Capsules PDF

Pharmaceutics-3 PT 505 Pharmaceutics department Capsules Asmaa Ashraf El-kashef, PhD.  Capsule in Latin "capsula": meaning a small box. Capsules are considered the second most popular oral dosage form. ❖ Capsule administration 1. Swallowed as whole. 2. Capsule is opened & conten...

Pharmaceutics-3 PT 505 Pharmaceutics department Capsules Asmaa Ashraf El-kashef, PhD.  Capsule in Latin "capsula": meaning a small box. Capsules are considered the second most popular oral dosage form. ❖ Capsule administration 1. Swallowed as whole. 2. Capsule is opened & contents are sprinkled on food. ❖ Capsules advantages over compressed tablets: 1. Elegant. 2. Easier to swallow. 3. Completely mask unpleasant odours & tastes. 4. Can be easily made opaque (advantage in photosensitive drugs). ❖ Types of capsules Hard gelatine capsule Soft gelatine capsule Consists of two pieces: cap & body that Manufactured & filled in a single fit one inside the other. operation. Produced empty & filled in a separate operation. ❖ Raw material for gelatine capsules: Raw materials used are similar for both hard & soft capsules. First stage of process is to prepare a gelatine solution in demineralized water 1. Gelatine Major component. The only material from which capsules successfully made. 1. Good film forming material. 2. Water-glycerol blend undergoes a reversible phase change from a solution to a gel at temperature only a few degrees above ambient. 3. Readily soluble in biological fluids at body temperature. 4. Non-toxic. **** Animal bones & skins are the raw material. It is prepared by hydrolysis of collagen. There are 2 types of gelatine: 1. Type A: produced by acid hydrolysis. 2. Type B: produced by basic hydrolysis. *** We should maintain hard capsules in an environment free from excessive humidity or dryness. Gelatine is subject to microbial decomposition when it becomes moist, distorted and lose their rigid shape. In extreme dryness, the capsules may become brittle. 2. Plasticizers Walls of hard gelatine Walls of soft gelatine capsules are softer & capsules are firm & rigid. more flexible. It contains a large It contains a smaller proportion of plasticizers. proportion of plasticizers. Plasticizer most frequently used: glycerol, sorbitol, propylene glycol, sucrose & acacia have been used also. 3. Colorants Soluble dyes: Insoluble pigments: The pigments used are Mainly synthetic in either: origin. 1. Titanium dioxide. This is white & is used as an opacifying agent. 2. Oxides of iron: Black, red, yellow. In last years, there is a move away from the use o f soluble dyes over to pigments, particularly the iron oxides. 4. Preservatives Sometimes added as an in-process aid to prevent microbiological contamination during manufacture.   Hard gelatine capsules Made in a range of 8 sizes from: size 000 (the largest) to size 5 (the smallest). The most popular are sizes 0 to 4. Capacity (by weight) varies according to density and compressibility of powder. Hard capsules filled with (solids like powders, granules, tablets, pellets, beads, semi-solids, and thermo- softening materials. ❖ Basic requirements for formulations to be filled into capsules: 1. Accurately dosed. 2. Release their active contents in available form to patient. 3. They should not react with gelatine, e.g. aldehyde. 4. Not interfere with integrity of shell e.g. water soften the wall. ❖ Incompatible drugs can be separated by: 1. Inserting a coated tablet of one ingredient into a capsule containing the other. 2. Pack one substance into a small capsule to be inserted into larger capsule containing the other. 3. Fixed oil should not dissolve gelatine, filling is done with a pipette or calibrated dropper. 4. Liquids could be sorbed into inert carrier to form dry powder suitable for capsule filling. ❖ Locking & Sealing of Capsules 1) To prevent accidental separation of capsules caps during handling & shipping. 2) In high-speed automatic filling & packaging machine. 3) For beads which tend to separate on handling because the fills are not compacted. ❖ Techniques of sealing 1) By a narrow band of gelatine. 