CAPSULES

Introduction

The word capsule is derived from the latin capsula meaning a small box. In pharmacy, the word capsule is used to describe an edible package made from gelatin which is filled with medicines to produce a unit dose, mainly for oral use. There are two types of capsule, differentiated by adjectives hard and soft. The hard capsule consists of two pieces, a cap and a body, that fit one inside the other.

They are produced empty and are filled in a separate operation. The soft gelatin capsule is a capsule which is manufactured and filled in one operation.

Raw Material for Gelatin Capsule

The raw material used in manufacture are similar for both hard and soft capsules. The first stage of the process is to prepare a gelatine solution in demineralized water or a mixture of demineralized water and glyserol. To this are added, colorants, preservatives and process aid depending upon the type of capsule required.

Gelatin Gelatin is the major component of the capsule and has been the only material from which they have been successfully made. The reason for this is this gelatin possesses four essential basic properties : 1. It is non-toxic.

2. It is readily soluble in biological fluid at body temperature. 3. It is a good film forming material. 4. As solution in water or water-glycerol blend it undergoes a reversible phase change from sol to a gel at temperatures only a few degree above ambient.

Plasticizers

The walls of hard gelatin capsules are firm and rigid. The walls of soft gelatin capsules on the other hand are more soft and flexible. It is turgid because it is manufactured and filled in one operation which results in the pressure of the contents maintaining the capsule shape. The capsule is soft because it contains a large proportion of a plasticizer. This can be varied to produce capsules for different applications. The plasticizer which is most frequently used is glycerol, sorbitol, propylene glycol, sucrose and acacia have been used also.

Table 1. Control of the plasticizer content of shell for soft gelatin capsules in conjunction with their intended use. Hard gelatin capsules rarely, if ever, contain added plasticizer

Glycerol : Gelatin ratio (parts of dry glycerol to one part of dry gelatin) 0.35 0.46 0.55 0.65

Application

Oral capsules with oil fills where final capsule should be hard Oral capsule with oil fills where shell requires to be more elastic Capsules containing oils with added surfactant or products with hydrophilic liquid fills

0.76

Oral capsules where a chewable shell is required

Colorants The colorants which are used can be of two kinds : soluble dyes or insoluble pigments. The soluble dyes are mainly synthetic in origin and the use of mixtures of dyes, capsule can be made in all colors of the spectrum. The pigment used are of two types. The one which is used in the largest quantity is titanium dioxide. This is white and used as an opacifying agent. The other class of pigments is the oxide of iron; three are used : black, red and yellow.

Preservatives Preservatives are sometimes added to capsule as an in-process aid in order to prevent microbiological contamination during manufacture. In the finished capsules, the moisture levels are such that the capsule will not support bacterial growth. Soft gelatin capsules sometimes have antifungal agents added to them to prevent growth on their surfaces when they are stored in non-protective packages.

Hard Gelatin Capsules

Size of Hard Gelatin Capsule Shell The hard gelatin capsule is made in a range of eight size from size 000, the largest, to size 5, the smallest. The most popular sizes in practice are size 0 through to 4. The hard gelatin capsule shape has basically remained unchanged since its invention, except for the development of self-locking capsule.

Table 2. Hard Gelatin Capsule Sizes and Fill Volume

No. 5 4 3 2 1 0 00 000 Volume in ml 0.13 0.2 0.27 0.37 0.48 0.67 0.95 1.36

Filling Hard gelatin capsules are most frequently filled with powder. The only limitation is that they should not react with gelatin, e.g. aldehydes, or interfere with the integrity of the shell, e.g. water which will soften the wall. All formulations for filling into capsules must possess two basic requirement. They must : 1. be able to be accurately dosed into the capsule shell, 2. release their active contents in a form which is available to the patient. To accomplish this the formulation is usually a simple blend of the active ingredients together with adjuvants which aid the process, e.g. diluents, glidants, lubricants and surfactants.

Formulation of Powder for Filling The factor which contributes most to a uniformly filled capsule is powder flow. Low dose drugs can be made to flow well by mixing with free flowing diluents, e.g. maize starch. Small quantities (up to about 5% w/w) of highly active materials are used glidants, which improve flow by reducing interparticulate friction (e.g. Fumed Silicon Dioxide) and lubricants, which reduce powder to metal adhesion (e.g. magnesium stearate) thus enabling the dosing devices to function properly. The factor in the formulation which control drug release are the natures of the active ingredient and the adjuvants. Smaller particles which give higher blood level can not be utilized in all cases because of particle aggregation.

