Capsules

Capsules

are solid dosage forms in which one or more medicinal or inert substances (as powder, compact, beads, or granulation) are enclosed within a small gelatin shell.

Extemporaneously compounded capsules

are usually filled by the punch method.

Solids may be encapsulated into soft gelatin capsules

as solutions in a suitable liquid solvent, suspensions, dry powders, granules, pellets, or small tablets.

SELECTING CAPSULES

1. If the drug dose is inadequate to fill the capsule, a diluent (e.g., lactose) is added. 2. If the amount of drug needed for a usual dose is too large to place in a single capsule, two or more capsules may be required. 3. Lubricants such as magnesium stearate (0.25 - 1%) are added to facilitate the flow of the powder when an automatic capsule-filling machine is used. 4. Wetting agents (e.g., sodium lauryl sulfate) may be added to capsule formulations to enhance drug dissolution.

TETRACYCLINE CAPSULES

1.Active ingredient 2.Filler 3. Lubricant/glidant 4. Capsule colorants 5. Capsule opaquant 1. Tetracycline hydrochloride 250 mg 2. Lactose 3. Magnesium stearate 4. FD&C Yellow No. 6, D&C Yellow No. 10, D&C Red No. 28, FD&C Blue No. 1 5. Titanium dioxide

FETON CAPSULE FILLING MACHINE

A. With empty capsules in the loader tray, the tray placed on top of the filler unit. B. The loader inserts the capsules into the filling unit and is removed, and the top plate is lifted to separate the caps from the bodies. C. The powder is placed on the unit and the capsule bodies are filled. D. The top plate is returned to the unit and the caps are placed on filled capsule bodies.

Content Labeling Requirement

All official capsules must be labeled to express the quantity of each active ingredient in each dosage unit.

capsules sealing another process

Another process uses a liquid wetting agent that lowers the melting point in the contact areas of the capsule's cap and body and then thermally bonds the two parts using low temperatures (40°C-45°C).

Disintegrant

Breakup and distribution of the capsule's contents in the stomach. Pregelatinized starch, croscarmellose, sodium starch glycolate

heat-welding

Capsules may also be sealed through a heat-welding process that fuses the capsule cap to the body through the double wall thickness at their juncture. The process results in a distinctive ring around the capsule where heat welded.

HARD GELATIN CAPSULES

During the closing process, the capsule body is inserted into the cap. With the high- capacity filling rates of the modern capsule filling machines (more than 180,000 capsules per hour), splitting (telescoping) and/or denting of the capsule shell occur with the slightest contact between the two rims when they are joined.

Soft gelatin capsules are prepared to contain a variety of liquid, paste, and dry fills.

Liquids that can be encapsulated into soft gelatin capsules include the following. 1. Water-immiscible volatile and nonvolatile liquids such as vegetable and aromatic oils, aromatic and aliphatic hydrocarbons, chlorinated hydrocarbons, ethers, esters, alcohols, and organic acids 2. Water-miscible nonvolatile liquids, such as polyethylene glycols, and nonionic surface-active agents, such as polysorbate 80 3. Water-miscible and relatively nonvolatile compounds such as propylene glycol and isopropyl alcohol, depending on factors such as concentration used and packaging conditions

Capsules Sealing

Manufacturers make tamper-evident capsules by sealing the joint between the two capsule parts.

Capsule Disadvantages

Not suitable for administering very soluble ionic salts (e.g., potassium chloride, ammonium chloride)

colored band of gelatin

One manufacturer makes distinctive-looking capsules by sealing them with a colored band of gelatin (Kapseals, Parke-Davis). If removed, the band cannot be restored without expert resealing with gelatin.

