively few steps: i)Milling of drug and excipients. ii) Mixing of drug and excipients. iii) Tablet compression.

Figure.23. Manufacturing Steps For Direct Compression
1.8.1.7 Direct compression Excipients

Direct compression excipients mainly include diluents, binders and disintegrants. Generally these are common materials that have been modified during the chemical manufacturing process, in such a way to improve compressibility and flowability of the material. The physicochemical properties of the ingredients such as particle size, flowability and moisture are critical in direct compression tableting. The success of direct compression formulation is highly dependent on functional behavior of excipients.
1.8.1.7.1 An ideal direct compression excipient should possess the following attributes

i)It should have good compressibility. ii)It should possess good hardness after compression, that is material should not possess any deformational properties; otherwise this may lead to capping and lamination of tablets. iii) It should have good flowability. iv) It should be physiologically inert. v) It should be compatible with wide range of API.

vi) It should be stable to various environmental conditions (air, moisture, heat, etc.). vii) It should not show any physical or chemical change in its properties on aging. viii) It should have high dilution potential. i.e. Able to incorporate high amount of API. ix) It should be colourless, odorless and tasteless. x) It should accept colourants uniformity. xi) It should possess suitable organoleptic properties according to formulation type, that is in case of chewable tablet diluent should have suitable taste and flavor. For example mannitol produces cooling sensation in mouth and also sweet test. xii) It should not interfere with bioavailability and biological activity of active ingredients. xiii)It should be easily available and economical in cost.
1.8.1.7.2 Major excipients required in direct compression

I.Diluents II.Binders III.Disintegrants Diluents Selection of direct compression diluent is extremely critical, because the success or failure of direct compression formulation completely depends on characteristics of diluents. There are number of factors playing key role in selection of optimum diluent. Factors like- Primary properties of API (particle size and shape, bulk density, solubility), the characteristics needed for processing (flowability, compressibity), and factors affecting stability (moisture, light, and other environmental factors), economical approach and availability of material. After all, one can say that raw material specifications should be framed in such a way that they provide an ease in manufacturing procedures and reduce chances of batch to batch variation. This becomes possible only when the raw material specifications reflect most of properties of diluents as mentioned in section 1.5.

Binders (56) Binders are the agents used to impart cohesive qualities to the powdered material. The quality of binder used has considerable influence on the characteristic of the direct compression tablets. The direct compression method for preparing tablets requires materials which are not only free flowing but also sufficiently cohesive to act as binder. Key Phrases Ø Direct compression is one of the most advanced technologies to prepare tablets. Ø It requires only blending and compression of excipients. Ø It is an economical process. Ø It is suitable for heat and moisture sensitive API. It is not suitable for very low and very high dose drugs. 1.8.2 Granulation (1,4,5,57) What will you gain? 1.8.2.1 Introduction 1.8.2.2 Wet granulation 1.8.2.2.1 Introduction 1.8.2.2.2 Important steps involved in the wet granulation 1.8.2.2.3 Limitation of wet granulation 1.8.2.2.4 Special wet granulation techniques 1.8.2.2.4.1 High shear mixture granulation 1.8.2.2.4.2 Fluid bed granulation

1.8.2.2.4.3 Extrusion and Spheronization 1.8.2.2.4.4 Spray drying granulation 1.8.2.2.5 Lists of equipments for wet granulation 1.8.2.2.6 Current topics related to wet granulation 1.8.2.3 Dry granulation 1.8.2.3.1 Introduction 1.8.2.3.2 Advantages 1.8.2.3.3 Disadvantages 1.8.2.3.4 Steps in dry granulation 1.8.2.3.5 Two main dry granulation processes 1.8.2.3.5.1Slugging process 1.8.2.3.5.2 Roller compaction 1.8.2.3.6 Formulation for dry granulation 1.8.2.3 Advancement in Granulations 1.8.2.3.1 Steam Granulation 1.8.2.3.2 Melt Granulation/Thermoplastic Granulation 1.8.2.3.3 Moisture Activated Dry Granulation 1.8.2.3.4 Moist Granulation Technique (MGT) 1.8.2.3.5 Thermal Adhesion Granulation Process (TAGP) 1.8.2.3.6 Foam Granulation
1.8.2.1 Introduction

Granulation may be defined as a size enlargement process which converts small particles into physically stronger & larger agglomerates. Granulation method can be broadly classified into two types: Wet granulation and Dry granulation
Ideal characteristics of granules

The ideal characteristics of granules include spherical shape, smaller particle size distribution with sufficient fines to fill void spaces between granules, adequate moisture (between 1-2%), good flow, good compressibility and sufficient hardness. The effectiveness of granulation depends on the following properties i) Particle size of the drug and excipients ii) Type of binder (strong or weak) iii) Volume of binder (less or more) iv) Wet massing time ( less or more) v) Amount of shear applied vi) Drying rate ( Hydrate formation and polymorphism)
1.8.2.2 Wet granulation

1.8.2.2.1 Introduction

The most widely used process of agglomeration in pharmaceutical industry is wet granulation. Wet granulation process simply involves wet massing of the powder blend with a granulating liquid, wet sizing and drying.
1.8.2.2.2 Important steps involved in the wet granulation

i) Mixing of the drug(s) and excipients ii) Preparation of binder solution

iii) Mixing of binder solution with powder mixture to form wet mass. iv) Coarse screening of wet mass using a suitable sieve (6-12 # screens). v) Drying of moist granules. vi) Screening of dry granules through a suitable sieve (14-20 # screen). vii) Mixing of screened granules with disintegrant, glidant, and lubricant.
1.8.2.2.3 Limitation of wet granulation

i) The greatest disadvantage of wet granulation is its cost. It is an expensive process because of labor, time, equipment, energy and space requirements. ii) Loss of material during various stages of processing iii) Stability may be major concern for moisture sensitive or thermo labile drugs iv) Multiple processing steps add complexity and make validation and control difficult v) An inherent limitation of wet granulation is that any incompatibility between formulation components is aggravated.
1.8.2.2.4 Special wet granulation techniques

i) High shear mixture granulation ii) Fluid bed granulation iii) Extrusion-spheronization iv)Spray drying
1.8.2.2.4.1 High shear mixture granulation

High shear mixture has been widely used in Pharmaceutical industries for blending and granulation. Blending and wet massing is accompanied by high mechanical agitation by an impeller and a chopper. Mixing, densification and agglomeration are achieved through shear and compaction force exerted by the impeller.

Advantages: i) Short processing time ii) Less amount of liquid binders required compared with fluid bed. iii) Highly cohesive material can be granulated.
1.8.2.2.4.2 Fluid bed granulation

Fluidization is the operation by which fine solids are transformed into a fluid like state through contact with a gas. At certain gas velocity the fluid will support the particles giving them free mobility without entrapment. Fluid bed granulation is a process by which granules are produced in a single equipment by spraying a binder solution onto a fluidized powder bed. The material processed by fluid bed granulation are finer, free flowing and homogeneous.
1.8.2.2.4.3 Extrusion and Spheronization

It is a multiple step process capable of making uniform sized spherical particles. It is primarily used as a method to produce multi-particulates for controlled release application. Advantages: i) Ability to incorporate higher levels of active components without producing excessively larger particles. ii) Applicable to both immediate and controlled release dosage form.
1.8.2.2.4.4 Spray drying granulation

It is a unique granulation technique that directly converts liquids into dry powder in a single step. This method removes moisture instantly and converts pumpable liquids into a dry powder. Advantages: i) Rapid process ii) Ability to be operated continuously

iii) Suitable for heat sensitive product
1.8.2.2.5 Lists of equipments for wet granulation

High Shear granulation: i)Little ford Lodgie granulator ii)Little ford MGT granulator iii)Diosna granulator iv)Gral mixer Granulator with drying facility: i)Fluidized bed granulator ii) Day nauta mixer processor iii)Double cone or twin shell processor iv)Topo granulator Special granulator: i)Roto granulator ii)Marumerizer
1.8.2.2.6 Current topics related to wet granulation

I. Hydrate formation For example, theophylline anhydrous during high shear wet granulation transfers to theophylline monohydrate. The midpoint conversion occurs in three minutes after the binder solution is added. For online monitoring of the transformation from one form to another, Raman spectroscopy is most widely used. II. Polymorphic transformation The drying phase of wet granulation plays a vital role for conversion of one form to another. For example, glycine which exist in three polymorphs that is a, β, g . g is the most stable form and a

is the metastable form. The stable Glycine polymorph (g) converts to metastable form (a) when wet granulated with microcrystalline cellulose. 1.8.2.3 Dry granulation
1.8.2.3.1 Introduction

In dry granulation process the powder mixture is compressed without the use of heat and solvent. It is the least desirable of all methods of granulation. The two basic procedures are to form a compact of material by compression and then to mill the compact to obtain a granules. Two methods are used for dry granulation. The more widely used method is slugging, where the powder is precompressed and the resulting tablet or slug are milled to yield the granules. The other method is to precompress the powder with pressure rolls using a machine such as Chilosonator.
1.8.2.3.2 Advantages

The main advantages of dry granulation or slugging are that it uses less equipments and space. It eliminates the need for binder solution, heavy mixing equipment and the costly and time consuming drying step required for wet granulation. Slugging can be used for advantages in the following situations: i) For moisture sensitive material ii) For heat sensitive material iii) For improved disintegration since powder particles are not bonded together by a binder
1.8.2.3.3 Disadvantages

i) It requires a specialized heavy duty tablet press to form slug ii) It does not permit uniform colour distribution as can be iii) Achieved with wet granulation where the dye can be incorporated into binder liquid. iv) The process tends to create more dust than wet granulation, increasing the potential contamination.
1.8.2.3.4 Steps in dry granulation

i) Milling of drugs and excipients

ii) Mixing of milled powders iii) Compression into large, hard tablets to make slug iv) Screening of slugs v) Mixing with lubricant and disintegrating agent vi) Tablet compression 1.8.2.3.5 Two main dry granulation processes
1.8.2.3.5.1 Slugging process

Granulation by slugging is the process of compressing dry powder of tablet formulation with tablet press having die cavity large enough in diameter to fill quickly. The accuracy or condition of slug is not too important. Only sufficient pressure to compact the powder into uniform slugs should be used. Once slugs are produced they are reduced to appropriate granule size for final compression by screening and milling. Factors which determine how well a material may slug i) Compressibility or cohesiveness of the mater ii) Compression ratio of powder iii) Density of the powder iv) Machine type v) Punch and die size vi) Slug thickness vii) Speed of compression viii) Pressure used to produce slug
1.8.2.3.5.2 Roller compaction

The compaction of powder by means of pressure roll can also be accomplished by a machine called chilsonator. Unlike tablet machine, the chilsonator turns out a compacted mass in a steady continuous flow. The powder is fed down between the rollers from the hopper which contains a spiral auger to feed the powder into the compaction zone. Like slugs, the aggregates are screened or milled for production into granules.

