Tablet Manufacturing Process & Tablet Manufacture Problems With CAUSES & REMEDIES

SUBMITTED BY

Md. Tareq hasan

Chapter 01

Introduction of Pharmaceutical dosage form – Tablet

1.1 Definition of Tablet:

Tablets may be defined as the solid unit dosage form of medicament or medicaments with or without suitable diluents and prepared either by molding or by compression.

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.

1.2 Advantages and disadvantages of tablet as a dosage form

1.2.1The advantages are listed below:

Large scale manufacturing is feasible in comparison to other dosage forms. Therefore, economy can be achieved.

Accuracy of dose is maintained since tablet is a solid unit dosage form.

Longer expiry period and minimum microbial spillage owing to lower moisture content.

As tablet is not a sterile dosage form, stringent environmental conditions are not required in the tablet department.

Ease of packaging (blister or strip) and easy handling over liquid dosage form.

Easy to transport in bulk. Emergency supply supplies can be carried by patients.

Organoleptic properties (taste, appearance and odour are best improved by coating of tablet.

Product identification is easy and markings done with the help of grooved punches and printing with edible ink.

Different types of tablets are available like buccal, floating, colon targeting, effervescent, dispersible, soluble, and chewable, etc.

In composition to parenterals dosage form, a doctor or a nurse is not required for administration. I.e. self administration is possible.

In comparison to capsules, tablets are more tamperproof.

1.2.2 The disadvantages are listed below:

It is difficult to convert a high dose poorly compressible API into a tablet of suitable size for human use.

Difficult to formulate a drug with poor wettability, slow dissolution into a tablet.

Slow onset of action as compared to parenterals, liquid orals and capsules.

The amount of liquid drug (e.g. Vitamin E, Simethicone) that can be trapped into a tablet is very less.

Difficult to swallow for kids, terminally ill and geriatric patients.

Patients undergoing radiotherapy cannot swallow tablet.

1.3 Essential qualities of Good Tablets:

They should be accurate and uniform in weight. The size and shape should be reasonable for easy administration.

There should not be any incompatibilities.

They should not break during transportation of crumble in the hands of the patient.

There should not be any manufacturing defects like cracking, chipping, or discoloration.

They should be easy and economical in production.

The drug should be uniformly distributed throughout the tablets.

The tablet should not be too hard that it takes long time to disintegrate in the stomach.

They should be chemically and physically stable during storage.

They should be attractive in appearance.

After administration it should disintegrate readily.

Chapter 02

Types of Tablets

2. Tablets are classified on the basis of Administration.

2.1 ORAL TABLETS FOR INGESTION –

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.

2.1.1. Standard compressed tablets

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.

2.1.2. Multiple compressed tablets

Compression coated tablet

This type of tablet has two parts, internal core and surrounding coat. The core is small porous tablet and prepared on one turret.

FIGURE- COMPRESSION COATED TABLET

Layered tablet

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.

Paracetamol + phenyl ephedrine Hydrochloride

FIGURE- MULTILAYERED TABLET

2.1.3. Modified Release tablet

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- GRAPHICAL COMPARISON OF BLOOD CONCENTRATION V/S TIME

It has some advantages

Patient can take an undisturbed sleep at night

It’s also beneficial for psychiatric patients who forget to take their tablets regularly

The dose related side effects and toxicities are reduced.

2.1.4. Delayed action tablet

Enteric coated tablet is such an example of delayed action tablet. This formulation is preferred when,

The API irritates gastric mucosa e.g., aspirin or strong electrolytes Drugs that produce nausea and vomiting.

API is sensitive to low pH e.g., erythromycin.

2.1.5. Targeted tablet

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. Floating 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-. FLOATING TABLET

II. Colon targeting tablet

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.

2.1.6. Chewable tablet

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.

2.1.7. Dispersible tablet

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.

2.2. TABLETS USED IN THE ORAL CAVITY

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.

2.2.1. 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.

2.2.2. Sublingual tablets

They are to be placed under the tongue and produce immediate systemic effect by enabling the drug absorbed directly.

FIGURE- SUBLINGUAL TABLETS

2.2.3. Buccal tablets

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.

2.2.4. Mouth dissolved tablet

These kinds of tablets are preferred when fast action or relief is desired. 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.