DISSOLUTION TEST FOR CAPSULES

Paddle method- USP Apparatus 2 Basket method - USP Apparatus 1

Lubricant or Glidant

Powder mix or granules must be free- flowing to allow steady passage of the capsule fill from the hopper through the encapsulating equipment and into the capsule shells. To enhance flow properties Magnesium stearate, Fumed silicon dioxide, Talc (0.25 -1%)

Diluent

Produce proper capsule fill volume Provide cohesion to powders, useful in transfer of the powder blend into capsule shells Lactose, Microcrystalline cellulose, starch

Soft Gelatin Capsules Preparation

Soft gelatin capsules are prepared from gelatin shells. • Glycerin or a polyhydric alcohol such as sorbitol is added to these shells to make them elastic or plastic-like. • These shells contain preservatives (e.g., methyl and propyl parabens, sorbic acid) to prevent the growth of fungi. • Soft gelatin shells are oblong, elliptical, or spherical. • They are pharmaceutically elegant and easily swallowed. • They are used to contain liquids, suspensions, pastes, dry powders, or pellets and even preformed tablets.

Added Substances

Substances added to official preparations, including capsules, to enhance their stability, usefulness, or elegance or to facilitate their manufacture may be used only if they: 1. Are harmless in the quantities used 2. Do not exceed the minimum amounts required to provide their intended effect 3. Do not impair the product's bioavailability, therapeutic efficacy, or safety 4. Do not interfere with requisite compendial assays and tests

Hard Capsules

Ten capsules are individually weighed and their contents removed. The emptied shells are individually weighed and the net weight of the contents is calculated by subtraction. From the results of an assay performed as directed in the individual monograph, the content of the active ingredient in each of the capsules is determined.

MOISTURE PERMEATION TEST

The USP requires determination of the moisture permeation characteristics of single-unit and unit-dose containers to ensure their suitability for packaging capsules.

Soft Capsules

The gross weight of 10 intact capsules is determined individually. Then each capsule is cut open and the contents are removed by washing with a suitable solvent. The solvent is allowed to evaporate at room temperature over about 30 minutes, with precautions to avoid uptake or loss of moisture. The individual shells are weighed and the net contents calculated. From the results of the assay directed in the individual monograph, the content of the active ingredient in each of the capsules is determined.

PREPARATION OF FILLED HARD GELATIN CAPSULES

The large-scale or small-scale preparation of filled hard gelatin capsules is divided into the following general steps. 1. Developing and preparing the formulation and selecting the capsule size 2. Filling the capsule shells 3. Capsule sealing (optional) 4. Cleaning and polishing the filled capsules

STABILITY

USP <795> Pharmacy Compounding § 6 months if prepared from USP/NF ingredients § 25% of remaining expiration dating if prepared from commercial products § Unless evidence is available to support other dating

Surface active agent/ surfactant

Wetting of powder particles by gastrointestinal fluid, Displace the air that surrounds the dry powder Sodium lauryl sulfate

If the patient cannot swallow an intact solid dosage form,

an alternative product, such as a chewable tablet, instant dissolving tablet, oral liquid, oral or nasal inhalation solution, suppository, or injection, may be employed.

If these are not available,

an extemporaneously prepared liquid dosage form may be prepared.

Moisture may be absorbed by gelatin capsules

and may affect hygroscopic agents within, many capsules are packaged along with a small packet of a desiccant material to protect against the absorption of atmospheric moisture.

Large capsules

are available for veterinary medicine

Hard capsules

are available in a variety of sizes. The capacity varies because of varying densities of powdered drug materials and the degree of pressure used to fill the capsules.

Capsule shells

are cast by dipping cold metallic molds or pins into gelatin solutions that are maintained at a uniform temperature and an exact degree of fluidity.

The degree and rate of moisture penetration

are determined by packaging the dosage unit together with a color-revealing desiccant pellet, exposing the packaged unit to known relative humidity over a specified time, observing the desiccant pellet for color change (indicating the absorption of moisture), and comparing the pretest and posttest weight of the packaged unit.