1.8.2.3.6 Formulation for dry granulation

The excipients used for dry granulation are basically same as that of wet granulation or that of direct compression. With dry granulation it is often possible to compact the active ingredient with a minor addition of lubricant and disintegrating agent. Fillers that are used in dry granulation include the following examples: Lactose, dextrose, sucrose, MCC, calcium sulphate, Sta-Rx® etc . Examples of some tablet formulation prepared by dry granulation: Aspirin tablet Aspirin effervescent tablet Rx Rx Starch Sodium bicarbonate Cab-o-sil ® Citric acid Aspirin Fumaric acid Aspirin Antacid tablet Rx Aluminum hydroxide Magnesium hydroxide Magnesium carbonate Sucrose PEG 1.8.2.3 Advancement in Granulations
1.8.2.3.1 Steam Granulation

It is modification of wet granulation. Here steam is used as a binder instead of water. Its several benefits includes higher distribution uniformity, higher diffusion rate into powders, more favourable thermal balance during drying step, steam granules are more spherical, have large surface area hence increased dissolution rate of the drug from granules, processing time is shorter therefore more number of tablets are produced per batch, compared to the use of organic solvent water vapour is environmentally friendly, no health hazards to operators, no restriction by ICH on traces left in the granules, freshly distilled steam is sterile and therefore the total count can be kept under control, lowers dissolution rate so can be used for preparation of taste masked granules without modifying availability of the drug. But the limitation is that it is unsuitable for thermolabile drugs. Moreover special equipments are required and are unsuitable for binders that cannot be later activated by contact with water vapour.
1.8.2.3.2 Melt Granulation / Thermoplastic Granulation (24)

Here granulation is achieved by the addition of meltable binder. That is binder is in solid state at room temperature but melts in the temperature range of 50 – 80˚C. Melted binder then acts like a binding liquid. There is no need of drying phase since dried granules are obtained by cooling it to room temperature. Moreover, amount of liquid binder can be controlled precisely and the production and

equipment costs are reduced. It is useful for granulating water sensitive material and producing SR granulation or solid dispersion. But this method is not suitable for thermolabile substances. When water soluble binders are needed, Polyethylene Glycol (PEG) is used as melting binders. When water insoluble binders are needed, Stearic acid, cetyl or stearyl alcohol, various waxes and mono-, di-, & triglycerides are used as melting binders.
1.8.2.3.3 Moisture Activated Dry Granulation (MADG) (58)

It involves moisture distribution and agglomeration. Tablets prepared using MADG method has better content uniformity. This method utilizes very little granulating fluid. It decreases drying time and produces granules with excellent flowability.
1.8.2.3.4 Moist Granulation Technique (MGT) (59)

A small amount granulating fluid is added to activate dry binder and to facilitate agglomeration. Then a moisture absorbing material like Microcrystalline Cellulose (MCC) is added to absorb any excess moisture. By adding MCC in this way drying step is not necessary. It is applicable for developing a controlled release formulation.
1.8.2.3.5 Thermal Adhesion Granulation Process (TAGP) (60)

It is applicable for preparing direct tableting formulations. TAGP is performed under low moisture content or low content of pharmaceutically acceptable solvent by subjecting a mixture containing excipients to heating at a temperature in the range from about 30ºC to about 130ºC in a closed system under mixing by tumble rotation until the formation of granules. This method utilizes less water or solvent than traditional wet

granulation method. It provides granules with good flow properties and binding capacity to form tablets of low friability, adequate hardness and have a high uptake capacity for active substances whose tableting is poor.
1.8.2.3.6 Foam Granulation (61)

Here liquid binders are added as aqueous foam. It has several benefits over spray(wet) granulation such as it requires less binder than Spray Granulation, requires less water to wet granulate, rate of addition of foam is greater than rate of addition of sprayed liquids, no detrimental effects on granulate, tablet, or invitro drug dissolution properties, no plugging problems since use of spray nozzles is eliminated, no overwetting, useful for granulating water sensitive formulations, reduces drying time, uniform distribution of binder throughout the powder bed, reduce manufacturing time, less binder required for Immediate Release (IR) and Controlled Release (CR) formulations. Key Phrases Ø In wet granulation process a granulating liquid is used to facilitate the agglomeration process. Wet granulation has been and continues to be the most widely used agglomeration process. Typically wet massing of pharmaceutical powder is carried out in the high shear mixture

before wet screening and dried in fluidized bed equipment. Ø In the dry granulation process granulation takes place without utilizing liquid. In this process dry powder particles may be brought together mechanically by compression into slug or by rolled compaction. Ø Steam Granulation, Melt Granulation, MADG, MGT, TAGP, Foam Granulation are some of the new advancements in granulation and show better quality granule formation as compared to conventional granulation methods.

Tablet coating
Submitted by on Sun, 12/06/2009 - 19:54

1.9 Tablet coating
What will you gain? 1.9.1 Introduction 1.9.2 Aspects of tablet coating 1.9.3 Basic principle of tablet coating 1.9.4 Type of tablet coating process 1.9.4.1 Sugar coating 1.9.4.2 Film coating 1.9.4.3 Enteric coating 1.9.4.3.1 Enteric sugar coating

1.9.4.3.2 Enteric film coating 1.9.4.3.3 Controlled release coating 1.9.4.4 Specialized coating 1.9.4.4.1 Compressed coating 1.9.4.4.2 Electrostatic coating 1.9.4.4.3 Dip coating 1.9.4.4.4 Vacuum film coating 1.9.5 Equipments 1.9.6 Processing parameters

1.9.1 Introduction (1-3,5)
Coated tablets are defined as “tablets covered with one or more layers of mixture of various substances such as natural or synthetic resins ,gums ,inactive and insoluble filler, sugar, plasticizer, polyhydric alcohol ,waxes ,authorized colouring material and some times flavoring material . Coating may also contain active ingredient. Substances used for coating are usually applied as solution or suspension under conditions where vehicle evaporates.

1.9.2 Aspects of tablet coating
I. Therapy i) Avoid irritation of oesophagus and stomach ii) Avoid bad taste iii) Avoid inactivation of drug in the stomach iv) Improve drug effectiveness v) Prolong dosing interval

vi) Improve dosing interval vii) Improve patient compliance II. Technology i) Reduce influence of moisture ii) Avoid dust formation iii) Reduce influence of atmosphere iv) Improve drug stability v) Prolong shelve life III. Marketing i) Avoid bad taste ii) Improve product identity iii) Improve appearance and acceptability

1.9.3 Basic principle of tablet coating
The principle of tablet coating is relatively simple. Tablet coating is the application of coating composition to moving bed of tablets with concurrent use of heated air to facilitate evaporation of solvent. Basic principles involve i) Insulation which influences the release pattern as little as possible and does not markedly change the appearance. ii) Modified release with specific requirement and release mechanism adapted to body function in the digestive tract iii) Colour coating which provides insulation or is combined with modified release coating.

1.9.4 Type of tablet coating process
1.9.4.1 Sugar coating (1,3,5)

Compressed tablets may be coated with coloured or uncoloured sugar layer. The coating is water soluble and quickly dissolves after swallowing. The sugarcoat protects the enclosed drug from the environment and provides a barrier to objectionable taste or order. The sugar coat also enhances the appearance of the compressed tablet and permit imprinting manufacturing’s information. Sugar coating provides a combination of insulation, taste masking, smoothing the tablet core, colouring and modified release. The disadvantages of sugar coating are the time and expertise required in the coating process and thus increases size, weight and shipping costs. Sugar coating process involves five separate operations: I. Sealing/Water proofing: provides a moisture barrier and harden the tablet surface. II. Subcoating: causes a rapid buildup to round off the tablet edges. III. Grossing/Smoothing: smoothes out the subcoated surface and increases the tablet size to predetermine dimension. IV. Colouring: gives the tablet its colour and finished size. V. Polishing: produces the characteristics gloss. I. Sealing/Water proofing Prior to applying any sugar/water syrup, the tablet cores must be sealed, thoroughly dried and free of all residual solvents. The seal coat provides a moisture barrier and hardness the surface of the tablet in order to minimize attritional effects. Core tablets having very rapid disintegration rates conceivably could start the disintegration process during the initial phase of sugar coating. The sealants are generally water-insoluble polymers/film formers applied from an organic solvent solution. The quantities of material applied as a sealing coat will depend primarily on the tablet porosity, since highly porous tablets will tend to soak up the first application of solution, thus preventing it from spreading uniformly across the surface of every tablet in the batch. Hence, one or more further application of resin solution may be required to ensure that the tablet cores are sealed effectively.

Common materials used as a sealant include Shellac, Zine, Cellulose acetate phthalate (CAP), Polyvinylacetate phthalate, Hyroxylpropylcellulose, Hyroxypropylmethylcellulose etc. II. Subcoating Subcoating is the actual start of the sugar coating process and provides the rapid buildup necessary to round up the tablet edge. It also acts as the foundation for the smoothing and colour coats. Generally two methods are used for subcoating: i) The application of gum based solution followed by dusting with powder and then drying. This routine is repeated until the desired shape is achieved. ii) The application of a suspension of dry powder in gum/sucrose solution followed by drying. Thus subcoating is a sandwich of alternate layer of gum and powder. It is necessary to remove the bulk o the water after each application of coating syrup. Table.23. Typical Binder Solution Formulation For Subcoating(1) %W/W Gelatin Gum acacia (powdered) Sucrose (powdered) Distilled water 6 8 45 to 100 3.3 8.7 55.3 to 100 %W/W

Table.24. Typical Dusting Powder Formulation For Subcoating(1) %W/W Calcium carbonate Titanium dioxide Talc, asbestos free Sucrose( powdered ) Gum acacia (powdered) 40.0 5.0 25.0 28.0 2.0 1.0 61.0 38.6 %W/W

Table.25. Typical Suspension Subcoating Formulation(1)

%W/W Sucrose Calcium carbonate Talc, asbestos free Gum acacia(powdered) Titanium dioxide Distilled water III. Grossing/ smoothing The grossing/smoothing process is specifically for smoothing and filing the irregularity on the surface generated during subcoating. It also increases the tablet size to a predetermined dimension. If the subcoating is rough with high amount of irregularities then the use of grossing syrup containing suspended solids will provide more rapid buildup and better filling qualities. Smoothing usually can be accomplished by the application of a simple syrup solution (approximately 60-70 % sugar solid). This syrup generally contains pigments, starch, gelatin, acacia or opacifier if required. Small quantities of colour suspension can be applied to impart a tint of the desired colour when there are irregularities in coating. IV.Colour coating This stage is often critical in the successful completion of a sugar coating process and involves the multiple application of syrup solution (60-70 % sugar solid) containing the requisite colouring matter. Mainly soluble dyes were used in the sugar coating to achieve the desired colour, since the soluble dye will migrate to the surface during drying. But now a days the insoluble certified lakes have virtually replaced the soluble dyes in pharmaceutical tablet coating. The most efficient process for colour coating involves the use of a predispersed opacified lake suspension. V. Polishing Sugar-coated tablets needs to be polished to achieve a final elegance. Polishing is achieved by applying the mixture of waxes like beeswax, carnubawax, candelila wax or hard paraffin wax to tablets in polishing pan. 40.0 20.0 12.0 2.0 1.0 25.0

1.9.4.2 Film Coating Film coating is more favored over sugar coating. Table.26. Comparison Between Film Coating And Sugar Coating(1) FEATURES Tablet: Appearance Retain contour of original Rounded with high degree of core. polish Usually not as shiny as sugar coat type FILM COATING SUGAR COATING

