Manufacture of Pharmaceutical Tablets

The design and manufacture of pharmaceutical tablets is a complex multi-stage process whereby formulation scientists ensure that the correct amount of drug substance in the right form is delivered at the appropriate time, at the proper rate and in the desired location with its chemical integrity protected to that point. Most drug substances do not possess the required properties which give satisfactory flow from the hopper to the die cavity of tablet presses. As a result, they are subjected to pre-treatment either alone or in combination with suitable excipients to form free-flowing granules that lend themselves to tabletting.

Tablets are commonly manufactured by wet granulation, dry granulation or direct compression. These methods may be considered to consist of a series of steps (unit processes) – weighing, milling, mixing, granulation, drying, compaction, (frequently) coating and packaging. Regardless of the method used the unit processes – weighing, milling and mixing, are the same; subsequent steps differ.

Primary goals of tablet manufacturing process

The primary goals include:

1. To formulate tablets that are strong and hard to withstand mechanical shock encountered during manufacturing, packing, shipping, dispensing and use.
2. To formulate tablets that are uniform in weight and in drug content.
3. To formulate tablets that are bioavailable according to indication requirements.
4. To formulate tablets that are chemically and physically stable over a long period of time.
5. To formulate tablets that have elegant product identity which is free from any tablet defects.

Factors that influence the choice of manufacturing process used during tablet formulation

In general, the choice of formulation process employed during tablet manufacture is dependent upon such factors as:

1.  Compression properties of the Active Pharmaceutical Ingredient (API)/ drug substance.
2. Physical and chemical stability of the API during the manufacturing process.
3. Particle size of the formulation ingredients.
4. Availability of the necessary processing equipment.
5. Cost of the manufacturing/formulation process.

Personnel requirements during manufacture of pharmaceutical tablets

• Production pharmacists/ supervisors
• Manufacturing chemist
• Analytical chemist
• Quality assurance manager
• Machine operators
• Mechanics

In addition to the job-specific responsibilities of these personnel, all manufacturing employees must be versed and trained in Current Good Manufacturing Practices (CGMPs) and in the appropriate Standard Operating Procedures (SOPs) governing their area.

Area required for manufacture of tablets

• Raw material warehouse
  • Receiving quarantine
  • Approved raw material section
• Dispensary
• Production room
  • Mixing, Granulation and Drying Section
  • Tablet Punching Section
  • Coating Section
• Quality control section
• Packaging Section.

Layout of Tablet manufacturing section

Excipients used in tablet formulation/ Tablet raw materials

Tablets in addition to the therapeutic agent(s) also contain excipients that are required to ensure satisfactory production process. These materials which are inert may be added to the drug substance to increase its bulk and give those desirable properties lacking in the drug substance alone. Depending on the intended use, tablet excipients may be subcategorized into:

1. Those that help to impart satisfactory processing and compression properties to the formulation and
2. Those that help to give additional desirable physical characteristics to the compressed tablet.

Many excipients used in tablet formulation are multi-functional that is, they may serve more than one function and thus can affect the properties of powders or tablets in various ways at varying concentrations.

Some multiple-use excipients in tablet formulation

All excipients used in tablet formulation may not be present in all tablet formula. Some such as lactose, stearates, microcrystalline cellulose are common to the vast majority of tablets. Excipients used in tablet formulations include binders or granulating fluid, diluents, disintegrants, lubricants, glidants, colourants, sweeteners, flavourants, adsorbents, and surfactants.

Read Also: Excipients used in tablet formulation.

Evaluation/ quality control of raw materials used in the manufacture of tablets

Quality control of tablet raw materials (APIs and excipients) is one of the main tasks of the quality control unit in any drug manufacturing industry. Raw materials described in monograph of relevant Pharmacopoeia must undergo the necessary tests as stated in the monograph. It is often sufficient if identification testing is conducted on the individual packages/containers and content and purity determination in mixed samples.

Every manufacturer has the opportunity to carry out further testing if they deem it necessary for guaranteeing a smooth-running production process or a very high-quality product. Starting materials are released only after their quality are established or judged as satisfactory. Raw materials that fail the quality control test are rejected and returned to the supplier.

Any risks that may emanate from starting materials of inappropriate quality must be avoided to prevent product failure and to ensure a consistent level of quality, as well as safety in consumer and industrial products.

