Tablet Formulation

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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.

Tablet Formulation Design And Manufacture:

Oral Immediate Release Application

Jayesh Parmar & Manish Rane

Colorcon Asia Pvt. Limited

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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 extrusion-spheronization, 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.

Article

Email: jparmar@colorcon.com mrane@colorcon.com

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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. Aid processing of the system during

manufacture or

2. Protect, support or enhance stability, bioavailability or patient acceptability or 3. Assist in product identification or 4. 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 1 : Tablet manufacturing methods - advantages and limitations Method Advantages Limitations

Direct compression z Simple, economical process. zNot suitable for all API, zNo heat or moisture, so good generally limited to lower

for unstable compounds. dose compounds. zSegregation potential. zExpensive excipients. Wet granulation zRobust process suitable for zExpensive: time and energy

most compounds. consuming process. zImparts flowability to zSpecialized equipment

a formulation. required.

zCan reduce elasticity problems. zStability issues for moisture zCoating surface with hydrophilic sensitive and thermolabile

polymer can improve wettability. API with aqueous zBinds API with excipient, thus granulation.

reducing segregation potential.

Wet granulation zSuitable for moisture sensitive zExpensive equipment. (non-aqueous) API. zNeeds organic facility.

zVacuum drying techniques can zSolvent recovery issues. remove/reduce need for heat. zHealth and environment

issues.

Dry granulation zEliminates exposure to moisture z Dusty procedure. (slugging or roll and drying. zNot suitable for all

compaction) compounds.

zSlow process.

Table 2: Effect of different physicochemical properties of API on the formulation Property of API Effects on tablet formulation Examples of API

Dose Low dose may have content uniformity effects. Misoprostol, ramipril - low dose. High dose may result in direct physical impact of the API on tablet Metformin, paracetamol - high dose. roperties.

Solubility Low solubility of API may dictate the choice of manufacturing process Nifedipine, gliclazide have low solubility. from dissolution point of view. A wet granulation is the preferred method

with such API.

Melting point Low melting point of API may result in sticking problems or Ibuprofen (M.P. ~ 560 C) is known to soft tablets during compression. cause tablet punch sticking. Particle size Lower particle size of API may be important for higher solubility and Celecoxib, Albendazole.

dissolution. However, this may give rise to capping problem in tablets.

pKa It dictates the pH level at which ionization takes place and subsequent Aspirin, meloxicam exhibit better solubilization. Acidic API having pKa (3-5) will solubilize at higher pH. solubility in basic pH.

Flow properties Poor flow of API may lead to loss of tablet hardness and weight variation Paracetamol bulk powder has poor flow. issues. This may restrict the formulator to use granulation techniques or Hence needs to be granulated for tablet higher levels of lubricants/glidants to impart the flow, which may preparation.

adversely affect dissolution and compaction.

Bulk density Density plays a significant role in the blend uniformity of API along Glucosamine sulphate has high bulk with other excipients. In general, for a high density API, the diluent density, whereas Chondroitin sulphate selected should have high density and vice-versa in order to avoid has low bulk density.

segregation issues in a directly compressible formulation.

Moisture content High moisture content of API may result in sticking issues during Ampicillin trihydrate formulation often compression of tablets. cause tablet punch sticking problem.

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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.

Property of API Effects on tablet formulation Examples of API

Hygroscopicity Highly hygroscopic API may result in problems such as tablet punch Divalproex sodium and L-Carnitine. sticking. Careful selection of manufacturing process, low humidity

conditions in processing area become critical for such API.

Polymorphism Certain API exhibit polymorphic forms, which may have differences Desloratadine, Clopidogrel 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.

Degradation Certain API are unstable to heat or moisture or light. Formulating Nifedipine is photosensitive. profile such API into tablets may be challenging. Rabeprazole is sensitive to heat and

moisture.