Weight increase because of coating 2-3% material

30-50%

Logo or ‘break lines’ Process Operator training required

Possible

Not possible

Process tends itself to Considerable automation and easy training of operator

High Adaptability to GMP Usually single stage Process stages Easily adaptable for controlled release Functional coatings Process description (1) Not usually possible apart from enteric coating Multistage process Difficulty may arise

Film coating is deposition of a thin film of polymer surrounding the tablet core. Conventional pan equipments may be used but now a day’s more sophisticated equipments are employed to have a high degree of automation and coating time. The polymer is solubilized into solvent. Other additives like plasticizers and pigments are added. Resulting solution is sprayed onto a rotated tablet bed. The drying conditions cause removal of the solvent, giving thin deposition of coating material around each tablet core. Process details (1) Usually spray process is employed in preparation of film coated tablets. Accela cota is the prototype of perforated cylindrical drum providing high drying air capacity. Fluidized bed equipment has made considerable impact where tablets are moving in a stream of air passing through the perforated bottom of a cylindrical column. With a smaller cylindrical insert, the stream of cores is rising in the center of the device together with a spray mist applied in the middle of the bottom. For fluidized bed coating, very hard tablets (hardness > 20 N) have to be used. Basic process requirements for film coating (2) The fundamental requirements are independent of the actual type of equipments being used and include adequate means of atomizing the spray liquid for application to the tablet core, adequate mixing and agitation of tablet bed, sufficient heat input in the form of drying air to provide the latent heat of evaporation of the solvent. This is particularly important with aqueous-based spraying and good exhaust facilities to remove dust and solvent laden air. Development of film coating formulations (1) If the following questions are answered concomitantly then one can go for film coating: i) Is it necessary to mask objectionable taste, colour and odor? ii) Is it necessary to control drug release? iii) What tablets size, shape, or colour constrains must be placed on the developmental work? Colour, shape and size of final coated tablet are important for marketing and these properties have a significant influence on

the marketing strategies. An experienced formulator usually takes the pragmatic approach and develops a coating formulations modification of one that has performed well in the past. Spraying or casting films can preliminarily screen film formulations. Cast films cab is prepared by spreading the coating composition on teflon, glass or aluminum foil surface using a spreading bar to get a uniform film thickness. Sprayed films can be obtained by mounting a plastic-coated surface in a spray hood or coating pan. Coating formula optimization (1) Basic formula is obtained from past experience or from various sources in the literature. Modifications are required to improve adhesion of the coating to the core, to decrease bridging of installations, to increase coating hardness, etc. Usually concentration of colorant and opaquant are fixed to get predetermined shade. Common modification is to alter polymer-to-plasticizer ratio or addition of different plasticizer/ polymer. Experimentation of this type can be best achieved by fractional Materials used in film coating (1,13) I. Film formers, which may be enteric or nonenteric II. Solvents III. Plasticizers IV. Colourants V. Opaquant-Extenders VI. Miscellaneous coating solution components I. Film formers (1) Ideal requirements of film coating materials are summarized below: i) Solubility in solvent of choice for coating preparation ii) Solubility requirement for the intended use e.g. free water-solubility, slow water-solubility or pH -dependent solubility iii) Capacity to produce an elegant looking product

iv) High stability against heat, light, moisture, air and the substrate being coated v) No inherent colour, taste or odor vi) High compatibility with other coating solution additives vii) Nontoxic with no pharmacological activity viii) High resistance to cracking ix) Film former should not give bridging or filling of the debossed tablet x) Compatible to printing procedure Commonly used film formers are as follow i. Hydroxy Propyl Methyl Cellulose (HPMC) It is available in different viscosity grades. It is a polymer of choice for air suspension and pan spray coating systems because of solubility characteristic in gastric fluid, organic and aqueous solvent system. Advantages include: it does not affect tablet disintegration and drug availability, it is cheap, flexible, highly resistant to heat, light and moisture, it has no taste and odor, colour and other additives can be easily incorporated. Disadvantage includes: when it is used alone, the polymer has tendency to bridge or fill the debossed tablet surfaces. So mixture of HPMC and other polymers/ plasticizers is used. ii. Methyl Hydroxy Ethyl Cellulose (MHEC) It is available in wide variety of viscosity grades. It is not frequently used as HPMC because soluble in fewer organic solvents. iii. Ethyl Cellulose (EC)

Depending on the degree of ethoxy substitution, different viscosity grades are available. It is completely insoluble in water and gastric fluids. Hence it is used in combination with water-soluble additives like HPMC and not alone. Unplasticized ethyl cellulose films are brittle and require film modifiers to obtain an acceptable film formulation. Aqua coat is aqueous polymeric dispersion utilizing ethyl cellulose. These pseudolatex systems contain high solids, low viscosity compositions that have coating properties quite different from regular ethyl cellulose solution. iv. Hydroxy Propyl Cellulose (HPC) It is soluble in water below 40oc (insoluble above 45 oC), gastric fluid and many polar organic solvents. HPC is extremely tacky as it dries from solution system. It is used for sub coat and not for colour or glass coat. It gives very flexible film. v. Povidone Degree of polymerization decides molecular weight of material. It is available in four viscosity grades i.e. K-15, K-30, K-60 and K-90. Average molecular weight of these grades is 10000, 40000, 160000 and 360000 respectively. K-30 is widely used as tablet binder and in tablet coating. It has excellent solubility in wide variety of organic solvents, water, gastric and intestinal fluids. Povidone can be cross-linked with other materials to produce films with enteric properties. It is used to improve dispersion of colourants in coating solution. vi. Sodium carboxy methyl cellulose It is available in medium, high and extra high viscosity grades. It is easily dispersed in water to form colloidal solutions but it is insoluble in most organic solvents and hence not a material of choice for coating solution based on organic solvents. Films prepared by it are brittle but adhere well to tablets. Partially dried films of are tacky. So coating compositions must be modified with additives.

viii. Polyethylene glycols (PEG) Lower molecular weights PEG (200-600) are liquid at room temperature and are used as plasticizers. High molecular weights PEG (900-8000series) are white, waxy solids at room temperature. Combination of PEG waxes with CAP gives films that are soluble in gastric fluids. ix. Acrylate polymers It is marketed under the name of EudragitÒ. EudragitÒE is cationic co-polymer. Only EudragitÒE is freely soluble in gastric fluid up to pH 5 and expandable and permeable above pH 5. This material is available as organic solution (12.5% in isopropanol/acetone), solid material or 30% aqueous dispersion. EudragitÒRL & RS are co-polymers with low content of quaternary ammonium groups. These are available only as organic solutions and solid materials. They produce films for delayed action (pH dependent). II. Solvents(1) Solvents are used to dissolve or disperse the polymers and other additives and convey them to substrate surface. Ideal requirement are summarized below: i) Should be either dissolve/disperse polymer system ii) Should easily disperse other additives into solvent system iii) Small concentration of polymers (2-10%) should not in an extremely viscous solution system creating processing problems iv) Should be colourless, tasteless, odorless, inexpensive, inert, nontoxic and nonflammable v) Rapid drying rate vi) No environmental pollution

Mostly solvents are used either alone or in combination with water, ethanol, methanol, isopropanol, chloroform, acetone, methylene chloride, etc. Water is more used because no environmental and economic considerations. For drugs that readily hydrolyze in presence of water, non aqueous solvents are used. III. Plasticizers(1) As solvent is removed, most polymeric materials tend to pack together in 3-D honey comb arrangement. “Internal” or “External” plasticizing technique is used to modify quality of film. Combination of plasticizer may be used to get desired effect. Concentration of plasticizer is expressed in relation to the polymer being plasticized. Recommended levels of plasticizers range from 1-50 % by weight of the film former. Commonly used plasticizers are castor oil, PG, glycerin, lower molecular weight (200-400 series), PEG, surfactants, etc. For aqueous coating PEG and PG are more used while castor oil and spans are primarily used for organic-solvent based coating solution. External plasticizer should be soluble in the solvent system used for dissolving the film former and plasticizer. The plasticizer and the film former must be at least partially soluble or miscible in each other. IV. Colourants(1) Colourants can be used in solution form or in suspension form. To achieve proper distribution of suspended colourants in the coating solution requires the use of the powdered colourants (<10 microns). Most common colourants in use are certified FD & C or D & C colourants. These are synthetic dyes or lakes. Lakes are choice for sugar or film coating as they give reproducible results. Concentration of colourants in the coating solutions depends on the colour shade desired, the type of dye, and the concentration of opaquant-extenders. If very light shade is desired, concentration of less than 0.01 % may be adequate on the other hand, if a dark colour is desired a concentration of more than 2.0 % may be required. The inorganic materials (e.g. iron oxide) and the natural colouring materials (e.g. anthrocyanins, carotenoids, etc) are also used to prepare coating solution. Magenta red dye is non absorbable in biologic system and resistant to degradation in the gastro intestinal track. OpasrayÒ (opaque colour concentrate for film coating) and OpadryÒ (complete film coating concentrate) are promoted as achieving less lot-to-lot colour variation.

V. Opaquant-Extenders(1) These are very fine inorganic powder used to provide more pastel colours and increase film coverage. These inorganic materials provide white coat or mask colour of the tablet core. Colourants are very expensive and higher concentration is required. These inorganic materials are cheap. In presence of these inorganic materials, amount of colourants required decreases. Most commonly used materials are titanium dioxide, silicate (talc &aluminum silicates), carbonates (magnesium carbonates), oxides (magnesium oxide) & hydroxides (aluminum hydroxides). Pigments were investigated in the production of opaque films and it was found that they have good hiding power and film-coated tablets have highlighted intagliations. VI. Miscellaneous coating solution component (1) Flavors, sweeteners, surfactants, antioxidants, antimicrobials, etc. may be incorporated into the coating solution. 1.9.4.3 Enteric coating (1, 2, 13) This type of coating is used to protect tablet core from disintegration in the acid environment of the stomach for one or more of the following reasons: i) To prevent degradation of acid sensitive API ii) To prevent irritation of stomach by certain drugs like sodium salicylate iii) Delivery of API into intestine iv) To provide a delayed release component for repeat action tablet Several kinds of enteric layer systems are now available One layer system - The coating formulation is applied in one homogeneous layer, which can be whites-opaque or coloured. Benefit is only one application needed. Two layer system - To prepare enteric tablets of high quality and pleasing appearance the enteric formulation is applied first, followed by coloured film. Both layers can be of enteric

polymer or only the basic layer contains enteric polymer while top layer is fast disintegrating & water-soluble polymer Ideal properties of enteric coating material are summarized as below i) Resistance to gastric fluids ii) Susceptible/permeable to intestinal fluid iii) Compatibility with most coating solution components and the drug substrate iv) Formation of continuous film v) Nontoxic, cheap and ease of application vi) Ability to be readily printed Polymers used for enteric coating are as follow i. Cellulose acetate phthalate (CAP) It is widely used in industry. Aquateric is reconstituted colloidal dispersion of latex particles. It is composed of solid or semisolid polymer spheres of CAP ranging in size from 0.05 - 3 microns. Cellulose acetate trimellitate (CAT) developed as an ammoniated aqueous formulation showed faster dissolution than a similar formulation of CAP. Disadvantages include: It dissolves above pH 6 only, delays absorption of drugs, it is hygroscopic and permeable to moisture in comparison with other enteric polymer, it is susceptible to hydrolytic removal of phthalic and acetic acid changing film properties. CAP films are brittle and usually used with other hydrophobic film forming materials. ii. Acrylate polymers Eudragit®L & Eudragit®S are two forms of commercially available enteric acrylic resins. Both of them produce films resistant to gastric fluid. Eudragit®L & S are soluble in intestinal fluid at pH 6 & 7 respectively. Eudragit®L is available as an

organic solution (Isopropanol), solid or aqueous dispersion. Eudragit®S is available only as an organic solution (Isopropanol) and solid. iii Hydroxy propyl methyl cellulose phthalate HPMCP 50, 55 & 55-s (also called HP-50, HP-55 & HP-55-s) is widely used. HP-55 is recommended for general enteric preparation while HP-50 & HP-55-s for special cases. These polymers dissolve at a pH 5-5.5. iii. Polyvinyl acetate phthalate It is similar to HP-55 in stability and pH dependent solubility.
1.9.4.3.1 Enteric sugar coating (2)

