Article
Tablet Formulation Design And Manufacture: Oral Immediate Release Application Jayesh Parmar & Manish Rane Colorcon Asia Pvt. Limited
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Abstract
Tablet is the most preferred oral dosage form, due to many advantages it offers to formulators as well as physicians and patients. However, the process of manufacturing tablets is complex. Hence, careful consideration has to be given to select right process, and right excipients to ultimately give a robust, high productivity and regulatory compliant product of good quality.
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Introduction
Tablets are solid dosage forms containing medicinal substances with or without suitable diluents. They are the most widely preferred form of medication both by pharmaceutical manufacturer as well as physicians and patients. They offer safe and convenient ways of active pharmaceutical ingredients (API) administration with excellent physicochemical stability in comparison to some other dosage forms, and also provide means of accurate dosing. They can be mass produced with robust quality controls and offer different branding possibilities by means of colored film coating, different shapes, sizes or logos. The objective of this review article is to provide a comprehensive overview of the tablet core manufacturing process with emphasis on oral immediate release formulations, along with common excipients used.
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Types of Tablet
The tablet dosage form is a versatile drug delivery system. Different types of tablet formulations are available, which could be broadly classified based on: (1) route of administration such as tablets for oral delivery, sublingual delivery, buccal delivery, rectal delivery or vaginal delivery, and (2) formulation characteristics such as immediate release tablets, effervescent tablets, melt-in-mouth or fast dissolving tablets, delayed release or extended release tablets. In all the cases, the general manufacturing process, machinery used for preparation of tablets and materials used are similar. The process of manufacturing a robust tablet dosage form and consistently maintain its quality is a key challenge to all formulators. Hence the manufacturing process and formulation components take pivotal importance.
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Tablet Manufacturing
Tablets are compressed powders and their manufacturing is a complex, multistep process. The ultimate aim of these compressed solids is to easily disperse in gastrointestinal fluid, aid in complete absorption of API and, at the same time, offer stability to the formulation. The tablet manufacturing process can be broadly classified as granulation (wet granulation or dry granulation) and direct compression. Granulation is an agglomeration process to improve the flow, density and compressibility of particulate material by size enlargement and densification. Granulation can be achieved by the use of binder solution (wet granulation) or dry binder (dry granulation). Wet granulation is often chosen over dry granulation because of dust elimination, single pot processing, uniformity of API content (low dose API) and obtaining predictable granulation end point determination. Examples of wet granulation methods include fluid bed, high shear, pelletization techniques, such as extrusionspheronization, spray drying, etc. The quality of this solid oral dosage form is, as a general rule, primarily governed by the physicochemical properties of the powder/ granulation from which the tablets are composed. Dry granulation (roll compaction or slugging) involves the compaction of powders at high pressures into large, often poorly formed tablets or compacts. These compacts are then milled and screened to form a granulation of the desired particle size. The advantage of dry granulation is the elimination of heat and moisture in the processing. Dry granulations can be produced by extruding powders between hydraulically-operated rollers to produce thin cakes that are subsequently screened or milled to give the desired granule size.
Direct compression avoids many of the problems associated with wet and dry granulations. However, the inherent physical properties of the individual filler materials are highly critical, and minor variations can alter flow and compression characteristics, so as to make them unsuitable for direct compression. Excipients are now available that allow production of tablets at high speeds without prior granulation steps. These directly compressible excipients consist of special physical forms of substances, such as lactose, sucrose, dextrose, or cellulose, which possess the desirable properties of fluidity and compressibility. Some of the most widely used direct compression fillers are cellulose derivatives (e.g. microcrystalline cellulose), saccharides (e.g. lactose and mannitol), mineral salts (e.g. dicalcium phosphate, calcium carbonate), and partially pregelatinzed starch (Starch 1500®). Table 1 provides the advantages and limitations of different table manufacturing methods.
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Tablet Components
Tablet dosage form is composed of two main ingredients: (1) API and, (2) inactive ingredients also termed as excipients. The different physicochemical properties of API and manufacturing process selected dictates addition of different types of excipients, depending on the specific function they provide to aid in manufacture of tablets, efficacy and stability of the product. Active Pharmaceutical Ingredients API play a very important role in selecting the excipients, method of manufacture, size of tablet, etc. Some of the important characteristics of API, which influence the tablet performance are listed in Table 2.