2.3. TABLETS ADMINISTERED BY OTHER ROUTES

These tablets are administered by other route except for the oral cavity and so the drugs are avoided from passing through gastro intestinal tract.

Vaginal tablet

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.

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. They are sterile formulation without excipients.

2.4. 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

qapplication or for topical use depending upon type of medicament used.

Effervescent tablet

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.

FIGURE- EFFERVESCENT TABLETS

Hypodermic tablet

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.

Soluble tablet

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.

Chapter 03

Recipients

3.1. Definition of Excipients: An excipient is generally a pharmacologically inactive substance used as a carrier for the active ingredients of a medication. In many cases, an "active" substance (such as acetylsalicylic acid) may not be easily administered and absorbed by the human body; in such cases the substance in question may be dissolved into or mixed with an excipient.

3.2 Types of Excipients:

Diluents Binders Disantigrants Antifrictional agents Antiadherents Glidants Miscellaneous Excipients3.2.1. Diluents:

Introduction

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:

To provide improved cohesion To allow direct compression manufacturing

To enhance flow

To adjust weight of tablet as per die capacity

Classification of diluents

Tablet diluents or fillers can be divided into following categories:

Organic materials - Carbohydrate and modified carbohydrates. Inorganic materials – Calcium phosphates and others.

Co-processed Diluents.

Carbohydrate substances such as sugars, starches and celluloses may also function as binders during wet granulation process. Where as 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.

INSOLUBLE TABLET DILUENTS SOLUBLE TABLET DILUENTSStarch Lactose

Microcrystalline cellulose

Calcium phosphates, etc.

Mannitol

Sorbitol, etc.

Organic diluents Carbohydrates

Sugar and Sugar alcohols

Lactose α-lactose monohydrate, spray dried lactose and anhydrous lactose are widely used as diluents.

Characteristics of α -Lactose monohydrate (hydrous)

It has poor flow properties.

It is usually not reactive.

It is inexpensive.

Characteristics of Lactose spray dried

It exhibits free flowing characteristics.

Expensive compared to anhydrous and hydrous lactose.

Characteristics of Lactose anhydrous

It does not exhibit free flowing property.

It is inexpensive.

Sucrose

Characteristics of Sucrose or sugar

It is water soluble.

It possesses good binding properties.

It is inexpensive.

Mannitol

Characteristics of Mannitol

It exhibits poor flow properties.

It can be used in vitamin formulation, where moisture sensitivity may create a problem.

It is comparatively non hygroscopic.

Sorbitol

Characteristics of Sorbitol

It is water soluble.

It is hygroscopic in nature.

It has good mouth feel and sweet cooling taste.

Microcrystalline cellulose

Characteristics of Microcrystalline cellulose

It exhibits fair flowability.

It exhibits binding properties.

It is water insoluble.

Inorganic diluents Calcium phosphates

They are granular insoluble materials. They are widely used both as wet granulation and direct compression diluents in tablet formulation. They are used extensively in vitamin and mineral preparations.

. Characteristic of Calcium Phosphates

They exhibit good flow properties.

They are non hygroscopic.

They are inexpensive.

Co-processed diluents

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.

3.2.2. Binders

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.

Types of Binders

SUGARS NATURAL BINDERS SYNTHETIC/SEMISYNTHETIC POLYMER

Sucrose Acacia Methyl Cellulose

Liquid glucose

Tragacanth Ethyl Cellulose

Gelatin Hydroxy Propyl Methyl Cellulose ( HPMC)

Characteristics of Commonly Used Binder:

BINDER SPECIFIED CONCENTRATION

COMMENTS

Starch Paste 5-25%w/w - Freshly prepared starch paste is used as a binder.

Hydroxypropyl Methyl Cellulose (HPMC)

2-5%w/w- Comparable to Methyl Cellulose.

- Used as a binder in either wet or dry granulation processes.

Polyvinyl Pyrrolidone (PVP)

0.5-5%w/w- Soluble in both water and alcohol.

- Used in wet granulation process.

- Valuable binder for chewable tablets.

3.2.3. Disintegrants

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.

Types of disintegrants:

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.

Pregelatinized starch

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. One of them is SODIUM STARCH GLYCOLATE.