Here the sealing coat is tailored to include one of the enteric polymers in sufficient quantity to pass the enteric test for disintegration. The sub coating and subsequent coating steps are then as for conventional sugar coating.
1.9.4.3.2 Enteric film coating (2)

Enteric polymers are capable of forming a direct film in a film coating process. Sufficient weight of enteric polymer has to be used to ensure an efficient enteric effect. Enteric coating can be combined with polysaccharides, which are enzyme degraded in colon e.g. Cyclodextrin & galactomannan.
1.9.4.3.3 Controlled release coating (2)

Polymers like modified acrylates, water insoluble cellulose (ethyl cellulose), etc. used for control release coating. 1.9.4.4 Specialized coating (1)
1.9.4.4.1 Compressed coating

This type of coating requires a specialization tablet machine. Compression coating is not widely used but it has advantages in some cases in which the tablet core cannot tolerate organic solvent or water and yet needs to be coated for taste masking or to provide delayed or enteric properties to the finished product and also to avoid incompatibility by separating incompatible ingredients.

1.9.4.4.2 Electrostatic coating

Electrostatic coating is an efficient method of applying coating to conductive substrates. A strong electrostatic charge is applied to the substrate. The coating material containing conductive ionic species of opposite charge is sprayed onto the charged substrate. Complete and uniform coating of corners and adaptability of this method to such relatively nonconductive substrate as pharmaceutical is limited.
1.9.4.4.3 Dip coating

Coating is applied to the tablet cores by dipping them into the coating liquid. The wet tablets are dried in a conventional manner in coating pan. Alternative dipping and drying steps may be repeated several times to obtain the desired coating. This process lacks the speed, versatility, and reliability of spray-coating techniques. Specialized equipment has been developed to dip-coat tablets, but no commercial pharmaceutical application has been obtained.
1.9.4.4.4 Vacuum film coating

Vacuum film coating is a new coating procedure that employs a specially designed baffled pan. The pan is hot water jacketed, and it can be sealed to achieve a vacuum system. The tablets are placed in the sealed pan, and the air in the pan is displaced by nitrogen before the desired vacuum level is obtained. The coating solution is then applied with airless spray system. The evaporation is caused by the heated pan, and the vapour is removed by the vacuum system. Because there is no high-velocity heated air, the energy requirement is low and coating efficiency is high. Organic solvent can be effectively used with this coating system with minimum environmental or safety concerns.

1.9.5 Equipments
Three general types of equipments are available 1. Standard coating pan e.g., Pellegrin pan system Immersion sword system Immersion tube system 2. Perforated pan system e.g., Accela cota system Hicoater system

Glattcoater system Driacoated system 3. Fluidized bed coater

1.9.6 Process parameters
Air capacity: This value represents the quantity of water or solvent that can be removed during the coating process which depends on the quantity of air flowing through the tablet bed, temperature of the air and quantity of water that the inlet air contains. Coating composition: The coating contains the ingredients that are to be applied on the tablet surface and solvents which act as carrier for the ingredients. Tablet surface area: It plays an important role for uniform coating. The total surface area for unit weight decreases significantly from smaller to larger tablets. Application of a film with the same thickness requires less coating composition. In the coating process only a portion of the total surface is coated. Continuous partial coating and recycling eventually results in fully coated tablets. Equipment efficiency: Tablet coaters use the expression “coating efficiency” a value obtained by dividing the net increase in coated tablet weight by the total nonvolatile coating weight applied to the tablet. Ideally 90-95 % of the applied film coating should be on the tablet surface. Coating efficiency for conventional sugar coating is much less and 60% would be acceptable. The significant difference in coating efficiency between film and sugar coating relates to the quantity of coating material that collects on the wall. Key Phrases Ø The sugar coating involves several steps like, sealing, subcoating, colour coating and printing. Ø Sugar coating process yields elegant and highly glossed tablet. Ø Newer techniques utilize spraying systems and varying degree of automation to improve coating efficiency and product uniformity. Ø Film coating is deposition of a thin film of polymer surrounding the tablet core.

Ø Film coating is more favored than sugar coating because weight increase is 2-3%, single stage process, easily adaptable to controlled release, it retains colour of original core, high adaptability to GMP, automation is possible, etc. Ø Accela cota and fluidized bed equipments are widely used for film coating Ø Basic formula is obtained from past experience or from literature and modifications are made accordingly. Common modifications are to alter polymer-to-plasticizer ratio or addition of different plasticizer/polymer. Experimentation of this type can be best achieved by fractional factorial study. Ø Materials used in film coating include film formers, solvents, plasticizers, colourants, opaquant-extenders, surfactant, anti oxidant, etc. Ø Widely used film formers are Hydroxy Propyl Methyl Cellulose (HPMC),Methyl Hydroxy Ethyl Cellulose (MHEC), Ethyl Cellulose (EC), Hydroxy Propyl Cellulose (HPC), PovidoneÒ (four grades available i.e. K-15, K-30, K-60and K-90), Sodium carboxy methyl cellulose, Polyethylene glycols (PEG) and Acrylate polymers (EudragitÒ, EudragitÒRL, EudragitÒRS, EudragitÒE) are used for film coating. Eudragit®L & S are used for enteric coating. Eudragit®RL, Eudragit®RS, Eudragit®S are available as organic solution and solid while Eudragit®L and Eudragit®E are available as organic, solid or aqueous dispersion. Ø Quality of film can be modified by plasticizer. Commonly used plasticizers include PG, glycerin, low molecular weight PEG, castor oils, etc. Castor oil and spans are more used for organic-solvent based coating solution while PE and PEG are used for aqueous coating. Ø FD & C or D & C certified colourants are used. Lakes are choice for film coating as they give reproducible results. Opaspray® (opaque colour concentrate for film coating) and Opadry® (complete film coating concentrate) are promoted as achieving less lot-to-lot variation. Ø Colourants are expensive and higher concentration is required. So materials like titanium dioxides,

silicates, and carbonates are used to provide more pastel colours and increase film coverage. Enteric Coating: Ø Enteric coating is used to protect tablet core from disintegration in the acid environment of stomach to prevent degradation of acid sensitive API, prevent irritation to stomach by certain drugs, delivery of API into intestine, to provide a delayed release components for repeat action, etc. Ø Several kinds of enteric layer systems are available like one layer system and two-layer system. Polymers used for enteric coating are cellulose Acetate Phthalate (CAP), Acrylates (Eudragit®L and Eudragit®S, Hydroxy Propyl Methyl Cellulose Phthalate (HPMCP50, HPMCP55 & HPMCP 55s) and polyvinyl acetate phthalate Enteric sugar coating: Ø Here sealing coat is modified to comprise one of the enteric polymers in sufficient quantity to pass the enteric test for disintegration. The sub coating and subsequent coating steps are then as for conventional sugar coating. Ø Enteric polymers are capable of forming a direct film in a film coating process. Sufficient weight of enteric polymer has to be used to ensure an efficient enteric effect. Ø Enteric coating can be combined with polysaccharides, which are enzymatically degraded in colon. For example, Cyclodextrin & Galactomannan. Controlled release coating: Ø Polymers like modified acrylates, ethyl cellulose, etc are used for the same.

Problems in tablet manufacture and related remedies

Submitted by Mukesh C Gohel on Sun, 12/06/2009 - 19:54

1.10 Problems In Tablet Manufacture And Related Remedies
What will you gain? 1.10.1 Introduction 1.10.1.1 Capping 1.10.1.2 Lamination / Laminating 1.10.1.3 Chipping 1.10.1.4 Cracking 1.10.1.5 Sticking / Filming 1.10.1.6 Picking 1.10.1.7 Binding 1.10.1.8 Mottling 1.10.1.9 Double impression 1.10.2 Problems and Remedies for tablet coating 1.10.2.1 Blistering 1.10.2.2 Chipping 1.10.2.3 Cratering 1.10.2.4 Picking 1.10.2.5 Pitting 1.10.2.6 Blooming

1.10.2.7 Blushing 1.10.2.8 Colour variation 1.10.2.9 Infilling 1.10.2.10 Orange peel/Roughness 1.10.2.11 Cracking/Splitting

1.10.1 Introduction (62,63)
An ideal tablet should be free from any visual defect or functional defect. The advancements and innovations in tablet manufacture have not decreased the problems, often encountered in the production, instead have increased the problems, mainly because of the complexities of tablet presses; and/or the greater demands of quality. An industrial pharmacist usually encounters number of problems during manufacturing. Majority of visual defects are due to inadequate fines or inadequate moisture in the granules ready for compression or due to faulty machine setting. Functional defects are due to faulty formulation. Solving many of the manufacturing problems requires an in–depth knowledge of granulation processing and tablet presses, and is acquired only through an exhaustive study and a rich experience. Here, we will discuss the imperfections found in tablets along–with their causes and related remedies. The imperfections are known as: ‘VISUAL DEFECTS’ and they are either related to imperfections in any one or more of the following factors: I. Tableting Process II. Excipient III. Machine The defects related to Tableting Process are as follows:

i) CAPPING: It is due air-entrapment in the granular material. ii) LAMINATION: It is due air-entrapment in the granular material. iii) CRACKING: It is due to rapid expansion of tablets when deep concave punches are used. The defects related to Excipient are as follows: iv) CHIPPING: It is due to very dry granules v) STICKING vi) PICKING vii) BINDING These problems (v, vi, vii) are due to more amount of binder in the granules or wet granules. The defect related to more than one factor: viii) MOTTLING: It is either due to any one or more of these factors: Due to a coloured drug, which has different colour than the rest of the granular material? (Excipient- related); improper mixing of granular material (Process-related); dirt in the granular material or on punch faces; oil spots by using oily lubricant. The defect related to Machine ix) DOUBLE IMPRESSION: It is due to free rotation of the punches, which have some engraving on the punch faces. Further, in this section, each problem is described along-with its causes and remedies which may be related to either of formulation (granulation) or of machine (dies, punches and entire tablet press).