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Table 1 : Tablet manufacturing methods - advantages and limitations Method
Advantages
Limitations
Direct compression
z Simple, economical process. z No heat or moisture, so good for unstable compounds.
z Not suitable for all API, generally limited to lower dose compounds. z Segregation potential. z Expensive excipients.
Wet granulation
z Robust process suitable for z Expensive: time and energy most compounds. consuming process. z Imparts flowability to z Specialized equipment a formulation. required. z Can reduce elasticity problems. z Stability issues for moisture z Coating surface with hydrophilic sensitive and thermolabile polymer can improve wettability. API with aqueous z Binds API with excipient, thus granulation. reducing segregation potential.
Wet granulation (non-aqueous)
z Suitable for moisture sensitive API. z Vacuum drying techniques can remove/reduce need for heat.
Dry granulation (slugging or roll compaction)
z Eliminates exposure to moisture z Dusty procedure. and drying. z Not suitable for all compounds. z Slow process.
z z z z
Expensive equipment. Needs organic facility. Solvent recovery issues. Health and environment issues.
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Excipients
Pharmaceutical excipients can be defined as any substance other than the active API or pro-API that has been appropriately evaluated for safety and is included in API delivery system to either; 1. 2. 3. 4.
Aid processing of the system during manufacture or Protect, support or enhance stability, bioavailability or patient acceptability or Assist in product identification or Enhance any other attribute of the overall safety and effectiveness of the API product during storage or use (Blecher, L., 1995).
Ideally all the excipients must be chemically inert, non-hygroscopic, compatible with API, regulatory compliant, non-toxic, have acceptable taste and be inexpensive. The pharmaceutical industry uses many different types of excipients, which can be classified as primary excipients based on their functionality or as secondary excipients based on the way they are used. Primary excipients - This includes; fillers (diluents), binders, disintegrants, lubricants, glidants. They comprise the major part of a formulation and hold the key to its success.
Table 2: Effect of different physicochemical properties of API on the formulation
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Property of API
Effects on tablet formulation
Examples of API
Dose
Low dose may have content uniformity effects. High dose may result in direct physical impact of the API on tablet roperties.
Misoprostol, ramipril - low dose. Metformin, paracetamol - high dose.
Solubility
Low solubility of API may dictate the choice of manufacturing process from dissolution point of view. A wet granulation is the preferred method with such API.
Nifedipine, gliclazide have low solubility.
Melting point
Low melting point of API may result in sticking problems or soft tablets during compression.
Ibuprofen (M.P. ~ 560 C) is known to cause tablet punch sticking.
Particle size
Lower particle size of API may be important for higher solubility and dissolution. However, this may give rise to capping problem in tablets.
Celecoxib, Albendazole.
pKa
It dictates the pH level at which ionization takes place and subsequent solubilization. Acidic API having pKa (3-5) will solubilize at higher pH.
Aspirin, meloxicam exhibit better solubility in basic pH.
Flow properties
Poor flow of API may lead to loss of tablet hardness and weight variation issues. This may restrict the formulator to use granulation techniques or higher levels of lubricants/glidants to impart the flow, which may adversely affect dissolution and compaction.
Paracetamol bulk powder has poor flow. Hence needs to be granulated for tablet preparation.
Bulk density
Density plays a significant role in the blend uniformity of API along with other excipients. In general, for a high density API, the diluent selected should have high density and vice-versa in order to avoid segregation issues in a directly compressible formulation.
Glucosamine sulphate has high bulk density, whereas Chondroitin sulphate has low bulk density.
Moisture content
High moisture content of API may result in sticking issues during compression of tablets.
Ampicillin trihydrate formulation often cause tablet punch sticking problem.
Pharma Times - Vol 41 - No. 4 - April 2009
Property of API
Effects on tablet formulation
Examples of API
Hygroscopicity
Highly hygroscopic API may result in problems such as tablet punch sticking. Careful selection of manufacturing process, low humidity conditions in processing area become critical for such API.