List of Disintegrants:

DISINTEGRANTS CONCENTRATION IN GRANULES (%W/W)

SPECIAL COMMENTS

Starch USP 5-20 Higher amount is required, poorly compressible

Alginic acid 1-5 Acts by swelling

Na alginate 2.5-10 Acts by swelling

Cellulose and its derivatives

Sodium carboxy methylcellulose 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)

MCC exhibit very good disintegrating properties because MCC is insoluble. 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.

Alginates

Alginates are hydrophilic colloidal substances which has high absorption capacity. Chemically, they are alginic acid and salts of alginic acid. Alginic acid is insoluble in water, slightly acidic in reaction.

Ion-exchange resin

Ion exchange resin has highest water uptake capacity than other disintegrating agents like starch and Sodium CMC. It has tendency to adsorb certain drugs.

Super Disintegrants

Super disintegrants 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.

LIST OF SUPERDISINTEGRANTS

SUPERDISINTEGRANTS EXAMPLE OF

MECHANISM OF ACTION

SPECIAL COMMENT

Sodium starch glycolate

Crosslinked starch

-Swells 7-12 folds in <30 seconds

-Swells in three dimensions and high level serve as sustain release matrix

Alginic acid NFCrosslinked alginic acid

-Rapid swelling in aqueous medium

-Promote disintegration in both dry or wet granulation

Calcium silicate -Wicking action

-Highly porous,

-optimum concentration is between 20-40%

3.2.4. Antifrictional Agents

Lubricants

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.

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.

Classification of lubricants

Lubricant are classified according to their water solubility i.e. water insoluble and water soluble.

Water Insoluble Lubricants

Water insoluble lubricants are most effective and used at reduced concentration than water soluble lubricants.

LIST OF INSOLUBLE LUBRICANTS

INSOLUBLE LUBRICANTS CONCENTRATION COMMENTS

Stearates(Magnesium Stearate, Calcium Stearate, Sodium stearate)

0.25 -1 Reduce tablet strength; prolong disintegration; widely used.

Talc 1 -2 Insoluble but not hydrophobic; moderately effective.

Glyceryl 1 - 5 Both lubricant and binder;

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.

LIST OF SOLUBLE LUBRICANTS

WATER SOLUBLE LUBRICANTS CONCENTRATION RANGE (%W/W)

Boric acid 1

Sodium benzoate 5

Sodium Lauryl sulfate (SLS) 1 – 5

Magnesium lauryl sulfate (MLS) 1 - 2

3.2.5. Antiadherents:

Antiadherents are added, which prevent sticking to punches and die walls. Talc, magnesium stearate and corn starch have excellent antiadherent properties.

TABLE- LIST OF ANTIADHERENTS

ANTIADHERENT RANGE(%W/W) COMMENT

Talc 1 – 5 Lubricant with excellent antiadherents properties

Sodium lauryl sulfate

<1 Antiadherents with water soluble lubricant

Stearates <1 Antiadherents with water insoluble lubricant

3.2.6. Glidants:

GLIDANTS are added to the formulation to improve the flow properties of the material. If the flow properties are extremely poor then glidants are ineffective. Starch is a popular glidant. Concentration of starch is common up to 10%. Talc is also a glidant.

3.2.7. Miscellaneous Excipients

Wetting Agents

Wetting Agents in tablet formulation aid water uptake and thereby enhancing disintegration and assisting in drug dissolution. 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.

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.

Antioxidants

Antioxidants are added in tablet formulation to protect drug from undergoing oxidation. Chelators may act as antioxidant. Most commonly used antioxidants include ascorbic acid and their esters.

Colourants

Colourants neither contribute to therapeutic activity nor do they improve product bioavailability or stability. Most widely used colourants are dyes and lakes which are FD & C and D & C approved.

Flavours

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.

Sweeteners

Sweeteners are added primarily to chewable tablets.

TABLE- SOME OF THE SWEETENERS USED IN TABLET FORMULATION

NATURAL SWEETENERS ARTIFICIAL SWEETENERSMannitol

Lactose

Sucrose

Dextrose

Saccharin

Cyclamate

Aspartame

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.

Chapter-04

Operations involved in tablet manufacturing

4.1 Introduction:

Traditionally, tablets have been made by granulation. Both wet granulation and dry granulation (slugging and roll compaction) are used. Numerous unit processes are involved in making tablets, including particle size reduction and sizing, blending, granulation, drying, compaction, and coating.