Liquids that can easily migrate through the capsule shell

are not suitable for soft gelatin capsules. These materials include water above 5% and low molecular weight water-soluble and volatile organic compounds such as alcohols, ketones, acids, amines, and esters.

Empty capsules

are numbered from 000, which is the largest size that can be swallowed, to 5, the smallest size. 000 00 1,2,3,4,5

Gelatin capsules are unsuitable for aqueous liquids

because water softens gelatin and distorts the capsules, resulting in leakage of the contents.

some liquids, such as fixed or volatile oils

do not interfere with the stability of the gelatin shells may be placed in locking gelatin capsules (or the capsules may be sealed with a solution of gelatin thinly coating the interface of the cap and body) to ensure retention of the liquid.

The desiccant materials most often used are

dried silica gel, clay, and activated charcoal.

Crystalline materials

especially those that consist of a mass of filament-like crystals (e.g., quinine salts) will not fit into a capsule easily unless they are powdered.

Automated and semiautomated capsule-filling equipment

fill the capsule bodies with the formulation by gravity fill, tamping, or a screw-feed (i.e., auger) mechanism.

Empty hard capsule shells are manufactured from a mixture of

gelatin, colorants, and sometimes an opacifying agent (e.g., titanium dioxide). The USP also permits the addition of 0.15% sulfur dioxide to prevent decomposition of gelatin during manufacture.

Gelatin is soluble in

hot water and in warm gastric fluid; a gelatin capsule rapidly dissolves and exposes its contents.

Dosage forms that must be left intact

include enteric coated tablets, designed to pass through the stomach for drug release and absorption in the intestine, extended-release dosage forms, designed to provide prolonged release of the medication and sublingual or buccal tablets, formulated to dissolve under the tongue or in the mouth.

Variation in the viscosity of the gelatin solution

increases or decreases the thickness of the capsule wall.

Gelatin, being a protein

is digested by proteolytic enzymes and absorbed.

Although gelatin is insoluble

it does soften in cold water through the absorption of water up to 10 times its weight of water.

Gelatin capsules

may be hard or soft.

Extemporaneously prepared capsules

may be sealed by lightly coating the inner surface of the cap with a warm gelatin solution immediately prior to placement on the filled capsule body.

Eutectic mixtures of drugs

or mixtures of agents that have a propensity to liquefy when admixed, may be mixed with a diluent or absorbent such as magnesium carbonate, kaolin, or light magnesium oxide to separate the interacting agents and to absorb any liquefied material that may form.

Gelatin USP is obtained by

partial hydrolysis of collagen obtained from the skin, white connective tissue, and bones of animals. Types A and B are obtained by acid and alkali processing, respectively.

Preparation of filled hard capsules includes

preparing the formulation, selecting the appropriate capsule, filling the capsule shells, and cleaning and polishing the filled capsules.

volume occupied

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Granular material

that does not lend itself well to the punch method can be poured into each capsule from the powder paper on which it was weighed.

Whether on a large or a small-production scale

the cap is first separated from the body of the capsule before filling the capsule body with the formulation and then reattaching the cap.

Rather than placing a liquid as such in a capsule

the liquid may be mixed with an inert powder to make a wet mass or paste, which may then be placed in capsules in the usual manner.

Coni-snap capsule

the rim of the capsule body is not straight but tapered slightly. This reduces the risk of the capsule rims touching on joining and essentially eliminates the problem of splitting during large-scale filling operations. In the Coni-snap Supro capsules, the upper capsule part extends so far over the lower part that only the rounded edge of the latter is visible.

After the pins are withdrawn from the gelatin solution

they are rotated while being dried in kilns. A strong blast of filtered air with controlled humidity is forced through the kilns. •Each capsule is then mechanically stripped, trimmed, and joined.

Most capsules are intended

to be swallowed whole, but occasionally, the contents are removed from the gelatin shell and used as a premeasured dose.

Some patients prefer to swallow a capsule wetted

with water or saliva because a wetted capsule slides down the throat more readily than a dry capsule.