Excipient Certain API may be incompatible with specific excipients and may Aspirin is incompatible with compatibility limit their selection. Excipient compatibility testing would help in magnesium stearate, Primary amine

selecting right excipient. based API's are incompatible with Lactose (due to Malliard's reaction) Compactability Good ability to compact renders ease in direct compression of Acetaminophen has poor ability to

tablets. Certain API's, however, have poor ability to compact and compact, whereas Aspirin is good. hence granulation techniques may be required as a means

of formulation velopment.

Diluent Advantages Limitations Comments

Lactose z Lactose deforms by brittle fracture. z Lactose intolerance. z Available as anhydrous and z Less sensitive to Mg. stearate z Bovine derived. monohydrate; anhydrous material

over blending. z Abrasive - requires high levels used for direct compression due z Less sensitive to press speed. of lubricant. to superior compressibility. z Granulation does impart some z May brown on aging/Maillard

plastic nature to the end product. reaction.

z Good compressibility. z Slowest dissolving sugar -z Soluble in water. formulations need adequate z Many different grades available. disintegrant.

z Spray dried forms may contain amorphous material.

Mannitol z Non-hygroscopic. z Very abrasive. Requires high levels z It is not a reducing sugar and can be z Partly soluble in water. of lubricant. substituted for lactose (lactose not z Non reactive. z Can cause punch filming/ picking. acceptable in certain markets). z Negative heat of solution - z Potential laxative effect at high dose. z 10 - 90% usage level.

cooling mouth feel. z Expensive.

z Many grades available. z Has both plastic and brittle nature depending on grade.

MCC z Highly compactable. z Insoluble. z Very popular.

z Has some disintegrant properties z The wet massing process and the z Used at concentrations of 20 - 90%. due to wicking properties. drying of the granules can lead to z Plastically deforming.

z Non-abrasive. a considerable decrease in

z Inert. compaction properties.

z Can be used in roller compaction z Incompatible with strong oxidizing and extrusion/ spheronization. agents.

z Variety of particle size, moisture z Disintegrant should be used in content and bulk density is formulations.

available.

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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 bound or surface-absorbed 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).

Today pharmaceutical companies increasingly use high speed tablet press for faster and higher productivity. For such high speed

tablet press, key process and corresponding diluent knowledge has become important. Use of combination of diluents with synergistic properties or processed excipients, such as StarCap 1500®, co-processed 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

Diluent Advantages Limitations Comments

Sucrose z Sucrose serves as a dry binder z Powdered sucrose is a cohesive solid. Sucrose is also available as invert (2-20% w/w) or as a bulking agent z Tablets that contain large amounts sugar, compressible sugar and and sweetener in chewable tablets of sucrose may harden over time to as sugar spheres.

and lozenges. give poor disintegration. z Crystalline sucrose is free flowing.

Partial z Has better compaction properties z For direct compression, it may be z Can be used up to 75% in pregelatinized than native starch. advantageous to combine partial wet granulation.

starch z Partial gelatinization improves pregelatinized starch with MCC or z Can be used up to 50% in binding yielding, improved granule lactose in a 1:1 ratio for enhancing direct compression. strength and enhanced tablet tablet hardness. z Globally accepted. hardness.

z Multifunctional - acts as binder and disintegrants.

z Self lubricant and reduces requirement of lubricants.

Dicalcium z Excellent flow properties. z Practically insoluble in water, soluble z Not used extensively in phosphate z Ability to compact is good and in acid but not alkali. wet granulations.

independent of machine speed. z Not recommended for use with z Deforms by brittle fracture. z Less susceptible to Mg. stearate poorly soluble API. z Used up to 50%.

over-blending. z Loses water of crystallization at z Available in milled and z Non-hygroscopic. elevated temperatures. unmilled forms.

z Can "trap" API under a cone or heap in a dissolution vessel.

z Abbrasive - can cause accelerated tooling and machine wear.

Figure 1: Water activity Vs Moisture content of some commonly used fillers.

