Manufacturing methods of tablets

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Manufacturing methods of tablets

1.8 Tablet 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.

Manufacturing Steps For Direct 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.

About the Author

Dr.Mukesh Gohel's picture
Author: Dr.Mukesh Gohel

Dr. Mukesh Gohel is principal, professor at the LMCP, Ahmedabad served in academics for more than 40 years. He provides training in leading pharmaceutical industries in the areas of Design of Experiments and Quality by Design. His current areas of interest are direct compression and improvement of drug dissolution.