1.10.1.1 Capping (1,5)
Definition: ‘Capping’ is the term used, when the upper or lower segment of the tablet

separates horizontally, either partially or completely from the main body of a tablet and comes off as a cap, during ejection from the tablet press, or during subsequent handling. Reason: Capping is usually due to the air–entrapment in a compact during compression, and subsequent expansion of tablet on ejection of a tablet from a die. Table.27. The Causes And Remedies Of Capping Related To ‘Formulation’ (Granulation) Sr. No. CAUSES REMEDIES 1. Large amount of fines in Remove some or all fines the granulation through 100 to 200 mesh screen 2. Too dry or very low Moisten the granules moisture content (leading to loss of suitably. Add hygroscopic substance e.g.: proper binding action). sorbitol, methyl- cellulose or PEG-4000. 3. Not thoroughly dried Dry the granules properly. granules. 4. Insufficient amount of Increasing the mount of binder or improper binder. binder OR Adding dry binder such as pre-gelatinized starch, gum acacia, powdered sorbitol, PVP, hydrophilic silica or powdered sugar. Increase the amount of lubricant or change the type of lubricant. Compress at room temperature.

5. 6.

Insufficient or improper lubricant. Granular mass too cold to compress firm.

Table.28. The Causes And Remedies Of Capping Related To ‘Machine’ (Dies, Punches And Tablet Press) Sr. No. CAUSES 1. Poorly finished dies REMEDIES Polish dies properly. Investigate other steels or other materials. Use flat punches. Make proper setting of lower punch during ejection. Adjust sweep-off blade correctly to facilitate proper ejection. Reduce speed of turret

2. 3. 4.

Deep concave punches or beveled-edge faces of punches. Lower punch remains below the face of die during ejection. Incorrect adjustment of sweep-off blade. High turret speed.

5.

(Increase dwell time). 1.10.1.2 Lamination / Laminating (1,5) Definition: ‘Lamination’ is the separation of a tablet into two or more distinct horizontal layers. Reason: Air–entrapment during compression and subsequent release on ejection. The condition is exaggerated by higher speed of turret. Table.29. The Causes And Remedies Of Lamination Related To Formulation (Granulation) Sr. No. CAUSES 1. Oily or waxy materials in granules 2. Too much of hydrophobic lubricant e.g.: Magnesiumstearate. REMEDIES Modify mixing process. Add adsorbent or absorbent. Use a less amount of lubricant or change the type of lubricant.

Table.30. The Causes And Remedies Of Lamination Related To Machine (Dies, Punches And Tablet Press) Sr. No. CAUSES 1. Rapid relaxation of the peripheral regions of a tablet, on ejection from a die. 2. Rapid decompression REMEDIES Use tapered dies, i.e. upper part of the die bore has an outward taper of 3° to 5°. Use pre-compression step. Reduce turret speed and reduce the final compression pressure.

1.10.1.3 Chipping (1) Definition: ‘Chipping’ is defined as the breaking of tablet edges, while the tablet leaves the press or during subsequent handling and coating operations. Reason: Incorrect machine settings, specially mis-set ejection take-off. Table.31. The Causes And Remedies Of Chipping Related To Formulation (Granulation) Are As Follows

Sr. No. CAUSES 1. Sticking on punch faces 2. 3. Too dry granules. Too much binding causes chipping at bottom.

REMEDIES Dry the granules properly or increase lubrication. Moisten the granules to plasticize. Add hygroscopic substances. Optimize binding, or use dry binders.

Table.32. The Causes And Remedies Of Chipping Related To Machine (Dies, Punches And Tablet Press) Sr. No. CAUSES 1. Groove of die worn at compression point. 2. Barreled die (center of the die wider than ends) 3. Edge of punch face turned inside/inward. 4. Concavity too deep to compress properly. 1.10.1.4 Cracking (1) Definition: Small, fine cracks observed on the upper and lower central surface of tablets, or very rarely on the sidewall are referred to as ‘Cracks’. Reason: It is observed as a result of rapid expansion of tablets, especially when deep concave punches are used. Table.33. The Causes And Remedies Of Cracking Related To Formulation (Granulation) Sr. No. CAUSES 1. Large size of granules. 2. 3. 4. Too dry granules. Tablets expand. Granulation too cold. REMEDIES Reduce granule size. Add fines. Moisten the granules properly and add proper amount of binder. Improve granulation. Add dry binders. Compress at room temperature. REMEDIES Polish to open end, reverse or replace the die. Polish the die to make it cylindrical Polish the punch edges Reduce concavity of punch faces. Use flat punches.

Table.33. The Causes And Remedies Of Cracking Related To Formulation (Granulation)

Sr. No. CAUSES 1. Tablet expands on ejection due to air entrapment. 2. Deep concavities cause cracking while removing tablets 1.10.1.5 Sticking / Filming (1)

REMEDIES Use tapered die. Use special take-off.

Definition: ‘Sticking’ refers to the tablet material adhering to the die wall. Filming is a slow form of sticking and is largely due to excess moisture in the granulation. Reason: Improperly dried or improperly lubricated granules. Table.35. The Causes And Remedies Of Sticking Related To Formulation (Granulation) Sr. No. CAUSES 1. Granules not dried properly. 2. 3. 4. 5. 6. Too little or improper lubrication. Too much binder Hygroscopic granular material. Oily or way materials Too soft or weak granules. REMEDIES Dry the granules properly. Make moisture analysis to determine limits. Increase or change lubricant. Reduce the amount of binder or use a different type of binder. Modify granulation and compress under controlled humidity. Modify mixing process. Add an absorbent. Optimize the amount of binder and granulation technique.

Table.36. The Causes And Remedies Of Sticking Related To Machine (Dies, Punches And Tablet Press) Sr. No. CAUSES 1. Concavity too deep for granulation. 2. Too little pressure. 3. Compressing too fast. 1.10.1.6 Picking (1) REMEDIES Reduce concavity to optimum. Increase pressure. Reduce speed.

Definition: ‘Picking’ is the term used when a small amount of material from a tablet is sticking to and being removed off from the tablet-surface by a punch face. The problem is more prevalent on the upper punch faces than on the lower ones. The problem worsens, if tablets are repeatedly manufactured in this station of tooling because of the more and more material getting added to the already stuck material on the punch face. Reason: Picking is of particular concern when punch tips have engraving or embossing letters, as well as the granular material is improperly dried. Table.37. The Causes And Remedies Of Picking Related To Formulation (Granulation) Sr. No. CAUSES 1. Excessive moisture in granules. 2. Too little or improper lubrication. REMEDIES Dry properly the granules, determine optimum limit. Increase lubrication; use colloidal silica as a ‘polishing agent’, so that material does not cling to punch faces. Add high melting-point materials. Use high meting point lubricants. Refrigerate granules and the entire tablet press. Compress at room temperature. Cool sufficiently before compression. Reduce the amount of binder, change the type or use dry binders.

3.

4. 5.

Low melting point substances, may soften from the heat of compression and lead to picking. Low melting point medicament in high concentration. Too warm granules when compressing. Too much amount of binder.

6.

Table.38. The Causes And Remedies Of Picking Related To Machine (Dies, Punches And Tablet Press) Sr. No. CAUSES 1. Rough or scratched punch faces. 2. Embossing or engraving letters on punch faces such as B, A, O, R, P, Q, G. REMEDIES Polish faces to high luster. Design lettering as large as possible. Plate the punch faces with chromium to produce a smooth and nonadherent face.

3. 4.

Bevels or dividing lines too deep. Pressure applied is not enough; too soft tablets.

Reduce depths and sharpness. Increase pressure to optimum.

1.10.1.7 Binding (1) Definition: ‘Binding’ in the die, is the term used when the tablets adhere, seize or tear in the die. A film is formed in the die and ejection of tablet is hindered. With excessive binding, the tablet sides are cracked and it may crumble apart. Reason: Binding is usually due to excessive amount of moisture in granules, lack of lubrication and/or use of worn dies. Table.39. The Causes And Remedies Of Binding Related To Formulation (Granulation) Sr. No. CAUSES 1. Too moist granules and extrudes around lower punch. 2. Insufficient or improper lubricant. 3. Too coarse granules. REMEDIES Dry the granules properly. Increase the amount of lubricant or use a more effective lubricant. Reduce granular size, add more fines, and increase the quantity of lubricant. Modify granulation. Reduce granular size. If coarse granules, reduce its size. Use wear-resistant dies. Reduce temperature. Increase clearance if it is extruding. Table.40. The Causes And Remedies Of Binding Related To Machine (Dies, Punches And Tablet Press) Sr. No. CAUSES 1. Poorly finished dies. 2. Rough dies due to REMEDIES Polish the dies properly. Investigate other steels

4. 5.

Too hard granules for the lubricant to be effective. Granular material very abrasive and cutting into dies.

6.

Granular material too warm, sticks to the die.

3.

abrasion, corrosion. Undersized dies. Too little clearance. Too much pressure in the tablet press.

or other materials or modify granulation. Rework to proper size. Increase clearance. Reduce pressure. OR Modify granulation.

4.

1.10.1.8 Mottling (1) Definition: ‘Mottling’ is the term used to describe an unequal distribution of colour on a tablet, with light or dark spots standing out in an otherwise uniform surface. Reason: One cause of mottling may be a coloured drug, whose colour differs from the colour of excipients used for granulation of a tablet. Table.41. The Causes And Remedies Of Mottling Sr. No. CAUSES 1. A coloured drug used along with colourless or whitecoloured excipients. 2. A dye migrates to the surface of granulation while drying. REMEDIES Use appropriate colourants. Change the solvent system, Change the binder, Reduce drying temperature and Use a smaller particle size. Mix properly and reduce size if it is of a larger size to prevent segregation. Incorporate dry colour additive during powder blending step, then add fine powdered adhesives such as acacia and tragacanth and mix well and finally add granulating liquid.

3.

4.

Improperly mixed dye, especially during ‘Direct Compression’. Improper mixing of a coloured binder solution.

1.10.1.9 Double impression (1) Definition: ‘Double Impression’ involves only those punches, which have a monogram or other engraving on them.

Reason: At the moment of compression, the tablet receives the imprint of the punch. Now, on some machines, the lower punch freely drops and travels uncontrolled for a short distance before riding up the ejection cam to push the tablet out of the die, now during this free travel, the punch rotates and at this point, the punch may make a new impression on the bottom of the tablet, resulting in ‘Double Impression’. If the upper punch is uncontrolled, it can rotate during the short travel to the final compression stage and create a double impression. Table.42. The Causes And Remedies Of Double Impression Sr. No. CAUSE 1. Free rotation of either upper punch or lower punch during ejection of a tablet. REMEDIES -Use keying in tooling, i.e. inset a key alongside of the punch, so that it fits the punch and prevents punch rotation. -Newer presses have anti-turning devices, which prevent punch rotation.

1.10.2 Problems and remedies for tablet coating
1.10.2.1 Blistering (1,64) Definition: It is local detachment of film from the substrate forming blister. Reason: Entrapment of gases in or underneath the film due to overheating either during spraying or at the end of the coating run. Table.43. The Cause And Remedy Of Blistering Sr. No. CAUSE REMEDY 1. Effect of temperature on Use mild drying condition. the strength, elasticity and adhesion of the film. 1.10.2.2 Chipping (1,64) Definition: It is defect where the film becomes chipped and dented, usually at the edges of the tablet. Reason: Decrease in fluidizing air or speed of rotation of the drum in pan coating.