TYPICAL UNIT OPERATION INVOLVED IN WET GRANULATION, DRY GRANULATION AND DIRECT COMPRESSION

WET GRANULATION DRY GRANULATION DIRECT COMPRESSION

1. Milling and mixing of drugs and excipients

1. Milling and mixing of drugs and excipients

1. Milling and mixing of drugs and excipients

2. Preparation of binder solution

2. Compression into slugs or roll compaction

2. Compression of tablet

3. Wet massing by 3. Milling and screening of

addition of binder solution or granulating solvent

slugs and compacted powder

4. Screening of wet mass

4. Mixing with lubricant and disintegrant

5. Drying of the wet granules

5. Compression of tablet

6. Screening of dry granules

7. Blending with lubricant and disintegrant to produce

8. Compression of tablet

4.2 Dispensing

(Weighing and measuring)

Dispensing is the first step in any pharmaceutical manufacturing process. In this step, the weight of each ingredient in the mixture is determined according to dose.

4.3 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.

Advantages associated with size reduction in tablet manufacture are as follows:

It increases surface area, which may enhance an actives dissolution rate and hence bioavailability.

Controlled particle size distribution of dry granulation

Improved flow properties of raw materials.

Improved colour and/or active ingredient dispersion in tablet excipients.

Uniformly sized wet granulation to promote uniform drying.

4.4 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.

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 .

The various blenders used include blender, Oblicone blender, Container blender, Tumbling blender, Agitated powder blender, etc.

4.5 Granulation

Following particle size reduction and blending, the formulation may be granulated, which provides homogeneity of drug distribution in blend.

4.6 Drying

Drying is a most important step in the formulation and development of pharmaceutical product. The commonly used dryer includes Fluidized bed dryer, Vacuum tray dryer, Microwave dryer, Spray dryer, Freeze dryer, Turbo - tray dryer, Pan dryer, etc.

4.7 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).

Fig: Compression process

Common stages occurring during compression

FIGURE.22. STAGE 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 withdrawn 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

Chapter: 05

Manufacturing methods of Tablet.

1. Direct compression

2. Granulation

5.1. Direct compression:

Introduction

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.

Merits

Direct compression is more efficient and economical process as compared to other processes.

The most important advantage of direct compression is economical process.

Prime particle dissolution.

The chances of batch-to-batch variation are negligible, because the unit operations required for manufacturing processes is fewer.

Chemical stability problems for API and excipient would be avoided.

Provides stability against the effect of aging which affects the dissolution rates.

Demerits

Excipient Related

Problems in the uniform distribution of low dose drugs. High dose drugs having high bulk volume, poor compressibility and poor

flowability are not suitable for direct compression.

The choice of excipients for direct compression is extremely critical.

Many active ingredients are not compressible either in crystalline or amorphous forms.

Direct compression blends may lead to unblending because of difference in particle size or density of drug and excipients.

Non-uniform distribution of colour, especially in tablets of deep colours.

Manufacturing steps for direct compression

Direct compression involves comparatively few steps:

Milling of drug and excipients. Mixing of drug and excipients.

Tablet compression.

Direct compression Excipients

Direct compression excipients mainly include diluents, binders and disintegrants. The physicochemical properties of the ingredients such as particle size, flowability and moisture are critical in direct compression tableting.

An ideal direct compression excipient should possess the following attributes

It should have good compressibility. It should have good flowability.

It should be physiologically inert.

It should be stable to various environmental conditions (air, moisture, heat, etc.).

It should be colourless, odorless and tasteless.

5.2. Granulation:

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 three types: Wet granulation, Dry granulation, and Dry Granulation incorporating bound moisture.

Ideal characteristics of granules

The ideal characteristics of granules include uniformity, good flow, and compactibility.

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) Drying rate (Hydrate formation and polymorphism)

5.2.1. Wet granulation

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.

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

v) Drying of moist granules.

vi) Screening of dry granules through a suitable sieve (14-20

vii) Mixing of screened granules with disintegrant, glidant, and lubricant.

Special wet granulation techniques

i) High shear mixture granulation

ii) Fluid bed granulation

iii) Extrusion-spheronization

iv) Spray drying

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.

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.

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.

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

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

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 α β γ . γ is the most stable form and αis the metastable form. The stable Glycine polymorph (γ) converts to metastable form (α) when wet granulated with microcrystalline cellulose.

5.2.2. Dry granulation

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.

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

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.