Tablet Manufacturing Equipment/ Machines

Common equipment used in pharmaceutical tablet manufacturing include:

1.  Size reduction equipment/ communition equipment e.g., hammer mill, vibration mill, roller mill, pin mill, fluidized energy mill, end-runner mill, edge-runner mill, cutter mill and ball mill.
2. Weighing balance/ balances e.g., bulk weighing balance (weighs in kilogram), electronic weighing balance (weighs in grams and milligrams).
3. Mixing equipment e.g., pneumatic mixers (air-mix mixer or air-driven mixer), diffusion/ tumbling mixers (e.g., V-blender, double cone blender, cubic mixer, drum blender), convective mixers (e.g., ribbon blenders, orbiting screw mixers, horizontal high-intensity blenders, planetary blenders, diffusion mixer with intensifier bar/agitator, Forberg blenders, horizontal double arm mixers, vertical high-intensity mixer).
4. Granulators e.g., rotating shape granulators, mechanical agitator granulators (e.g., ribbon or paddle blender, sigma blade mixer, planetary mixer, orbiting screw mixers), high-shear granulator, fluidized bed granulator, dry granulator etc.
5. Dying equipment e.g., spray dryer, rotary dryer, fluidized bed dryer etc.
6. Tabletting machine – single punch tablet press and multi-station/ rotary tablet press (e.g., High-speed rotary tablet machines and multi-layer rotary tablet machines).
7. Quality control equipment e.g., disintegration equipment (Manesty single unit disintegrating apparatus or Erweka multiple unit disintegrating apparatus), USP Dissolution Tester, Tablet Hardness Tester, Tablet Thickness Tester, Tablet Friability Testers etc.
8. Coating and polishing machines for coated tablets e.g., standard coating pan, perforated pan, fluidized bed/ Air suspension coating system etc.
9. Packaging machines e.g., blister packaging machines, strip packing machine, aluminium foil packaging machine, etc.

Tablet Manufacturing Equipment continues to improve in both production speed and uniformity of the tablets compressed.

Steps Involved In Tablet Formulation/ Procedure for Manufacturing Tablets

1. Dispensing: Each ingredient in the tablet formula is weighed and accurately dispensed as per dose. This is one of the critical steps in any type of formulation process and should be done under technical supervision.
2. Sizing: Formulation ingredients must be in finely divided form, otherwise, size reduction should be carried out for better flow property and easy mixing.
3. Powder blending: Powders are mixed using a suitable blender to obtain a uniform and homogeneous powder mix. The drug substance and excipients are mixed in geometric dilution.
4. Granulation: Here small powder particles are gathered together into layers, and permanent aggregates to render them into free-flowing states.
5. Drying and dry screening: Screened wet granules need to be dried for a particular time period in tray dry or fluid bed dryer at controlled temperature not exceeding 55⁰C. Dried granules are screened through the appropriate mesh screen.
6. Tablet compression: This step involves the compression of granules into a flat or convex, round, oblong, or unique shaped, scored or unscored tablets; engraved with an identifying symbol and/ or code number using tablet press.
7. Coating: Tablets and granules are coated if there is need to mask the unpleasant taste/odour of some drug substance or to increase the aesthetic appeal of uncoated tablets as well as to modify the release or control the release of drug substance from tablets. This is achieved by enclosing or covering the core tablet or granules with coating solutions.

Some of the steps above are skipped depending on the manufacturing process used during tablet formulation.

Techniques/ Methods Used in Tablet Formulation

Tablets are commonly manufactured by

1. Wet granulation
2. Dry granulation or
3. Direct compression.

One important requirement is that the drug mixture flows freely from the hopper of the tabletting machine into the dies to enable high-speed compression of the powder mix into tablets.

Manufacture of tablets by wet granulation method

Wet granulation is a widely used method for the production of compressed tablet. It is essentially a process of size enlargement involving several steps and the use of an adhesive substance known as binder. The granules produced using this method of granulation has a greater probability of meeting all the physical requirements for tablet formation.

Flowchart of wet granulation process

A stepwise summary of the manufacturing steps used in the manufacture of tablets by the wet granulation method are listed below.

1. Weighing, milling and mixing of the APIs with powdered excipients (excluding the lubricant)
2. Preparation of binder solution
3. Mixing of binder solution with powders to form a damp mass
4. Screening the dampened powder into pellets or granules (wet screening) using 6- to 12-mesh screen
5. Drying of moist granules
6. Sizing the granulation by dry screening using 14- to 20-mesh screen
7. Mixing of the dried granules with lubricant and disintegrants
8. Compression of granules into tablets.

Tablets manufactured by wet granulation exhibit sufficient mechanical properties to be subsequently exposed to other unit operations, e.g. film coating.

Read: Manufacture of tablets by wet granulation method

Manufacture of tablets by dry granulation method

The formation of granules by compacting powder mixtures into large pieces or compacts which are subsequently broken down or sized into granules (often referred to as dry granulation, double compression or pre-compression) is a possible granulation method which, however, is not widely used in the manufacture of tablets. This method is used when tablet excipients have sufficient inherent binding properties. The procedure can also be used as a means to avoid exposure of drug substances to elevated temperatures (during drying) or moisture. Double compression method eliminates a number of steps but still includes weighing, mixing, slugging, dry screening, lubrication, and compression of granules into tablets. Compaction for the dry granulation process is generally achieved either by slugging or roller compaction.

Slugging

In this method, the powder mix is compressed into a soft large flat tablet (about 1 inch in diameter) using a tablet press that is capable of applying high stress. Following this, the slugs are broken by hand or milled using conventional milling equipment to produce granules of the required size. Lubricant is added in the usual manner, and the granules then compressed into tablets. Aspirin is a good example of where slugging is satisfactory. Other materials, such as aspirin combinations, acetaminophen, thiamine hydrochloride, ascorbic acid, magnesium hydroxide, and other antacid compounds, may be treated similarly.