Table.44. The Cause And Remedy Of Chipping Sr. No. CAUSE 1. High degree of attrition associated with the coating process. REMEDY Increase hardness of the film by increasing the molecular weight grade of polymer.

1.10.2.3 Cratering (1,64) Definition: It is defect of film coating whereby volcanic-like craters appears exposing the tablet surface. Reason: The coating solution penetrates the surface of the tablet, often at the crown where the surface is more porous, causing localized disintegration of the core and disruption of the coating. Table.45. The Causes And Remedies Of Cratering Sr. No. CAUSES 1. Inefficient drying. REMEDIES Use efficient and optimum drying conditions. Increase viscosity of coating solution to decrease spray application rate.

2.

Higher rate of application of coating solution.

1.10.2.4 Picking (1,64) Definition: It is defect where isolated areas of film are pulled away from the surface when the tablet sticks together and then part. Reason: Conditions similar to cratering that produces an overly wet tablet bed where adjacent tablets can stick together and then break apart. Table.46. The Causes And Remedies Of Picking Sr. No. 1. CAUSE REMEDY

Inefficient drying.

Use optimum and efficient drying conditions or increase the inlet air temperature.

2.

Higher rate of application of coating solution

Decrease the rater of application of coating solution by increasing viscosity of coating solution.

1.10.2.5 Pitting (1,64) Definition: It is defect whereby pits occur in the surface of a tablet core without any visible disruption of the film coating. Reason: Temperature of the tablet core is greater than the melting point of the materials used in the tablet formulation. Table.47. The Cause And Remedy Of Pitting Sr. No. CAUSE 1. Inappropriate drying (inlet air ) temperature REMEDY Dispensing with preheating procedures at the initiation of coating and modifying the drying (inlet air) temperature such that the temperature of the tablet core is not greater than the melting point of the batch of additives used.

1.10.2.6 Blooming (1,64) Definition: It is defect where coating becomes dull immediately or after prolonged storage at high temperatures. Reason: It is due to collection on the surface of low molecular weight ingredients included in the coating formulation. In most circumstances the ingredient will be plasticizer. Table.48. The Cause And Remedy Of Blooming Sr. No. CAUSE 1. High concentration and low molecular weight of plasticizer. REMEDY Decrease plasticizer concentration and increase molecular weight of plasticizer.

1.10.2.7 Blushing (1,64) Definition: It is defect best described as whitish specks or haziness in the film.

Reason: It is thought to be due to precipitated polymer exacerbated by the use of high coating temperature at or above the thermal gelation temperature of the polymers. Table.49. The Causes And Remedies Of Blushing Sr. No. CAUSES 1. High coating temperature 2. Use of sorbitol in formulation which causes largest fall in the thermal gelation temperature of the Hydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose, Methyl Cellulose and Cellulose ethers. REMEDIES Decrease the drying air temperature Avoid use of sorbitol with Hydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose, Methyl Cellulose and Cellulose ethers.

1.10.2.8 Colour variation (1,64) Definition: A defect which involves variation in colour of the film. Reason: Alteration of the frequency and duration of appearance of tablets in the spray zone or the size/shape of the spray zone. Table.50. The Cause And Remedy Of Colour Variation Sr. No. CAUSE 1. Improper mixing, uneven spray pattern, insufficient coating, migration of soluble dyesplasticizers and other additives during drying. 1.10.2.9 Infilling (1,64) Definition: It is defect that renders the intagliations indistinctness. Reason: Inability of foam, formed by air spraying of a polymer solution, to break. The foam droplets on the surface of the tablet breakdown readily due to attrition but the intagliations form a protected area allowing the foam to accumulate and “set”. Once the foam has accumulated to a level approaching the outer contour of the tablet surface, normal REMEDY Go for geometric mixing, reformulation with different plasticizers and additives or use mild drying conditions.

attrition can occur allowing the structure to be covered with a continuous film. Table.51. The Cause And Remedy Of Infilling Sr. No. CAUSE 1. Bubble or foam formation because of air spraying of a polymer solution 1.10.2.10 Orange peel/Roughness (1,64) Definition: It is surface defect resulting in the film being rough and nonglossy. Appearance is similar to that of an orange. Reason: Inadequate spreading of the coating solution before drying. Table.52. The Causes And Remedies Of Orange Peel/Roughness Sr. No. CAUSES 1. Rapid Drying 2. High solution viscosity REMEDIES Use mild drying conditions Use additional solvents to decrease viscosity of solution. REMEDY Add alcohol or use spray nozzle capable of finer atomization.

1.10.2.11 Cracking/Splitting (1,64) Definition: It is defect in which the film either cracks across the crown of the tablet (cracking) or splits around the edges of the tablet (Splitting) Reason: Internal stress in the film exceeds tensile strength of the film. Table.53. The Cause And Remedy Of Cracking/Splitting Sr. No. CAUSE 1. Use of higher molecular weight polymers or polymeric blends. REMEDY Use lower molecular weight polymers or polymeric blends. Also adjust plasticizer type and concentration. Key Phrases Ø During tablet manufacture, an industrial pharmacist usually encounters many problems.

Solving these problems requires an indepth knowledge of tablet-formulation as well as machine-operating processes. Ø Capping and Lamination are the defects arising as a result of air-entrapment in the granular material. Ø Chipping is a defect related arising due to very dry granules. Ø Cracking is due to rapid expansion of tablets, when deep concave punches are used. Ø Sticking, Picking and Binding are the imperfections related to more amount of binder in granules. Ø Mottling is an imperfection arising due to more than one factor: a coloured drug, dirt in granules or the use of an oily lubricant. Ø Double-Impression is related to a machine defect: it is caused by the free rotation of punches that have some engraving on the punchfaces. Coating defects: Ø Blistering is related to entrapment of gases in or underneath the film due to overheating either during spraying or at the end of the coating run. Use of mild drying conditions can solve this problem. Ø Chipping is related to higher degree of attrition associated with the coating process. Increase in hardness of the film by increasing the molecular weight grade of polymer can solve this

problem. Ø Cratering is related to penetration of the coating solution into the surface of the tablet, often at the crown where the surface is more porous, causing localized disintegration of the core and disruption of the coating. Decrease in spray application rate and use of optimum and efficient drying conditions can solve this problem. Ø Pitting is defect in which temperature of the tablet core is greater than the melting point of the materials used in tablet formulation. Dispensing with preheating procedures at the initiation of coating and modifying the drying (inlet air) temperature can solve this problem. Ø Blooming or dull film is generally because of higher concentration and lower molecular weight of plasticizer. So use lower concentration and higher molecular grade of plasticizer. Ø Blushing/Whitish specks/Haziness of the film is related to precipitation of polymer exacerbated by the use of high coating temperature at or above the thermal gelation temperature of the polymers. Ø Colour variation is because of improper mixing, uneven spray pattern, insufficient coating or migration of soluble dyes during drying. Geometric mixing, mild drying conditions and reformulation with different plasticizers can solve this problem. Ø Infilling is because of bubble/foam formation during air spraying of a polymer

solution. Addition of alcohol or use of spray nozzle capable of finer atomization can solve this problem. Ø Orange peel/Roughness is related to inadequate spreading of the coating solution before drying. So decrease in viscosity of coating solution can counter this defect. Ø Cracking is seen when internal stresses in the film exceeds tensile strength of the film. This is common with higher molecular weight polymers or polymeric blends. So use lower molecular weight polymers or polymeric blends.

Quality Control tests for tablets

Submitted by Mukesh C Gohel on Sun, 12/06/2009 - 19:55

1.11 Quality Control Tests for Tablets
What will you gain? 1.11.1 Official Standards as per I.P. / B.P. / U.S.P. 1.11.2 Non – compendial standards 1.11.3 In – Process Quality Control

1.11.1 Official Standards as per I.P. / B.P. / U.S.P. (65-67)

Table: 54. Comparison Of Different Pharmacopoeial Quality Control Tests PHARMACOPOEIAS TYPE OF TABLET TESTS TO BE PERFORMED BRITISH For all tablets Content of active PHARMACOPOEIA ingredients Disintegration Uniformity of content Labeling Disintegration test Uniformity of weight Disintegration test Uniformity of weight Disintegration test

Uncoated tablet

Effervescent tablet

Coated tablet

Uniformity of weight Gastro resistant tablet Disintegration test Modified release tablet Uniformity of weight Tablet for use in mouth Uniformity of weight Soluble tablet Disintegration test Uniformity of weight Disintegration test Uniformity of dispersion Uniformity of weight Uniformity of container content Content of active ingredient Uniformity of weight Uniformity of content Disintegration test Disintegration test Uniformity of dispersion Disintegration Disintegration

Dispersible tablet

INDIAN PHARMACOPOEIA

Uncoated tablet

Enteric coated tablet Dispersible tablet

Soluble tablet

Effervescent tablet

Disintegration/ Dissolution / Dispersion test Bulk density /Tapped density of powder Powder fineness Loss on drying Disintegration test Tablet friability Dissolution test Drug release testing Uniformity of dosage form Container permeation test Labeling of inactive ingredients

UNITED STATES PHARMACOPOEIA

Physical tests applicable to tablet formulation

1.11.2 Non – compendial standards (2,13)
Measurement of mechanical properties is not covered pharmacopoeial monograph. There are also a number of tests frequently applied to tablets for which there are no pharmacopoeial requirement but will form a part of a manufacturer’s own product specification. I.Hardness tests/ Crushing strength The test measures crushing strength property defined as the compressional force applied diametrically to a tablet which just fractures it. Among a large number of measuring devices, the most favored ones are Monsanto tester, Pfizer tester, and Strong cobb hardness tester. All are manually used. So, strain rate depends on the operator. Heberlein Schleuniger, Erweka, Casburt hardness testers are motor driven. II.Friability (Official in USP)

The tablet may well be subjected to a tumbling motion. For example, Coating, packaging, transport, which are not severe enough to break the tablet, but may abrade the small particle from tablet surface. To examine this, tablets are subjected to a uniform tumbling motion for specified time and weight loss is measured. Roche friabilator is most frequently used for this purpose. Tests for coated tablets I. Water vapor permeability II. Film tensile strength III.Coated tablet evaluations: i)Adhesion test with tensile-strength tester: Measures force required toe peel the film from the tablet surface ii)Diametral crushing strength of coated tablet: Tablet hardness testers are used. This test gives information on the relative increase in crushing strength provided by the film and the contribution made by changes in the film composition iii)Temperature and humidity may cause film defects. Hence studies are to be carried out iv)Quantification of film surface roughness, hardness, & colour uniformity. Visual inspection or instruments are used. Resistance of coated tablet on a white sheet of paper. Resisilient films remain intact, & no colour is transferred to the paper; very soft coating are readily “erased” from the tablet surface to the paper

1.11.3 In – Process Quality Control (13)
The control of the tableting process in production is concerned with the following : I. Weight of tablet – Single pan electric balance. II. Crushing strength – Controls friability and disintegration time. III. Tablet thickness – Very thick tablet affect packaging particularly into blisters.