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

Two main dry granulation processes

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

a) Density of the powder

b) Machine type

c) Punch and die size

d) Slug thickness

e) Speed of compression

f) Pressure used to produce slug

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.

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 etc.

Chapter: 06

Tablet manufacturing Problems with it’s causes & remedies

Introduction

An ideal tablet should be free from any visual defect or functional defect.

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.

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 air-entrapment in the granular material.

ii) LAMINATION: It is separation of tablet into two or more layers due to 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: 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).

6.1. Capping

‘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.

THE CAUSES AND REMEDIES OF CAPPING RELATED TO ‘FORMULATION’ (GRANULATION)

Sr. No.

CAUSES REMEDIES

1. Too dry or very low moisture content

Moisten the granules suitably. Add hygroscopic substance e.g.: sorbitol, methyl- cellulose.

2. Not thoroughly dried granules.

Dry the granules properly.

3. Insufficient amount of Increasing the mount of binder.

binder or improper binder.

4. Insufficient or improper lubricant.

Increase the amount of lubricant or change the type of lubricant.

THE CAUSES AND REMEDIES OF CAPPING RELATED TO ‘MACHINE’ (DIES, PUNCHES AND TABLET PRESS)

Sr. No.

CAUSES REMEDIES

1. Poorly finished dies Polish dies properly. Investigate other steels or other materials.

2. Deep concave punches or beveled-edge faces of punches.

Use flat punches.

3. Lower punch remains below the face of die during ejection.

Make proper setting of lower punch during ejection.

5. High turret speed. Reduce speed of turret (Increase dwell time).

6.2. Lamination / Laminating

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 CAUSES AND REMEDIES OF LAMINATION RELATED TO FORMULATION (GRANULATION)

Sr. No.

CAUSES REMEDIES

1. Oily or waxy materials in granules

Modify mixing process. Add adsorbent or absorbent.

2. Too much of hydrophobic lubricant e.g.: Magnesium-stearate.

Use a less amount of lubricant or change the type of lubricant.

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

Sr. No.

CAUSES REMEDIES

1. Rapid relaxation of the peripheral regions of a tablet, on ejection from a die.

Use tapered dies, i.e. upper part of the die bore has an outward taper of 3° to 5°.

2. Rapid decompression Use pre-compression step. Reduce turret speed and reduce the final compression pressure.

6.3. Chipping

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.

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

Sr. No.

CAUSES REMEDIES

1. Sticking on punch faces Dry the granules properly or increase

lubrication.

2. Too dry granules. Moisten the granules to plasticize. Add hygroscopic substances.

3. Too much binding causes chipping at bottom.

Optimize binding, or use dry binders.

THE CAUSES AND REMEDIES OF CHIPPING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No.

CAUSES REMEDIES

1. Groove of die worn at compression point.

Polish to open end, reverse or replace the die.

2. Barreled die (center of the die wider than ends)

Polish the die to make it cylindrical

3. Edge of punch face turned inside/inward.

Polish the punch edges

4. Concavity too deep to compress properly.

Reduce concavity of punch faces. Use flat punches.

6.4. Cracking

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.

THE CAUSES AND REMEDIES OF CRACKING RELATED TO FORMULATION (GRANULATION)

Sr. No.CAUSES REMEDIES

1. Large size of granules.

Reduce granule size. Add fines.

2. Too dry granules. Moisten the granules properly and add proper amount of binder.

3. Tablets expand. Improve granulation. Add dry binders.

4. Granulation too cold. Compress at room temperature.

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.

2.Deep concavities cause cracking while

removing tabletsUse special take-off.

6.5. Sticking / Filming

Definition: ‘Sticking’ refers to the tablet material adhering to the die wall.

Reason: Improperly dried or improperly lubricated granules.

THE CAUSES AND REMEDIES OF STICKING RELATED TO FORMULATION (GRANULATION)

Sr. CAUSES REMEDIES

No.

1. Granules not dried properly.

Dry the granules properly. Make moisture analysis to determine limits.

2. Too little or improper lubrication.

Increase or change lubricant.

3. Too much binder Reduce the amount of binder or use a different type of binder.

THE CAUSES AND REMEDIES OF STICKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No.CAUSES REMEDIES

1. Concavity too deep for granulation. Reduce concavity to optimum.

2. Too little pressure. Increase pressure.

3. Compressing too fast. Reduce speed.

6.6. Picking

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.