Roller Compaction

Results similar to those accomplished by the slugging process are also obtained with powder compactors. In roller compaction method, the formulation ingredients are mixed and are passed between high-pressure (oppositely) rotating rollers that compress the powder at 1 to 6 tons of pressure. The compacted material is then milled to a uniform granule size and compressed into tablets after the addition of a lubricant. The roller compaction method is often preferred to slugging. Excessive pressures that may be required to obtain cohesion of certain materials may result in a prolonged dissolution rate.

Read: Manufacture of tablets by dry granulation method

Flowchart of dry granulation process

A stepwise summary of the manufacturing steps used in the manufacture of tablets by the dry granulation method are listed below.

1. Weighing and Milling of formulation ingredients (drug substance and excipients)
2. Mixing of milled powders.
3. Compression of mixed powders into slugs.
4. Milling and sieving of slugs.
5. Mixing with disintegrant and lubricant.
6. Compression into tablets.

Manufacture of tablets by direct compression method

As its name implies, direct compression involves direct compression of powdered materials into tablets without modifying the physical nature of the materials itself. The technology involved in this method assumes great importance in the tablet formulations, because it is often the cheapest means, particularly in the production of generics that the active substance permits. Direct compression avoids many of the problems associated with wet and dry granulations. Its successful application in tablet formulation rests on two fundamental issues:

1. The availability of suitable excipients
2. The availability of suitable machinery.

Flowchart of direct compression process

A stepwise summary of the manufacturing steps used in the manufacture of tablets by the dry granulation method are listed below.

1. Milling of therapeutic agent and excipients
2. Mixing of milled powders, disintegrants and lubricants
3. Compression into tablets.

It is worth noting that tablets produced by direct compression are often softer than their counterparts that have been produced by wet granulation and therefore they may be difficult to film-coat.

Read: Manufacture of tablets by direct compression method

Comparison of various steps used in different methods of tablet manufacturing processes

Tablets defects/ special problem in compressing tablet process

• Weight variation (granule size and size distribution)
• Poor mixing
• Poor flow
• Capping and lamination
• Picking of tablets
• Chipping and splitting
• Sticking
• Embossing/print defect
• Layered tablet splitting/layer not clearly defined
• Low hardness/ low mechanical strength of tablets/ soft tablets
• Variable hardness/ hardness variation
• Mottling
• Punch variation
• Double impression
• Presence of hairs/fibre on tablet surface
• Black spot/stain

Read Also: Common Defects in Film Coating Process: Causes and Possible Solutions

Quality control of tablets

Tablets should be subjected to a number of tests before they are deemed fit for marketing and consumption. These tests can be divided into two broad categories namely

1. Pharmacopoeial or official tests

   1. Content of active ingredient/ absolute drug content test/ assay of active ingredient.
   2. Weight uniformity test/ weight variation test
   3. Content uniformity test
   4. Disintegration time test
   5. Dissolution test

2. Non-pharmacopoeial or non-official tests

   1. Crushing strength test/  hardness test
   2. Friability test.
   3. Tensile strength determination.

Read Also: Quality Control Tests for Tablets

Packaging and storing of tablets

Before tablets are sent out for distribution, they are usually packaged using appropriate packaging materials. The type of packaging material used is a matter of choice and is dependent on several factors including:

1. The degree of protection required
2. Compatibility of the packaging material with the formulation.
3. Presentation, particularly for those products which may be the subject of impulse buying
4. Customer convenience in terms of size, weight, method of opening or reclosing legibility of printing, etc.
5. Filling method and
6. Cost

Tablets are commonly packaged using blister and strip packs and are kept in places of low humidity, and protected from extremes temperature. The packaging provides excellent environmental protection for each unit of tablet, coupled with an aesthetically pleasing and efficacious appearance. Blister and strip packaging also provide some degree of tamper resistance to the dosage form.
For larger quantities delivered to the pharmacist, glass or plastic bottles, metal containers, cartons, or paperboard drums may be used along with polyethylene liners, where necessary, to give added protection from moisture. If cotton wool stuffing is used under these circumstances it is an advantage for it to be external to the liners so that any moisture that it contains does not gain access to the tablets. Tablets that are decomposed when exposed to moisture can also be packaged with a desiccant packet. Light sensitive tablets are packaged in light-resistant containers. With a few exceptions, tablets that are properly stored will remain stable for many years.

Reference

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• Lachman, L., Lieberman, H. A., and Kanig, J. L. (1986 ), The Theory and Practice of Industrial Pharmacy, 3rd ed. , Philadelphia: Lea & Febiger.
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• Sakr, A. A and Alanazi, F. K (2012). Oral Solid Dosage Form. In L.A Felton (Eds.), Remington Essentials of Pharmaceutics (pp. 581-610). London: Pharmaceutical Press.
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