IV. Disintegration time. V. Friability As a part of Current Good Manufacturing Practice (cGMP), the production run is monitored under control chart. At regular interval (10 – 15minutes) the operator must sample specified number of tablets, weigh them individually, check thickness, crushing strength and all the properties as mentioned above. The process can be automated and interfaced with printer. Such data promotes process improvement. Key Phrases ØUSP mentions some of the quality control tests to be performed before the powder is compressed. e.g., powder fineness, density. etc. ØFriability is official test as per USP. ØAt regular interval (10 – 15minutes) during the course of manufacturing the operator must sample specified number of tablets for testing.

Tablet:Problems in tablet manufacturing
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Contents
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1 Introduction o 1.1 Capping o 1.2 Lamination / Laminating o 1.3 Chipping o 1.4 Cracking o 1.5 Sticking / Filming o 1.6 Picking o 1.7 Binding o 1.8 Mottling o 1.9 Double impression 2 Problems and remedies for tablet coating o 2.1 Blistering o 2.2 Chipping o 2.3 Cratering o 2.4 Picking o 2.5 Pitting o 2.6 Blooming o 2.7 Blushing o 2.8 Colour variation o 2.9 Infilling o 2.10 Orange peel/Roughness o 2.11 Cracking/Splitting 3 Key Phrases



Introduction
(62,63) An ideal tablet should be free from any visual defect or functional defect. The advancements and innovations in tablet manufacture have not decreased the problems, often encountered in the production, instead have increased the problems, mainly because of the complexities of tablet presses; and/or the greater demands of quality. An industrial pharmacist usually encounters number of problems during manufacturing. Majority of visual defects are due to inadequate fines or inadequate moisture in the granules ready for compression or due to faulty machine setting. Functional defects are due to faulty formulation. Solving many of the manufacturing problems requires an in–depth knowledge of granulation processing and tablet presses, and is acquired only through an exhaustive study and a rich experience. Here, we will discuss the imperfections found in tablets along–with their causes and related remedies. The imperfections are known as: ‘VISUAL DEFECTS’ and they are either related to imperfections in any one or more of the following factors:

I. Tableting Process II. Excipient III. Machine The defects related to Tableting Process are as follows: i) CAPPING: It is partial or complete separation of the top or bottom of tablet due airentrapment in the granular material. ii) LAMINATION: It is separation of tablet into two or more layers due to airentrapment in the granular material. iii) CRACKING: It is due to rapid expansion of tablets when deep concave punches are used. The defects related to Excipient are as follows: iv) CHIPPING: It is due to very dry granules. v) STICKING: It is the adhesion of granulation material to the die wall vi) PICKING: It is the removal of material from the surface of tablet and its adherance to the face of punch. vii) BINDING These problems (v, vi, vii) are due to more amount of binder in the granules or wet granules. The defect related to more than one factor: viii) MOTTLING: It is either due to any one or more of these factors: Due to a coloured drug, which has different colour than the rest of the granular material? (Excipient- related); improper mixing of granular material (Process-related); dirt in the granular material or on punch faces; oil spots by using oily lubricant. The defect related to Machine ix)DOUBLE IMPRESSION: It is due to free rotation of the punches, which have some engraving on the punch faces. Further, in this section, each problem is described along-with its causes and remedies which may be related to either of formulation (granulation) or of machine (dies, punches and entire tablet press).

Capping
(1,5) ‘Capping’ is the term used, when the upper or lower segment of the tablet separates horizontally, either partially or completely from the main body of a tablet and comes off as a cap, during ejection from the tablet press, or during subsequent handling. Reason: Capping is usually due to the air–entrapment in a compact during compression, and subsequent expansion of tablet on ejection of a tablet from a die. TABLE.27. THE CAUSES AND REMEDIES OF CAPPING RELATED TO ‘FORMULATION’ (GRANULATION) Sr. CAUSES No. Large amount of fines in the 1. granulation Too dry or very low moisture 2. content (leading to loss of proper binding action). 3. Not thoroughly dried granules. REMEDIES Remove some or all fines through 100 to 200 mesh screen Moisten the granules suitably. Add hygroscopic substance e.g.: sorbitol, methyl- cellulose or PEG-4000. Dry the granules properly. Increasing the mount of binder OR

4.

5. 6.

Insufficient amount of binder or Adding dry binder such as pre-gelatinized improper binder. starch, gum acacia, powdered sorbitol, PVP, hydrophilic silica or powdered sugar. Insufficient or improper Increase the amount of lubricant or change the lubricant. type of lubricant. Granular mass too cold to Compress at room temperature. compress firm.

TABLE.28. THE CAUSES AND REMEDIES OF CAPPING RELATED TO ‘MACHINE’ (DIES, PUNCHES AND TABLET PRESS) Sr. No. 1. 2. 3. 4. 5. CAUSES Poorly finished dies Deep concave punches or bevelededge faces of punches. Lower punch remains below the face of die during ejection. Incorrect adjustment of sweep-off blade. High turret speed. REMEDIES Polish dies properly. Investigate other steels or other materials. Use flat punches. Make proper setting of lower punch during ejection. Adjust sweep-off blade correctly to facilitate proper ejection. Reduce speed of turret (Increase dwell

time).

Lamination / Laminating
(1,5) Definition: ‘Lamination’ is the separation of a tablet into two or more distinct horizontal layers. Reason: Air–entrapment during compression and subsequent release on ejection. The condition is exaggerated by higher speed of turret. TABLE.29. THE CAUSES AND REMEDIES OF LAMINATION RELATED TO FORMULATION (GRANULATION) Sr. No. 1. 2. CAUSES Oily or waxy materials in granules Too much of hydrophobic lubricant e.g.: Magnesiumstearate. REMEDIES Modify mixing process. Add adsorbent or absorbent. Use a less amount of lubricant or change the type of lubricant.

TABLE.30. The Causes and Remedies of Lamination related to MACHINE (Dies, Punches and Tablet Press)

Sr. CAUSES REMEDIES</ b> No. Rapid relaxation of the peripheral Use tapered dies, i.e. upper part of the die 1. regions of a tablet, on ejection from a bore has an outward taper of 3° to 5°. die. Use pre-compression step. Reduce turret 2. Rapid decompression speed and reduce the final compression pressure.

Chipping
(1) Definition: ‘Chipping’ is defined as the breaking of tablet edges, while the tablet leaves the press or during subsequent handling and coating operations.

Reason: Incorrect machine settings, specially mis-set ejection take-off.

TABLE.31. THE CAUSES AND REMEDIES OF CHIPPING RELATED TO FORMULATION (GRANULATION) ARE AS FOLLOWS

Sr. No. 1. 2. 3.

CAUSES Sticking on punch faces Too dry granules. Too much binding causes chipping at bottom.

REMEDIES Dry the granules properly or increase lubrication. Moisten the granules to plasticize. Add hygroscopic substances. Optimize binding, or use dry binders.

TABLE.32. THE CAUSES AND REMEDIES OF CHIPPING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS) Sr. No. 1. 2. 3. 4. CAUSES Groove of die worn at compression point. Barreled die (center of the die wider than ends) Edge of punch face turned inside/inward. Concavity too deep to compress properly. REMEDIES Polish to open end, reverse or replace the die. Polish the die to make it cylindrical Polish the punch edges Reduce concavity of punch faces. Use flat punches.

Cracking
(1) Definition: Small, fine cracks observed on the upper and lower central surface of tablets, or very rarely on the sidewall are referred to as ‘Cracks’. Reason: It is observed as a result of rapid expansion of tablets, especially when deep concave punches are used.

TABLE.33. THE CAUSES AND REMEDIES OF CRACKING RELATED TO FORMULATION (GRANULATION) Sr. No. CAUSES REMEDIES 1. Large size of granules. Reduce granule size. Add fines. Moisten the granules properly and add proper 2. Too dry granules. amount of binder. 3. Tablets expand. Improve granulation. Add dry binders. 4. Granulation too cold. Compress at room temperature.

TABLE.34. THE CAUSES AND REMEDIES OF CRACKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS) Sr. No. CAUSES REMEDIES 1. Tablet expands on ejection due to air entrapment. Use tapered die. Deep concavities cause cracking while 2. Use special take-off. removing tablets

Sticking / Filming
(1) Definition: ‘Sticking’ refers to the tablet material adhering to the die wall. Filming is a slow form of sticking and is largely due to excess moisture in the granulation. Reason: Improperly dried or improperly lubricated granules. TABLE.35. THE CAUSES AND REMEDIES OF STICKING RELATED TO FORMULATION (GRANULATION) Sr. No. 1. 2. 3. CAUSES Granules not dried properly. Too little or improper lubrication. Too much binder REMEDIES Dry the granules properly. Make moisture analysis to determine limits. Increase or change lubricant. Reduce the amount of binder or use a different type of binder.

4. 5. 6.

Hygroscopic granular material. Oily or way materials

Modify granulation and compress under controlled humidity. Modify mixing process. Add an absorbent. Optimize the amount of binder and granulation Too soft or weak granules. technique.

TABLE.36. THE CAUSES AND REMEDIES OF STICKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS) Sr. No. 1. 2. 3. CAUSES Concavity too deep for granulation. Too little pressure. Compressing too fast. REMEDIES Reduce concavity to optimum. Increase pressure. Reduce speed.

Picking
(1) Definition: ‘Picking’ is the term used when a small amount of material from a tablet is sticking to and being removed off from the tablet-surface by a punch face. The problem is more prevalent on the upper punch faces than on the lower ones. The problem worsens, if tablets are repeatedly manufactured in this station of tooling because of the more and more material getting added to the already stuck material on the punch face. Reason: Picking is of particular concern when punch tips have engraving or embossing letters, as well as the granular material is improperly dried. TABLE.37. THE CAUSES AND REMEDIES OF PICKING RELATED TO FORMULATION (GRANULATION) Sr. CAUSES No. 1. 2. Excessive moisture in granules. Too little or improper lubrication. Low melting point substances, may soften from the heat of compression and lead to picking. Low melting point medicament in REMEDIES Dry properly the granules, determine optimum limit. Increase lubrication; use colloidal silica as a ‘polishing agent’, so that material does not cling to punch faces. Add high melting-point materials. Use high meting point lubricants. Refrigerate granules and the entire tablet

3. 4.

5. 6.

high concentration. Too warm granules when compressing. Too much amount of binder.

press. Compress at room temperature. Cool sufficiently before compression. Reduce the amount of binder, change the type or use dry binders.

TABLE.38. THE CAUSES AND REMEDIES OF PICKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS) Sr. No. 1. 2. 3. 4. CAUSES Rough or scratched punch faces. REMEDIES Polish faces to high luster. Design lettering as large as possible.

Embossing or engraving letters on punch faces such as B, A, O, R, P, Q, Plate the punch faces with chromium to G. produce a smooth and non-adherent face. Bevels or dividing lines too deep. Reduce depths and sharpness. Pressure applied is not enough; too Increase pressure to optimum. soft tablets.