Reason: Picking is of particular concern when punch tips have engraving or embossing letters, as well as the granular material is improperly dried.

THE CAUSES AND REMEDIES OF PICKING RELATED TO FORMULATION (GRANULATION)

Sr. CAUSES REMEDIES

No.

1. Excessive moisture in granules.

Dry properly the granules, determine optimum limit.

2. Too little or improper lubrication.

Increase lubrication; use colloidal silica as a ‘polishing agent’, so that material does not cling to punch faces.

3. Too much amount of binder.

Reduce the amount of binder, change the type or use dry binders.

THE CAUSES AND REMEDIES OF PICKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No.

CAUSES REMEDIES

1. Rough or scratched punch faces. Polish faces to high luster.

2. Embossing or engraving letters on punch faces such as B, A, O, R, P, Q, G.

Design lettering as large as possible.

3. Bevels or dividing lines too deep. Reduce depths and sharpness.

6.7. Binding

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.

THE CAUSES AND REMEDIES OF BINDING RELATED TO FORMULATION (GRANULATION)

Sr. No.

CAUSES REMEDIES

1. Too moist granules and extrudes around lower punch.

Dry the granules properly.

2. Insufficient or improper lubricant.

Increase the amount of lubricant or use a more effective lubricant.

3. Too coarse granules. Reduce granular size, add more fines, and increase the quantity of lubricant.

THE CAUSES AND REMEDIES OF BINDING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No.

CAUSES REMEDIES

1. Poorly finished dies. Polish the dies properly.

2. Rough dies due to abrasion, corrosion.

Investigate other steels or other materials or modify granulation.

3. Too much pressure in the tablet press.

Reduce pressure. OR

Modify granulation.

6.8 Mottling

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.

THE CAUSES AND REMEDIES OF MOTTLING

Sr. No.

CAUSES REMEDIES

1. A coloured drug used along with colourless or white-coloured excipients.

Use appropriate colourants.

2. A dye migrates to the surface of granulation while drying.

Change the binder,

Use a smaller particle size.

3. Improperly mixed dye, especially during ‘Direct Compression’.

Mix properly and reduce size if it is of a larger size to prevent segregation.

Problems and remedies for tablet coating

Blistering

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.

THE CAUSE AND REMEDY OF BLISTERING

Sr. No.

CAUSE REMEDY

1. Effect of temperature on the strength, elasticity and adhesion of the film.

Use mild drying condition.

Chipping

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.

THE CAUSE AND REMEDY OF CHIPPING

Sr. No.

CAUSE REMEDY

1.High degree of attrition associated with the coating process.

Increase hardness of the film by increasing the molecular weight grade of polymer.

Cratering

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.

THE CAUSES AND REMEDIES OF CRATERING

Sr. No. CAUSES REMEDIES

1.Inefficient drying.

Use efficient and optimum drying

conditions.

2. Higher rate of application of coating solution.

Increase viscosity of coating solution to decrease spray application rate.

Picking

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.

THE CAUSES AND REMEDIES OF PICKING

Sr.

No.CAUSE REMEDY

1. 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.

Pitting

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.

THE CAUSE AND REMEDY OF PITTING

Sr. No.

CAUSE REMEDY

1. Inappropriate drying (inlet air ) temperature

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.

Blooming

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.

THE CAUSE AND REMEDY OF BLOOMING

Sr. No. CAUSE REMEDY

1. High concentration and low molecular weight of plasticizer.

Decrease plasticizer concentration and increase molecular weight of plasticizer.

Colour variation

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.

THE CAUSE AND REMEDY OF COLOUR VARIATION

Sr. No.

CAUSE REMEDY

1. Improper mixing, uneven spray pattern, insufficient coating, migration of soluble dyes-plasticizers and other additives during drying.

Go for geometric mixing, reformulation with different plasticizers and additives or use mild drying conditions.

Orange peel/Roughness

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.

THE CAUSES AND REMEDIES OF ORANGE PEEL/ROUGHNESS

Sr. No.

CAUSES REMEDIES

1. Rapid Drying Use mild drying conditions

2. High solution viscosity

Use additional solvents to decrease viscosity of solution.

Cracking/Splitting

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.

THE CAUSE AND REMEDY OF CRACKING/SPLITTING

Sr. CAUSE REMEDY

No.