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%)

Formula 4 contains: Partially Pre-gelatinized Starch (Starch 1500®, 49.75%) +Microcrystalline Cellulose (Avicel® PH 102, 50%) + Magnesium Stearate (0.25%)

W

ater activity a

w

Mositure content

Tablet Breading Force (kp)

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as shown in Figure 3 (Colorcon technical data sheet). This property is important for direct compression based formulations that need low friability, high hardness yet acceptable disintegration time at a reasonable compression force.

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Binder

Binder is added during granulation step to an API-filler mixture to ensure that granules and tablets can be formed with the

required mechanical strength. During compaction, the binders provide the cohesive binding and deformation c h a r a c t e r i s t i c s necessary for the formation of tablets.

Table 4 lists some

commonly used binders in the pharmaceutical industry with their typical concentrations, advantages and limitations.

Before tableting, the powder mixture is granulated simply by adding water, hydro-alcoholic mixture or an organic solvent to form liquid bridges followed by the drying process. This granulation process results in powders of larger particle size and that are more free-flowing for tablet production. The most common method of adding binders is as a solution in the granulating fluid. It is also possible to add polymers, such as partially pregelatinized starch (e.g. Starch 1500), polyvinyl pyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC), as powders and use water as the granulating

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 Advantages Limitations concentration

used (%)

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 z Only functions as a binder.

than starch. The formulations with pregelatinized starch require separate

disintegrating agents.

Partially 5 - 15 z Acts as binder and also as disintegrant. z Different suppliers have different pregelatinized z Acts as a multifunctional agent. gelatinization level.

starch

Polyvinylpyrrolidone 2 - 8 z Available in range of molecular z Gives harder tablets upon stability weight/ viscosities. prolonging the disintegration time z Soluble in water and ethanol. and dissolution of the active. Hydroxypropyl 2 - 8 z It is soluble in different solvent systems z May give hard granules especially if methylcellulose and suitable for both aqueous, binder concentration and kneading

non-aqueous or hydro-alcoholic solvents. time is increased, during high z Can be used for modulation of shear granulation.

API release.

z Number of viscosity grades available for granulation.

Methylcellulose 1 - 5 z Good binder. z May give hard granules, especially z Small concentration required for if binder concentration and

effective binding. kneading time is increased, z Number of viscosity grades available for during high shear granulation.

granulation.

Disintegration T

ime

(min)

Compression Force (KN)

Figure 3: Effect of Press Speed on disintegration time (min) of tablets compressed at different compression pressures.

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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

immediate release preparations. To overcome the cohesive strength produced by the compression process, and to break down the tablet into the primary particles as rapidly as possible, disintegrants are added to the tablet formulations. The positioning of disintegrants within the intra- and extra-granular portions of granulated formulations can affect their water uptake and disintegration time.

Table 5 gives list of

some disintegrants commonly used in tablet formulations.

Starch was the first disintegrant used in tablet manufacture. The compaction properties of many disintegrants, including native starch, are not satisfactory and use of high concentration can also reduce tablet strength. Recent trend in pharmaceutical industry is towards use of

powerful disintegrating agents (superdisintegrants), such as croscarmellose sodium, sodium starch glycolate, crospovidone and certain ion exchange resins, which display excellent disintegration activity at low concentrations than native starches. Major limitations of these superdisintegrants are relatively high cost and hygroscopic nature, which could negatively affect the stability of moisture sensitive API (if the packaging does not provide adequate protection from the environment). Figure 5 depicts the moisture vapor sorption graph for different disintegrants (Cunnigham CR, 1999). Superdisintegrants, such as crospovidone, sodium starch glycollate and croscarmellose sodium, in general, have high moisture sorption tendency., Therefore, sometimes unsuitable for formulations containing moisture sensitive or hygroscopic API. Higher concentration of such superdisintegrants also causes problems during aqueous film coating, often giving rise to orange peel effect to the coating. Most pharmacopeias include a disintegration test which can be applied to tablets and the detailed monograph is given in the pharmacopeias.

Table 5 - List of some most commonly used disintegrants Typical

Disintegrant Concentation Comments used (%)

Native Starch 5 - 10 Probably works by wicking; swelling minimal at body temperature.