Divalproex sodium and L-Carnitine.
Polymorphism
Certain API exhibit polymorphic forms, which may have differences in solubility, chemical stability or bioavailability. The polymorphic trans formation may occur during manufacturing process due to application or generation of heat or presence of moisture.
Desloratadine, Clopidogrel
Degradation profile
Certain API are unstable to heat or moisture or light. Formulating such API into tablets may be challenging.
Nifedipine is photosensitive. Rabeprazole is sensitive to heat and moisture.
Excipient compatibility
Certain API may be incompatible with specific excipients and may limit their selection. Excipient compatibility testing would help in selecting right excipient.
Aspirin is incompatible with magnesium stearate, Primary amine based API's are incompatible with Lactose (due to Malliard's reaction)
Compactability
Good ability to compact renders ease in direct compression of tablets. Certain API's, however, have poor ability to compact and hence granulation techniques may be required as a means of formulation velopment.
Acetaminophen has poor ability to compact, whereas Aspirin is good.
Secondary excipients - This includes; film coating, colors, flavors, sweeteners, wetting agents. These excipients are responsible for appearance and performance.
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Diluents
Diluent is added to formulation to increase the bulk volume of the active and hence the size of the tablet suitable for handling. The selection of the diluent will depend on the type of processing and plasticity of materials to be used. In general, a direct-compression formulation will require a diluent with good flow and compaction properties. Table 3 lists some of the commonly used diluents. Table 3: List of most commonly used tablet diluents Diluent
Advantages
Lactose
z z z z z z z
Lactose deforms by brittle fracture. Less sensitive to Mg. stearate over blending. Less sensitive to press speed. Granulation does impart some plastic nature to the end product. Good compressibility. Soluble in water. Many different grades available.
Limitations z z z z z
z
Mannitol
z z z z z
MCC
z z z z z z
Non-hygroscopic. Partly soluble in water. Non reactive. Negative heat of solution cooling mouth feel. Many grades available.
z
Highly compactable. Has some disintegrant properties due to wicking properties. Non-abrasive. Inert. Can be used in roller compaction and extrusion/ spheronization. Variety of particle size, moisture content and bulk density is available.
z
z z z z
z
z z
Comments
Lactose intolerance. Bovine derived. Abrasive - requires high levels of lubricant. May brown on aging/Maillard reaction. Slowest dissolving sugar formulations need adequate disintegrant. Spray dried forms may contain amorphous material.
z
Available as anhydrous and monohydrate; anhydrous material used for direct compression due to superior compressibility.
Very abrasive. Requires high levels of lubricant. Can cause punch filming/ picking. Potential laxative effect at high dose. Expensive. Has both plastic and brittle nature depending on grade.
z
It is not a reducing sugar and can be substituted for lactose (lactose not acceptable in certain markets). 10 - 90% usage level.
Insoluble. The wet massing process and the drying of the granules can lead to a considerable decrease in compaction properties. Incompatible with strong oxidizing agents. Disintegrant should be used in formulations.
z
z
z z
Very popular. Used at concentrations of 20 - 90%. Plastically deforming.
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Advantages
Sucrose
z
z
Partial pregelatinized starch
z z
z z
Dicalcium phosphate
z z z z
Limitations
Sucrose serves as a dry binder (2-20% w/w) or as a bulking agent and sweetener in chewable tablets and lozenges. Crystalline sucrose is free flowing.
z
Has better compaction properties than native starch. Partial gelatinization improves binding yielding, improved granule strength and enhanced tablet hardness. Multifunctional - acts as binder and disintegrants. Self lubricant and reduces requirement of lubricants.
z
Excellent flow properties. Ability to compact is good and independent of machine speed. Less susceptible to Mg. stearate over-blending. Non-hygroscopic.
z
z
z z z z
Powdered sucrose is a cohesive solid. Tablets that contain large amounts of sucrose may harden over time to give poor disintegration.
Sucrose is also available as invert sugar, compressible sugar and as sugar spheres.