1. Use of higher molecular weight polymers or polymeric blends.

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

References

1. Lachman L., Liberman H. and Kanig J.; The Theory and Practice of Industrial Pharmacy; Third Edition: 293-345, 346-373.

2. Aulton M.; Pharmaceutics: The Science of Dosage Form Design; International Student Edition: 304-321, 347-668.

3. Ansel H., Allen L. and Jr. Popovich N.; Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems; Eighth Edition: 227-259.

4. Lachman L., Liberman L. and Schwartz J.; Pharmaceutical Dosage Forms: Tablets; Second Edition : Volume I.

5. Remington J., Remington: The Science and Practice of Pharmacy; Nineteenth Edition: Volume II : 1615-1641.

6. American Pharmaceutical Reviews; 2001; 4(3): 28-35.

7. Vyas S. and Khar R.; Controlled Drug Delivery Concepts and Advances; First Edition: 219-256.

8. www.ncbi.nlm.nih.gov

9. Swarbrick J. and Boylan J.; Encyclopedia of Pharmaceutical Technology; Volume 14: 355-348, 385-400, 401-418.

10. Chowhan Z.; Pharmaceutical Technology: Excipients and their functionality in drug product development; 1993; (9).

11. Taylor and Francis; International Journal of Toxicology: Toxicity of excipients- A food and drug administration perspective; 2003; 22(5): 377-380.

12. Banker G. and Rhodes C.; Drug and Pharmaceutical Sciences: Modern Pharmaceutics; Third Edition; Volume 72: 333-394.

13. Swarbrick J and Boylan J.; Encyclopedia of Pharmaceutical Technology; Volume 4: 37-84, 85-106.

14. Rowe R., Sheskey P. and Weller P.; Handbook of Pharmaceutical Excipients; Fourth Edition.

15. Kachrimanis K., Nikolakakis L. and Malamataris S.; Journal of Pharmaceutical Sciences: Tensile Strength and disintegration of tableted silicified Microcrystalline Cellulose. Influence of interparticle bonding; 2003; 92(7): 1489-1501.

16. Schlack H., Bauer-Brandl A., Schubert R. and Becker D.; Drug Development and Industrial Pharmacy: Properties of Fujicalin, a new modified anhydrous dibasic calcium phosphate for direct compression and comparison with dicalcium phosphate dihydrate; 2001; 27(8): 789-801.

17. Swarbrick J and Boylan J.; Encyclopedia of Pharmaceutical Technology; Volume 7: 121-160.

18. Swarbrick J and Boylan J.; Encyclopedia of Pharmaceutical Technology; Volume 1: 451-464.

19. Starch1500® 27. HPMC.

20. Zhang Y. and Chakrabarti S.; National Starch and Chemicals; AAPS Meeting Torento; Direct Compression Binder-Characteristic and functionality of commercial binders; 2002; Abstract # 4332

21. Swarbrick J and Boylan J.; Encyclopedia of Pharmaceutical Technology; Volume 16: 363-402.

22. Jorgensen A., Luukkonen P., Rantaren J., Schefer T., Juppo A. And Yllruusi J.; Jouranl of Pharmaceutical Sciences: Comparison of torque measurements and near-infrared spectroscopy in characterization of a wet granulation process; 2004; 93(9): 2232-2243.

23. Anneke M., Marinella R., Auko C., Johannes A. and Henderik W.; European Journal of Pharmaceutical Sciences; 2004; 23(2): 169-179.

24. Ferrari F., Bertoni M., Bonferoni M. and Rossi S.; International Journal of Pharmaceutics: Investigation on bonding and disintegration properties of pharmaceutical materials; 1996; 13: 71-79.

25. Guyot-Hermann; S.T.P. Pharmaceutical Science: The disintegration and disintegrating agent; 1992; 2(6): 445-462.

26. Boltzolaski and Augsburger; Drug Development and Industrial Pharmacy: Disintegrating agents in hard gelatin capsules; 1998; 14(9): 1235-1248.

27. Lowenthal W.; Journal of Pharmaceutical Sciences: Disintegration of tablets; 1972; 61(11): 1695-1711.

28. P.H.List and Muazzam V.; Drug Made Ger; 1985; 22: 161-163.

29. Patel N. and Hopponen R.; Journal of Pharmaceutical Sciences: Mechanism of action of starch as disintegrating agent in aspirin tablets; 1966; 55(10): 1065-1068.