Partially 5 - 10 Amylose part of partially pregelatinized pregelatinized starch causes swelling and gives disintegrant

starch action.

MCC 10 - 25 Strong wicking action; loses disintegrant action when highly compressed.

Insoluble ion 2 - 10 Strong wicking tendencies with some

exchange swelling action.

resings

Sodium starch 2 - 8 Free flowing powder that swells rapidly on contact

glycolate with water.

Croscarmellose 1 - 5 Swells on contact with water. sodium

Gums such as < 5 Swells on contact with water; forms viscous gels agar, guar gum, that can retard dissolution, thus limiting xanthan gum, etc concentration that can be used.

Alginic acid, 4 - 6 Swells like gums, but forms less viscous gels than sodium alginate guar gum, xanthan, etc.

Crospovidone 1 - 5 High wicking activity.

Figure 4: Effect of different disintegrants on the physical properties of Hydrochlorthiazide tablets

(Tablet are composed of Hydrochlorthiazide, Dicalcium Phosphate, Lactose spray dried, magnesium Stearate and disintegrants)

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Figure 5: Moisture uptake isotherms for powders of different disintegrating agents.

%

W

eight

Change

% Relative Humidity at 25 deg. C

Crospovidone

Socium starch glycolate Crosslinked CMC

Starch 1500

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Lubricant

Lubricants are used in formulations to aid in smooth ejection of tablet from die cavity, prevent sticking of powder on punch faces (anti-adherence), reduce interparticle friction during compression and, to improve flow of powder blend on the machine and into the die cavity. For a robust formulation, careful consideration has to be given in selecting right type, concentration, order and duration of mixing of lubricant in the formulation. Lubricants can be further classified into three types based on their detailed functionality: (1) glidant, which enhance flow property of powder blend by overcoming powder cohesiveness, (2) anti-adherent, which reduce the friction between the tablet punch faces and tablet punches, and (3) die wall lubricant, which reduce the friction between the tablet surface and the die wall during and after compaction to enable easy ejection of the tablet. Die-wall lubricants can be divided into two classes: fluid and boundary lubricants. Fluid lubricants work by separating moving surfaces completely with a layer of lubricant. These are typically mineral oils or vegetable oils, and they may be either added to the mix or applied directly to the die-wall by means of wicked punches. The oily lubricants may give a mottled tablet appearance due to uneven distribution, poor powder flow due to their tacky nature, and reduced tablet strength. Boundary lubricants work by forming a thin solid film at the interface of the die and the tablet. Metallic stearates are the most widely used boundary lubricants.

Talc is traditionally one of the most commonly used glidants, having the

adherent. The level of talc that can be added to a formulation is restricted by its hydrophobic nature; too high levels resulting in decreased wetting of the tablet and a subsequent reduction in the rate of dissolution. Fumed silicon dioxides are perhaps the most effective glidants. These are materials with very small (10 nm) spherical particles that act as dividing cohesive particles to provide their glidant properties. They are available in a number of grades with a range of hydrophobic and hydrophilic forms, and are commercially available under diverse brand names. Starch has also been used as a glidant. The use of large amounts of starch can also aid the disintegration properties. Table 6 gives list of some commonly used lubricants in the tablet formulations.

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Anti-adherent

Anti-adherent causes reduction in adhesion of powder to punch faces and thus

Table 6 - List of some commonly used lubricants in tablet formulations

Typical

Disintegrant Concentation Comments

used (%)

Glidant

Talc 1 - 5 Fine, crystalline powder, widely used as lubricant and diluent

Fumed silicon dioxide 0.1 - 0.5 Has small particle size and large surface area for good flowability; used for adsorbent, anti-tacking agent, disintegrant and glidant.

Native starch 1 - 10 Native starch powder is used as glidant and also as disintegrant.

Sodium lauryl sulfate 0.2 - 2 Anionic surfactant, lubricant and wetting agent.