Insoluble drugs are mixed with soluble diluents (adjuvant), e.g. lactose, in order to make the mixture more hydrophilic. Soluble drugs can be mixed with insoluble diluents, e.g. starch, in order to avoid competition for solution. Lubricants, Mg stearate are hydrophobic in nature, thus tending to slow down release. This effect can be minimized by using wetting agent, e.g. sodium lauryl sulphate.

1. 2. 3. 4.

Formulation Factors Affecting Release from Hard Gelatin Capsules Active ingredient. Diluent. Glidants and lubricants. Wetting : effects of porosity and the addition of surfactants.

Soft Gelatin Capsules

Description 1. Soft gelatin capsules (SGC) consist of units with a continuous gelatin shell surrounding a liquid fill material. 2. The capsules are formed, filled and sealed in one operation and may be of different sizes and shapes.

1.

2.

3. 4.

Problem may be experienced : A high dose of a poorly compressible drug may be difficult to form into tablets and there may be capping problems in production. There may be powder flow or mixing problems and the dose of the drug in each dosage unit may not be uniform. The drug may hydrolyse or oxidize on long term storage. The drug subtance may be poorly soluble in water or gastric juice and the bioavailability from some solid dosage forms might be poor.

1. 2.

3.

4.

An alternative approach is to consider the use of soft gelatin capsules. The problems mentioned above are overcome for the following reason : A compression stage is not included in the manufacturing process. The dose content uniformity is optimized because the drug is dissolved or dispersed in a liquid which is then dosed volumetrically into the capsules accurately. Drug sensitive to oxidation or hydrolysis can be protected by solution or dispersion in oil and encapsulation by gelatin. The drug is dissolved or dispersed in a water miscible or oily liquid and when the capsule is ingested, the capsule breaks and the solution dissolves or is emulsified to give a drug dispersion of high surface area and good bioavailability.

Compression
Compression problem can be minimized by careful choice of excipients and/or by granulation. However, the cost of granulation can be high and compression can be affected by interbatch variation in material properties. Any compound which is difficult to compress into tablets plus those which are liquids or which melt at the temperature of compaction could be formulated in a soft gelatine capsule.

Mixing and Powder Flow

The dose content uniformity of soft gelatin capsules is good because the product consists of encapsulated solutions or suspensions which flow readily and are homogeneous. The fill liquids are metered into capsules using accurate instrument. Thus improved content uniformity results in improved therapeutic consistency for potent compounds and the potential for reduced costs through the use of smaller overages in the case of high cost products.

Stability

The gelatin shell of a soft gelatin capsule provides a good barrier against the diffusion of oxygen from the environment into the liquid contents of the product. Soft gelatin capsules contain little residual water and compounds which are susceptible to hydrolysis are protected if dissolved or dispersed in an oily liquid fill material and encapsulated as soft gelatin capsule. The dielectric constant of an oily vehicle is low and the ionization of polar materials is impaired. The tendency for chemical reaction to occur is low.

Bioavailability
In soft gelatin capsule formulation the medicament is in solution or is dispersed as fine suspension in either hydrophilic vehicle or hydrophobic base. When a soft gelatin capsule is ingested, the gelatin shell dissolves quickly or breaks open at the heat sealed seam. The liquid medicament is released into the gastric content where water-miscible vehicle dissolve and oily liquids emulsify.

Formulation of The capsule Content of Soft Gelatin Capsule

1. 2.

3.

4.

Limitation for fill material Drug or exipients containing high concentrations of water or other gelatin solvents can not be incorporated. It is not recommended to fill emulsion (whether they be o/w or w/o) since they are unstable and will crack as the water is lost from the shell in the manufacturing process. Extreme pH must be avoided. pH below about 2.5 attack the gelatin leading to hydrolysis and subsequent leakage and pH above about 7.5 have tanning effect on the gelatin, effecting the subsequent solubility of the shell. Aldehydes must also be avoided since these have a tanning action on the proteins of the gelatin shell.

1.

2.