CONTENT UNIFORMITY

• 9 of 10 within 85% to 115% • None outside of 70% to 125% of label claim • Additional testing required if they are outside

FILLING CAPSULES

• After they are filled, capsules must be cleaned and polished. • On a small scale, capsules are cleaned individually or in small numbers by rubbing them on a clean gauze or cloth. • On a large scale, many capsule-filling machines have a cleaning vacuum that removes any extraneous material as the capsules leave the machine.

DISINTEGRATION TEST FOR CAPSULES

• Basket rack assembly • 37° C water or suitable fluid • Disintegrate completely into a soft mass with no palpable firm core and only some fragments of the gelatin shell

SELECTING CAPSULES

• Capsule size should be chosen carefully. A properly filled capsule should have its body filled with the drug mixture and its cap fully extended down the body. • The cap is meant to enclose the powder, not to retain additional powder. • Typically, hard gelatin capsules are used to encapsulate between 65 mg to 1g of powdered material, including the drug and any diluents needed.

PATIENT COUNSELING

• Capsules #0 through #5 are not difficult to swallow • Larger capsules: use syrup, honey, liquid candy to help patient swallow • Caution when emptying contents to food, etc. • Other routes of administration

Soft Gelatin Capsules

• Drugs that are commercially prepared in soft capsules include demeclocycline hydrochloride (Declomycin, Lederle), chloral hydrate, digoxin (Lanoxicaps, GlaxoSmith-Kline), vitamin A, and vitamin E. • Soft gelatin capsules are usually prepared by the plate process or by the rotary or reciprocating die process.

DEVELOPING THE FORMULATION AND SELECTING CAPSULE SIZE

• Goal is to prepare a capsule with accurate dosage, good bioavailability, ease of filling and production, stability, and elegance. • In dry formulations, the active and inactive components must be blended thoroughly to ensure a uniform powder mix for the fill. • Blending is especially important for low-dose drugs, since lack of homogeneity in blending may result in significant therapeutic consequences. • Uniformity in particle size by milling.

STORAGE

• Hard capsules should be stored in tightly closed glass containers and protected from dust and extremes of humidity and temperature. • These capsules contain 13%-16% water, varying with storage conditions. • When humidity is low, the hard gelatin capsules become brittle. When humidity is high, the hard gelatin capsules become flaccid and shapeless. • Storage at high temperatures also affects the quality of hard gelatin capsules. • Store in Tight, Well-closed, Light-resistant containers.

COUNTING

• In the pharmacy, capsules may be counted manually or by automated equipment. • Specially designed trays are used for counting small numbers of solid dosage units. With this method, the dosage units remain untouched by the pharmacist. • To prevent batch-to-batch contamination, the tray must be wiped clean after each use because powder, particularly from uncoated tablets, may remain. • In some community and hospital pharmacies, small automated counting and filling machines may be used

STABILITY TESTING

• Intrinsic stability of active drug molecule • Environmental factors: temperature, humidity, light, formulative components, and container and closure system

CAPSULE ADVANTAGES

• Mask odor and/or taste of unpleasant drugs • Easy to prepare • Can vary dosage and combination of drugs

APPLICATIONS

• Place on tongue and swallow with liquid • Dissolve contents in water or mix contents with food

FILLING CAPSULES- PUNCH METHOD

• The powder is placed on paper and flattened with a spatula so that the layer of powder is no more than approximately one third the length of the capsule. • The paper is held in the left hand. The body of the capsule is held in the right hand and repeatedly pressed into the powder until the capsule is filled. The cap is replaced and the capsule weighed.

INSPECTION

• Visual or electronic inspection should be undertaken to detect any flaws in the integrity and appearance of the capsules. • Defective capsules should be rejected. • In commercial manufacture, Current Good Manufacturing Practice regulations require that if the number of production flaws is excessive, the cause must be investigated and documented and steps undertaken to correct the problem.