Binding
(1) Definition: ‘Binding’ in the die, is the term used when the tablets adhere, seize or tear in the die. A film is formed in the die and ejection of tablet is hindered. With excessive binding, the tablet sides are cracked and it may crumble apart. Reason: Binding is usually due to excessive amount of moisture in granules, lack of lubrication and/or use of worn dies. TABLE.39. THE CAUSES AND REMEDIES OF BINDING RELATED TO FORMULATION (GRANULATION) Sr. No. 1. 2. 3. 4. CAUSES REMEDIES

Too moist granules and extrudes Dry the granules properly. around lower punch. Insufficient or improper Increase the amount of lubricant or use a more lubricant. effective lubricant. Reduce granular size, add more fines, and Too coarse granules. increase the quantity of lubricant. Too hard granules for the Modify granulation. Reduce granular size.

lubricant to be effective. 5. Granular material very abrasive and cutting into dies. Granular material too warm, sticks to the die. If coarse granules, reduce its size. Use wear-resistant dies. Reduce temperature. Increase clearance if it is extruding.

6.

TABLE.40. THE CAUSES AND REMEDIES OF BINDING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS) Sr. No. 1. 2. 3. CAUSES Poorly finished dies. Rough dies due to abrasion, corrosion. Undersized dies. Too little clearance. Too much pressure in the tablet press. REMEDIES Polish the dies properly. Investigate other steels or other materials or modify granulation. Rework to proper size. Increase clearance. Reduce pressure. OR Modify granulation.

4.

Mottling
(1) Definition: ‘Mottling’ is the term used to describe an unequal distribution of colour on a tablet, with light or dark spots standing out in an otherwise uniform surface. Reason: One cause of mottling may be a coloured drug, whose colour differs from the colour of excipients used for granulation of a tablet. TABLE.41. THE CAUSES AND REMEDIES OF MOTTLING Sr. CAUSES REMEDIES No. A coloured drug used along 1. with colourless or whiteUse appropriate colourants. coloured excipients. 2. A dye migrates to the Change the solvent system, surface of granulation while drying.

Change the binder, Reduce drying temperature and Use a smaller particle size. 3. Improperly mixed dye, especially during ‘Direct Compression’. Improper mixing of a coloured binder solution. Mix properly and reduce size if it is of a larger size to prevent segregation. Incorporate dry colour additive during powder blending step, then add fine powdered adhesives such as acacia and tragacanth and mix well and finally add granulating liquid.

4.

Double impression
(1) Definition: ‘Double Impression’ involves only those punches, which have a monogram or other engraving on them. Reason: At the moment of compression, the tablet receives the imprint of the punch. Now, on some machines, the lower punch freely drops and travels uncontrolled for a short distance before riding up the ejection cam to push the tablet out of the die, now during this free travel, the punch rotates and at this point, the punch may make a new impression on the bottom of the tablet, resulting in ‘Double Impression’. If the upper punch is uncontrolled, it can rotate during the short travel to the final compression stage and create a double impression. TABLE.42. THE CAUSES AND REMEDIES OF DOUBLE IMPRESSION Sr. CAUSE No. Free rotation of either upper punch or lower punch during ejection of a tablet. REMEDIES -Use keying in tooling, i.e. inset a key alongside of the punch, so that it fits the punch and prevents punch rotation. -Newer presses have anti-turning devices, which prevent punch rotation.

1.

Problems and remedies for tablet coating
Blistering
(1,64) Definition: It is local detachment of film from the substrate forming blister.

Reason: Entrapment of gases in or underneath the film due to overheating either during spraying or at the end of the coating run. TABLE.43. THE CAUSE AND REMEDY OF BLISTERING Sr. No. 1. CAUSE Effect of temperature on the strength, elasticity and adhesion of the film. REMEDY Use mild drying condition.

Chipping
(1,64) Definition: It is defect where the film becomes chipped and dented, usually at the edges of the tablet. Reason: Decrease in fluidizing air or speed of rotation of the drum in pan coating. TABLE.44. THE CAUSE AND REMEDY OF CHIPPING Sr. No. 1. CAUSE REMEDY

High degree of attrition associated with the coating process. Increase hardness of the film by increasing the molecular weight grade of polymer.

Cratering
(1,64) Definition: It is defect of film coating whereby volcanic-like craters appears exposing the tablet surface. Reason: The coating solution penetrates the surface of the tablet, often at the crown where the surface is more porous, causing localized disintegration of the core and disruption of the coating. TABLE.45. THE CAUSES AND REMEDIES OF CRATERING

Sr.

CAUSES

REMEDIES

No. Inefficient drying. 1. 2. Higher rate of application of coating solution. Use efficient and optimum drying conditions. Increase viscosity of coating solution to decrease spray application rate.

Picking
(1,64) Definition: It is defect where isolated areas of film are pulled away from the surface when the tablet sticks together and then part. Reason: Conditions similar to cratering that produces an overly wet tablet bed where adjacent tablets can stick together and then break apart. TABLE.46. THE CAUSES AND REMEDIES OF PICKING Sr. CAUSE No. 1. 2. Inefficient drying. Higher rate of application of coating solution Use optimum and efficient drying conditions or increase the inlet air temperature. Decrease the rater of application of coating solution by increasing viscosity of coating solution. REMEDY

Pitting
(1,64) Definition: It is defect whereby pits occur in the surface of a tablet core without any visible disruption of the film coating. Reason: Temperature of the tablet core is greater than the melting point of the materials used in the tablet formulation. TABLE.47. THE CAUSE AND REMEDY OF PITTING

Sr. CAUSE No.

REMEDY

1.

Dispensing with preheating procedures at the initiation of Inappropriate drying coating and modifying the drying (inlet air) temperature (inlet air ) such that the temperature of the tablet core is not greater temperature than the melting point of the batch of additives used.

Blooming
(1,64) Definition: It is defect where coating becomes dull immediately or after prolonged storage at high temperatures. Reason: It is due to collection on the surface of low molecular weight ingredients included in the coating formulation. In most circumstances the ingredient will be plasticizer. TABLE.48. THE CAUSE AND REMEDY OF BLOOMING Sr. No. 1. CAUSE High concentration and low molecular weight of plasticizer. REMEDY Decrease plasticizer concentration and increase molecular weight of plasticizer.

Blushing
(1,64) Definition: It is defect best described as whitish specks or haziness in the film. Reason: It is thought to be due to precipitated polymer exacerbated by the use of high coating temperature at or above the thermal gelation temperature of the polymers. TABLE.49. THE CAUSES AND REMEDIES OF BLUSHING Sr. CAUSES No. 1. 2. High coating temperature REMEDIES

Decrease the drying air temperature Use of sorbitol in formulation which causes Avoid use of sorbitol with largest fall in the thermal gelation temperature Hydroxy Propyl Cellulose, of the Hydroxy Propyl Cellulose, Hydroxy Hydroxy Propyl Methyl Cellulose, Propyl Methyl Cellulose, Methyl Cellulose Methyl Cellulose and Cellulose

and Cellulose ethers.

ethers.

Colour variation
(1,64) Definition: A defect which involves variation in colour of the film. Reason: Alteration of the frequency and duration of appearance of tablets in the spray zone or the size/shape of the spray zone. TABLE.50. THE CAUSE AND REMEDY OF COLOUR VARIATION Sr. CAUSE No. Improper mixing, uneven spray pattern, insufficient coating, migration of soluble 1. dyes-plasticizers and other additives during drying. REMEDY Go for geometric mixing, reformulation with different plasticizers and additives or use mild drying conditions.

Infilling
(1,64) Definition: It is defect that renders the intagliations indistinctness. Reason: Inability of foam, formed by air spraying of a polymer solution, to break. The foam droplets on the surface of the tablet breakdown readily due to attrition but the intagliations form a protected area allowing the foam to accumulate and “set”. Once the foam has accumulated to a level approaching the outer contour of the tablet surface, normal attrition can occur allowing the structure to be covered with a continuous film. TABLE.51. THE CAUSE AND REMEDY OF INFILLING Sr. No. 1. CAUSE REMEDY

Bubble or foam formation because of air Add alcohol or use spray nozzle spraying of a polymer solution capable of finer atomization.

Orange peel/Roughness

(1,64) Definition: It is surface defect resulting in the film being rough and nonglossy. Appearance is similar to that of an orange. Reason: Inadequate spreading of the coating solution before drying. TABLE.52. THE CAUSES AND REMEDIES OF ORANGE PEEL/ROUGHNESS Sr. No. CAUSES 1. Rapid Drying 2. REMEDIES Use mild drying conditions Use additional solvents to decrease viscosity of High solution viscosity solution.

Cracking/Splitting
(1,64) Definition: It is defect in which the film either cracks across the crown of the tablet (cracking) or splits around the edges of the tablet (Splitting) Reason: Internal stress in the film exceeds tensile strength of the film. TABLE.53. THE CAUSE AND REMEDY OF CRACKING/SPLITTING

Sr. No. 1.

CAUSE

REMEDY

Use of higher molecular Use lower molecular weight polymers or weight polymers or polymeric polymeric blends. Also adjust plasticizer type and blends. concentration.

Key Phrases


During tablet manufacture, an industrial pharmacist usually encounters many problems. Solving these problems requires an in-depth knowledge of tablet-formulation as well as machine-operating processes. Capping and Lamination are the defects arising as a result of air-entrapment in the granular material. Chipping is a defect related arising due to very dry granules. Cracking is due to rapid expansion of tablets, when deep concave punches are used.



• •



Sticking, Picking and Binding are the imperfections related to more amount of binder in granules. Mottling is an imperfection arising due to more than one factor: a coloured drug, dirt in granules or the use of an oily lubricant. Double-Impression is related to a machine defect: it is caused by the free rotation of punches that have some engraving on the punch-faces.





Coating defects:


Blistering is related to entrapment of gases in or underneath the film due to overheating either during spraying or at the end of the coating run. Use of mild drying conditions can solve this problem. Chipping is related to higher degree of attrition associated with the coating process. Increase in hardness of the film by increasing the molecular weight grade of polymer can solve this problem. Cratering is related to penetration of the coating solution into the surface of the tablet, often at the crown where the surface is more porous, causing localized disintegration of the core and disruption of the coating. Decrease in spray application rate and use of optimum and efficient drying conditions can solve this problem. Pitting is defect in which temperature of the tablet core is greater than the melting point of the materials used in tablet formulation. Dispensing with preheating procedures at the initiation of coating and modifying the drying (inlet air) temperature can solve this problem. Blooming or dull film is generally because of higher concentration and lower molecular weight of plasticizer. So use lower concentration and higher molecular grade of plasticizer. Blushing/Whitish specks/Haziness of the film is related to precipitation of polymer exacerbated by the use of high coating temperature at or above the thermal gelation temperature of the polymers. Colour variation is because of improper mixing, uneven spray pattern, insufficient coating or migration of soluble dyes













during drying. Geometric mixing, mild drying conditions and reformulation with different plasticizers can solve this problem.


Infilling is because of bubble/foam formation during air spraying of a polymer solution. Addition of alcohol or use of spray nozzle capable of finer atomization can solve this problem. Orange peel/Roughness is related to inadequate spreading of the coating solution before drying. So decrease in viscosity of coating solution can counter this defect. Cracking is seen when internal stresses in the film exceeds tensile strength of the film. This is common with higher molecular weight polymers or polymeric blends. So use lower molecular weight polymers or polymeric blends





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