Liquid vehicles Water immiscible oils : vegetable oils, aliphatic, aromatic and chlorinated hydrocarbons, and liquid ethers and esters. Water miscible liquids : PEG (400 600), isopropyl alcohol, polyglycerols, triacetin, glyceryl esters, sorbitan esters, sugar esters and polyglyceryl esters. Propylene glycol and glycerol can be used but the concentration must be low, e.g. 5 10 %, in order to prevent migration into gelatin and softening of the shell.

Suspension Insoluble drugs can be dispersed (with suspending agents and surfactants) in the above vehicle or combinations of vehicles. Suspending agent are added to maintain homogeneity. Examples : beeswax, paraffin wax, ethylcellulose, vegetable oil for oily bases and PEG for non-oily bases, surfactant (tween 80) for wetting the inggredients.

What is Gelatin ?
Gelatin is a substance of natural origin, but doest not occur as such in nature. It is prepared by the hydrolysis of collagen which is the main protein constituent of connective tissues. Thus animal bones and skins are the raw material for the manufacture.

Gelatin Types

1.
2.

There are two types of gelatin : Type A, which is produced by acid hydrolysis. Type B, which is produced by basic hydrolysis. The choice of manufacturing method depends upon the nature of the raw materials. Skins are mainly acid processed whereas bones are usually basic processed.

 1.

2.

3. 4.

For soft gelatin capsule : If the viscosity of standard aqueous gelatin solution is too low. A thin, low strength shell is produced which has the added disadvantage of requiring prolonged drying. If the viscosity of the gelatin solution is too high, a thick film is produced which may be too hard and brittle. High viscosity gelatin formulations also require higher sealing temperatures during manufacture. The mechanical properties of the gelatin shells are controlled by choice of gelatin grade and by adjusting the concentration of plasticizer in the shell.

Bioavailability Aspects of Hard Gelatin Capsules

= (The factors in the formulation of product to be filled in hard gelatin capsules) Disintegration and dissolution Formulation factors affecting release from hard gelatin capsules. 1. Active ingredient 2. Diluent 3. Glidants and lubricants 4. Wetting

Disintegration and Dissolution

How do the capsules disintegrate? The first stage in drug release from a capsule is disintegration of the capsule shell. When they are placed in a suitable liquid at body temperature the gelatin starts to dissolve, within 1 minute the shell splits, usually at the ends and with a properly formulated product, the contents start to empty before all the gelatin has dissolved. The powder mass in the capsule should be such that it does not interfere with the dissolution of gelatin shell and such that it will break up.

Formulation Factors Affecting Release from Hard Gelatin Capsules

1. 2.

3.
4. 5.

6.

Active ingredient It is necessary to know its physico-chemical properties such as solubility, melting point, crystalline form, etc. Most of the properties of the active ingredient are beyond the control of the formulator but one factor which can be modified is its particle size. It has been shown for several drugs in capsules that their rate of absorption is governed by their particle size. The smallest particle will give the maximum blood level. But when particles are too small they tend to aggregate together and this effect is lost. The other factors which can be manipulated are the other components in the formulation : diluents, lubricants, glidants and surfactants.

 1. 2. 3.

4.
5.

6.

Diluents The change of the diluent had significant effect on the bioavailability of the drug. The change of diluent to lactose gave higher blood level. The diluent should be chosen with reference to the solubility and proportion of the active ingredient. For soluble drug, an increase in the quantity of lactose in the formulation decreased its dissolution rate. This can be explained by saying that as lactose is readily soluble it passes into solution preferentially and thus the dissolution rate measured is that of the drug in saturated lactose solution. In the case of a readily soluble drug an insoluble diluent such as starch should be choose.

1.

2.

Glidant and lubricant This materials tend to make the mass hydrophobic thus the dissolution rate of drug will decrease. Wetting If hydrophobic compounds have to be included in formulations because of filling machine requirements, their deleterious effect on drug release can be overcome by addition of wetting agents, surfactant. The denser packing reduced the dissolution rate.

Bioavailability Aspect of Soft Gelatin Capsules

Acid soluble drugs, dissolved or dispersed in water-miscible vehicle, are distributed quickly throughout the stomach. Acid-insoluble compound administered as a solution in soft gelatin capsule precipitate as fine suspension in the stomach which redissolves to give a solution with optimum bioavailability. Drugs dissolved in an oil which emulsifies, or drugs which are themselves oils and emulsify will have high surface area and the bioavailability is good.