Boundary lubricants

Magnesium stearate 0.2 - 2 Hydrophobic, variable properties between suppliers. Calcium stearate 0.5 - 4 Hydrophobic.

Sodium stearyl fumarate 0.5 - 2 Less hydrophobic than metallic stearates, partially soluble.

Polyethylene glycol 2 - 20 Soluble, poorer lubricant activity than fatty 4000 & 6000 acid ester salts.

Sodium lauryl sulfate 1 - 3 Soluble, also acts as wetting agent. Magnesium lauryl sulfate 1 - 3 Acts as wetting agent.

Sodium benzoate 2 - 5 Soluble.

Fluid lubricants

Light mineral oil 1 - 3 Hydrophobic, can be applied to either formulation or tooling.

Hydrogenated 1 - 5 Hydrophobic, used at higher concentrations as vegetable oil controlled release agents.

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helps in preventing sticking. These materials do not influence ejection force or residual force. Thus they are most often used in combination with other lubricants to improve overall performance during compaction.

Magnesium stearate, a boundary wall lubricant, readily forms a thin film on the die-wall surface. This results in reduction in powder ability to form strong compacts. Also, due to hydrophobic nature, it can hinder disintegration and dissolution performance of tablets. When formulation contains disintegrating agents, the addition of lubricant should be at the end of the mixing process. If both lubricant and disintegrant are added together, then lubricant may form a hydrophobic film around the disintegrating

agent and ultimately result in prolonging disintegration time. Formulation containing high concentration of magnesium stearate may result in tablets of reduced hardness, even if the compression force is increased. Figure 6 gives the effect of different concentration of magnesium stearate on the breaking force of Hydrochlorthiazide tablets (Cunnigham CR, 2000). As the concentration of magnesium stearate increased from 0.25% to 1.0% the tablet breaking force reduced. The effect increased as a function of the compression force. However, when stearic acid was used, at even 1% concentration, the tablets produced were increased with compression pressure.

Also, higher concentration of magnesium stearate can retard the dissolution of API due to its hydrophobic nature. Figure 7 gives the effect of magnesium stearate on release profile of Hydrochlorthiazide.

Many pharmaceutical companies use combination of talc and stearic acid or talc and hydrogenated vegetable oils as an alternative to magnesium stearate. However, the major limitation to such combinations is high concentration required to give good lubricant properties in comparison to magnesium stearate.

The level of a lubricant required in a tablet is formulation dependent and can be optimized using an instrumented tableting machine. It should be remembered that the requirements for lubrication and anti-adherent may be very different when tablet presses are run at laboratory scale and at production scale. No single lubricant provides all the balanced functionality of each individual class of lubricant.

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Other excipients

Certain excipients, like anti-oxidants and surfactants, are used only in situations where they are expressly needed to ensure the stability or performance of the product.

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Excipient selection

The selection of excipients is influenced by range of interrelated factors, both objective and subjective. All the factors, like properties Tablets contained Hydrochlorthiazide, Dicalcium Phosphate, Lactose,

Starch 1500®, MCC, lubricant.

Figure 6: Effect of different concentrations of lubricants on the tablet breaking force

Figure 7: Effect of Magnesium Stearate on Dissolution of Hydrochlorthiazide

Properties of excipients z Stablity (chemical & physical) z Hygroscopic z Compatible z Particle size z Availability z Cost z Regulatory acceptance Properties of drug z Dose z Solubility/ pKa z Particle Size/ Shape z Melting Point/ Thermal

Stability z Flow Properties z Densities Manufacturing process requirement z Direct compression z Wet granulation z Fluid bed granulation z Spray drying z Extrusion &

spheronization z Other novel process

Selection of

excipients for

solid oral

dosage forms

Desired release characteristics z Immediate release

z Sustained release z Modified release

Figure 8: Factors affecting the selection of excipients.