For direct compression, it may be advantageous to combine partial pregelatinized starch with MCC or lactose in a 1:1 ratio for enhancing tablet hardness.
z
Practically insoluble in water, soluble in acid but not alkali. Not recommended for use with poorly soluble API. Loses water of crystallization at elevated temperatures. Can "trap" API under a cone or heap in a dissolution vessel. Abbrasive - can cause accelerated tooling and machine wear.
z
Diluents form a major portion of most of the tablet formulations due to newer high potency API's. The moisture content, more specifically water activity coefficient of such diluents, may influence API stability since many API are prone to degradation by hydrolysis. In general, moisture content may indicate hydrate form or tightly bound water molecule of crystallization, or surface-bound or surfaceabsorbed water on the excipient. The bound water may not cause hydrolysis of sensitive API, but free- or surface- absorbed water may be responsible for hydrolysis of sensitive API. This free water is termed as water activity coefficient. Figure 1 gives loss on drying (LOD) and water activity coefficient of some commonly used filler. Lactose, for instance, has low LOD, but very high water activity coefficient. On the other hand, Starch 1500 has very high LOD, but very low water activity coefficient. Hence, for API such as Aspirin or Ranitidine that undergo hydrolysis, Starch 1500 provides stable formulation, whereas lactose or plain microcrystalline cellulose leads to higher impurity levels on stability (Cunnigham CR 2001).
Mositure content
Today pharmaceutical companies increasingly use high speed tablet press for faster and higher productivity. For such high speed
Water activity aw
Comments
z z
z z z
Can be used up to 75% in wet granulation. Can be used up to 50% in direct compression. Globally accepted.
Not used extensively in wet granulations. Deforms by brittle fracture. Used up to 50%. Available in milled and unmilled forms.
tablet press, key process and corresponding diluent knowledge has become important. Use of combination of diluents with synergistic properties or co-processed excipients, such as StarCap 1500®, coprocessed starch excipient, are gaining significance in the pharmaceutical industry. Figure 2 shows impact of tablet press speed on the tablet breaking force (hardness) when compressed at increasing compression pressure. It can be seen that formulation with combination of MCC + Starch 1500 gives low yet acceptable hardness of tablets when compressed at higher speeds and at high compression pressures. This also means that the disintegration time is not affected for tablets compressed at higher compression pressure
Tablet Breading Force (kp)
Diluent
Compression Force (KN)
Figure 2: Effect of Press Speed on Hardness of tablets compressed at different compression pressures. Formula 3 contains: Dicalcium Phosphate Dihydrate (Emcompress®, 49.75%) +Microcrystalline Cellulose (Avicel® PH 102, 50%) + Magnesium Stearate (0.25%)
Figure 1: Water activity Vs Moisture content of some commonly used fillers.
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Formula 4 contains: Partially Pre-gelatinized Starch (Starch 1500®, 49.75%) +Microcrystalline Cellulose (Avicel® PH 102, 50%) + Magnesium Stearate (0.25%)
Disintegration Time (min)
required mechanical strength. During compaction, the binders provide the cohesive binding and deformation characteristics necessary for the formation of tablets. Table 4 lists some commonly used binders in the pharmaceutical industry with their typical concentrations, advantages and limitations. Compression Force (KN)
Before tableting, the powder mixture is Figure 3: Effect of Press Speed on disintegration time (min) of granulated simply by tablets compressed at different compression pressures. adding water, hydroalcoholic mixture or an organic solvent to as shown in Figure 3 (Colorcon technical form liquid bridges followed by the drying data sheet). This property is important for process. This granulation process results in direct compression based formulations that powders of larger particle size and that are need low friability, high hardness yet more free-flowing for tablet production. The acceptable disintegration time at a most common method of adding binders is reasonable compression force. as a solution in the granulating fluid. It is also possible to add polymers, such as Q partially pregelatinized starch (e.g. Starch 1500), polyvinyl pyrrolidone (PVP) and Binder is added during granulation step hydroxypropyl methylcellulose (HPMC), as to an API-filler mixture to ensure that powders and use water as the granulating granules and tablets can be formed with the
Binder
agent in normal equipment or using fluid bed equipment. When the granulate dries, the crystallization of any solids that had dissolved in the liquid will form solid bonds between the particles. Inclusion of granulating agents or binders to increase granule strength is necessary. Granulating agents are usually hydrophilic polymers that have cohesive properties that both aid the granulation process and impart strength to the dried granulate. The binder may vary the disintegration and dissolution and final performance of the tablet. Binders form films on the surface of the granules, which can aid in the wetting of hydrophobic API. However, if added at too great a concentration, the films can form viscous gels on the granule surface and may retard dissolution. Dry addition of binder is also possible in direct compression. Starch paste has been widely used as a binder. Starch paste is formed when starch grains are heated in water causing the rupture of the grains and release of the water soluble components. The paste is prepared by suspending the starch in water and then adding boiling water with stirring. Paste is cooled before adding to the powder, which on standing increases in viscosity and becomes an important property to control. Pregelatinized starch is an advanced, more
Table 4: List of some most commonly used binders Binders
Typical concentration used (%)
Advantages
Limitations
Native starch paste
5 - 25
z
Good binding ability.