30. Lowenthal W. and Wood J.; Journal of Pharmaceutical Sciences: Mechanism of action of starch as Tablet disintegrant VI : Location and structure of starch in tablet; 1973; 62(2): 287-293.

31. Rudnic E., Kanig J. and Rhodes C.; Journal of Pharmaceutical Sciences: Effect of molecular structure variation on the disintegrant action of sodium starch glycolate; 1985; 74(6): 647-650.

32. Burlinson H. and Pickering C.; Journal of Pharmacy and Pharmacology: The disintegration of Tablet; 1950; 2(6): 630-638.

33. Aslam A. and Parrott E.; Journal of Pharmaceutical Sciences: Effect of aging on some physical properties of Hydrochlorthiazide tablets; 1971; 60(2): 263-266.

34. Chebli C. and Cartlizer L.; International Journal of Pharmaceutics: Crosslinked cellulose as a tablet excipient: A binding or disintegrating agent; 1998; 171: 101-110.

35. Chofetz L.; Journal of Pharmaceutical Sciences: Stability Indicating assay method for drugs and their dosage forms; 1971; 60(3): 335-345.

36. Eyjolfsson R.; Drug Development and Industrial Pharmacy: Lisinopril- Lactose Incompatibility; 1998; 24(8): 797-798.

37. Gold G., Duvall R., Palermo B. and Slater J.; Journal of Pharmaceutical Sciences: Powder flow studies III- Factors affecting flow of lactose granules; 1968; 57(4): 667-671.

38. Danish F. and Parrott E.; Journal of Pharmaceutical Sciences: Flowrates of solid particulate pharmaceuticals; 1971; 60(4): 548-554.

39. Jones T.; Journal of Pharmaceutical Sciences: Mechanism of flow improvement by addition of fine particles to bulk solids; 1968; 57(11): 2015-2016.

40. Martin E.; Dispensing of Medication; Edition Seventh: 740-741.

41. Cadwallader D. and Islam Q.; Journal of Pharmaceutical Sciences: Urea as a tableting agent for benzalkonium chloride; 1969; 58(1): 238-241.

42. Shabbir D. and Rhodes C.; Drug Development and Industrial Pharmacy: The effect of moisture on powder flow and on compaction and physical stability of tablets; 1989; 15(10): 1577-1600.

43. Alderborn G. and Nysrom C.; Drugs and Pharmaceutical Sciences: Pharmaceutical Powder Compaction Technology: Volume 71: 11-12.

44. Gold G. and Palermo B.; Journal of Pharmaceutical Sciences: Hopper flow electrostatics of tableting material I; 1965; 54(2): 310-312.

45. Nystrom C., Mazur J. and Sjogren J.; International Journal of Pharmaceutics: Studies of direct compression of tablets II- The influence of

particle size of a dry binder on the mechanical strength of tablets; 1982; 10(3): 209-218.

46. Parikh D.; Drugs and Pharmaceutical Sciences: Handbook of Pharmaceutical Granulation Technology; Volume 81.

47. Ullah I., Carras R., Wiley G. and Lipper R.; Pharmaceutical Technology: Moisture activated dry granulation technique- A general process; 1987; 11(9): 48.

48. Aniruddha M., Railkar and Schwatz J.; Drug Development and Industrial Pharmacy: Use of moist granulation technique (MGT) to develop controlled release dosage forms of Acetaminophen; 2001; 27(4): 337-343.

49. Shoung Y. and Hungting Y.; United State Patent Application: Process for the preparation of direct tableting formulation and aids; 20030017198; 2003; 23(1).

50. Kerry C. and Sheskey P.; Preliminary report of discovery of a new pharmaceutical granulation process using foamed aqueous binder: Larjin Laboratory, The Dow Chemical Company; Midland, Michigan, USA.

51. Lachman L., Liberman L. and Schwartz J.; Pharmaceutical Dosage Forms: Tablets; Second Edition : Volume II.

52. McGinity J.; Drug and The Pharmaceutical Sciences: Aqueous polymeric coatings for pharmaceutical dosage forms; Volume 36: 419-428.

53. Indian Pharmacopoeia; 1996.

54. British Pharmacopoeia; 2001.

55. The United State Pharmacopoeia 24; The National Formulary 19; 2000.