Compression Force (KN)

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of API and excipients, desired release characteristics and even manufacturing process, play an important role in making a decision [Figure 8]. For example, the choice of manufacturing method depends on the infrastructure available with the company, associated cost and may be personal preference or experience. It also depends on the dose of API and its physicochemical properties. And finally, suitability and availability of excipient also play an important role. In the present scenario, even quality of service offered by supplier, batch-to-batch uniformity of product, regulatory acceptance, are also important parameters to be considered.

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Bibliography And

References

z Blecher, L., Excipients - The important components, Pharm. Process., 1995, 12 (1), pg 6 - 7.

z Cunnigham C. R. and Scattergood L. K., Optimizating lubricant usage in a direct compression hydrochlorthiazide

formulation containing a plastically deforming excipient, AAPS, October 2000.

z Cunnigham C. R. and Scattergood L. K., Evaluation of partially pregelatinized starch in comparison with superdisintegrants in a direct compression hydrochlorthiazide formulation, AAPS, October 1999. z Colorcon Technical Data Sheet, Dibasic

calcium phosphate replacement with Starch 1500® in a direct compression formula.

z Cunnigham C. R. and Scattergood L. K., The effect of Starch 1500® on the stability of aspirin tablets stored under accelerated conditions, AAPS, October 2001.

z Cunnigham C. R. and Scattergood L. K., Use of Starch 1500® to improve the uniformity of a low dose direct compression chlorpheniramine formulation, AAPS, October 2000. z Rowe RC, Sheskey PJ, Owen SC (Ed.),

Pharmaceutical Excipients. Pharmaceutical Press and American Pharmacists Association, Fourth edition, 2005.

z Kottke, M. K. and E. M. Rudnic, chapter 10 - Tablet dosage form in Modern Pharmaceutics, Ed. Banker GS, Rhodes C, Marcel Dekker Inc., 2002.

z Cunnigham, C. R. and Scattergood, L. K., Fluid bed granulation of Acetaminophen: Effect of key process variables on granule and tablet characteristics, AAPS, October 1999. z Do N., Farrel T., Control of dissolution

rate of immediate release tablets containing Starch 1500® with a combination of different types and grades of Methocel™, AAPS, Nov. 2006.

z Kadtare A, Chaubal M, Excipient Development for Pharmaceutical, Biotechnology, and API Delivery Systems, Informa Healthcare, USA, 2006.

UK company Paraytec has introduced a new instrument designed to allow formulation scientists to visualise - in real time - what is happening at a tablet surface when it dissolves.

The new device - called the ActiPix Dissolution Imager - was introduced to the marketplace at Pittcon on March 9 and could make it easier for drug developers to develop controlled-release medications.

Paraytec says the instrument offers formulation scientists an alternative to "high-cost, complex techniques such as terahertz spectroscopic imaging and magnetic resonance imaging "as they investigate the release of active compounds from dosage forms.

The ActiPix Dissolution Imager is "a powerful tool that can reduce the time it takes

Real-time analysis of tablet surfaces

Phil Taylor

a drug to come to market, thereby offering significant potential gains in earnings," according to a Paraytec statement.

Tablet holder enables accurate analysis

The instrument combines a specially designed tablet holder and Paraytec's ActiPix D-100 UV area imager. The holder is placed inside the ActiPix D-100 which enables real time recording and review of data. When liquid flows over the surface of the formulation, release of the active ingredient can be quantitatively monitored directly at the tablet surface.

"It is important ... to understand the mechanism of drug release behaviour, as this regulates the performance of many solid pharmaceutical dosage formulations," said Paraytec.

The ActiPix D-100 instrument has been

used in a number of other applications in the pharmaceutical industry, including enzyme assays and protein sizing. Paraytec has also been developing the technology for in-line testing in bioprocessing, for example by quantifying protein aggregation.

Paraytec spun of from University of York

Paraytec was spun out from the University of York to develop a series of instruments based on miniaturised ultraviolet-visible (UV-vis) absorbance detectors and capillary-based fluid handling technology.

UV absorbance detection is a laboratory technique widely employed to characterise and determine the levels of substances which dissolve in water and other liquids, with light absorbed at different wavelengths in the ultra-violet region indicating different compounds.

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