z
Time consuming process, high variability in preparation of starch paste.
Pregelatinized starch
5 - 10
z
Cold water soluble, so easier to prepare than starch.
z
Only functions as a binder. The formulations with pregelatinized starch require separate disintegrating agents.
Partially pregelatinized starch
5 - 15
z
Acts as binder and also as disintegrant. Acts as a multifunctional agent.
z
Different suppliers have different gelatinization level.
Polyvinylpyrrolidone
2-8
Available in range of molecular weight/ viscosities. Soluble in water and ethanol.
z
Gives harder tablets upon stability prolonging the disintegration time and dissolution of the active.
It is soluble in different solvent systems and suitable for both aqueous, non-aqueous or hydro-alcoholic solvents. Can be used for modulation of API release. Number of viscosity grades available for granulation.
z
May give hard granules especially if binder concentration and kneading time is increased, during high shear granulation.
Good binder. Small concentration required for effective binding. Number of viscosity grades available for granulation.
z
May give hard granules, especially if binder concentration and kneading time is increased, during high shear granulation.
z
z z
Hydroxypropyl methylcellulose
2-8
z
z z
Methylcellulose
1-5
z z z
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user-friendly version than native starch paste, since this material may be incorporated as a dry powder and granulated with water. It is also possible to prepare slurry and use it as a granulating agent. A next generation product is partially pregelatinized starch. This product offers disintegrant property along with binding capacity. Level of gelatinization is a key to product performance. PVP is a versatile binder used as solution in water, ethanol or hydro-alcoholic mixture, or added dry to powder blends and granulated with water. One disadvantage with PVP is that it tends to reduce the viscosity of granulations and makes the determination of the granulation end point more difficult with certain type of instrumentation. The tablet produced with PVP as binder also increases disintegration time and retards the API release over time. HPMC is soluble in both water and ethanol, and it is versatile and inert material. Generally, lower viscosity grades are preferred for wet granulation.
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Disintegrant
Disintegrant is included in the formulation to ensure that the tablet breaks up into small fragments in contact with liquid. Figure 4 shows influence of disintegrating agent on disintegration time of tablets. Tablets must have sufficient strength to withstand the stresses of subsequent manufacturing operations, such as the coating, packaging, and distribution process. However, once the tablet is taken by the patient, it must break up rapidly to ensure rapid dissolution of the active ingredient in
Table 5 - List of some most commonly used disintegrants
Disintegrant
Typical Concentation used (%)
Native Starch
5 - 10
Probably works by wicking; swelling minimal at body temperature.
Partially pregelatinized starch
5 - 10
Amylose part of partially pregelatinized starch causes swelling and gives disintegrant action.
MCC
10 - 25
Strong wicking action; loses disintegrant action when highly compressed.
Insoluble ion exchange resings
2 - 10
Strong wicking tendencies with some swelling action.
Sodium starch glycolate
2-8
Free flowing powder that swells rapidly on contact with water.
Croscarmellose sodium
1-5
Swells on contact with water.
Gums such as agar, guar gum, xanthan gum, etc