2) A small hot probe near the cap to form a spot-weld. 3) A 3-segmented raised collar around inner cap →a positive friction lock 4) By moistening the lower part of the inner surface of the cap with water. ❖ The manufacture of hard gelatine capsule shells Hard capsule shells are manufactured in two sections, the capsule body and a shorter cap. The shells are produced by the mechanical dipping of pegs into a temperature-controlled reservoir of melted gelatine mixture. The pegs on which the caps are formed are slightly larger in diameter than the pegs on which the bodies are formed. The gelatine is dried by a gentle flow of temperature-and humidity-controlled air. Then, trimmed mechanically to the proper length and removed from the pegs, and the capsule bodies and caps are joined together. ❖ Filling of Hard Gelatine Capsules: Small scale filling 1. Hand-operated For large-scale filling, industry uses 1. Semi-automatic 2. Fully automatic equipment *** Regardless of process, all have common basic operations of: 1. Removal of caps. 2. Filling of the bodies. 3. Replacement of caps. 4. Ejection of filled capsules. ❖ Semi-automatic machine The part The role Rectifier Align the capsules in the filling ring (so that the cap is up and the body is down) Capsule filling ring Where capsules are placed. Hopper contains auger Feeds powder into bodies and ensure filling of capsule by forcing it into the shell. Auger is not used when capsules are filled with granules as it’ll break the granules. Peg ring 1. Driven by air pressure, pushes the caps & bodies together (to ensure pressing of cap to the body). 2. Then it ejects the capsule. ❖Fully-automatic machine Soft gelatine capsules   Soft gelatine capsules Composition of soft gelatine differs from hard gelatine in: 1. Sugar is replaced by a plasticizer which imparts elastic properties. 2. However, up to 5 % sugar may be added to formulation to give “chewable” properties. Spherical or oval capsules called pearls or globules. Capacities range from 1 to 480 minims. The fill: it may be single liquids, blends of miscible liquids, solutions, suspensions, semisolids, dry powders, slugs. Only liquids that do not dissolve shell (gelatine) may be used, e.g.: animal, vegetable, or mineral oil & polyethylene glycols. ❖ Advantage: 1) Hermetically sealed, so uniquely suitable for: a. Liquid medication. b. Volatile drugs. c. Drugs subjected to atmospheric oxidation. 2) Attractive odourless & tasteless form of medication. 3) It can be used as a form of rectal or vaginal suppositories, topical, eye, ear, & nose preparations as well as cosmetics & food stuffs may be dispensed in soft gelatine capsules. ❖ Manufacture: 1. Plate method (Small scale preparation) a) Place the gelatine sheet over a die plate containing numerous die pockets. b) Vacuum is applied to draw the sheet into the die pockets. c) Fill the pockets with liquid or paste. d) Place another gelatine sheet over the filled pockets. e) Sandwich under a die press using pressure where the capsules are formed and cut out. * No dose uniformity and high manufacturing loss. 2. Rotary die process (Scherer process) Part Role Rotating drums Spread gelatine solution to form a pair of continuous sheets of gelatine to be fed between two matched rotary dies. Injection Guides gelatine sheets between rotary dies. wedges Heats gelatine to proper temperature for sealing. Metering pump Inject the fill under Pressure causing gelatine to swell into cavities to form capsules. Converging dies Seals capsules & cut capsules from gelatine sheets. 3. Seamless Gelatine Capsules: Since these are not sealed by pressure from two Drug Gelatine sheets of gelatine, they are seamless. Cold liquid paraffin 4°C is used because: Cold liquid paraffin 1. Non solvent for gelatine. 2. Will congeal it.  Sustained Released Capsules ❖ Advantages of sustained release medication 1. The drug is more efficiently utilized. 2. Total drug intake is reduced. 3. Administration is more convenient (less frequency of administration). ❖ Sustained release dosage forms consist of 2 parts (1) Immediate release portion. (2) Sustained release portion: rate of drug release = rate of its elimination or detoxification. Suitable for Not suitable for Drugs used for chronic Antibiotics or muscle relaxants conditions not acute illness which have large dose →large SR dosage forms Digitalis glycosides and reserpine (long-acting drugs) ❖ Sustained released dosage forms are divided into: A hard gelatine capsule where the medication is pan coated onto the surface of sugar starch beads using a non-aqueous solution of the drug. A portion of these drug-coated beads provide the initial release of medication. Spansule The remainder (approximately 2/3 to 3/4 of the beads) are then pan coated with a fatty, waxy material such as beeswax or glyceryl monostearate or ethyl cellulose. Release of drug is dependent on moisture penetration of the fatty material, which depends on the composition & thickness of the coat. The granules of the sustained release portions are coated with styrene-maleic acid copolymer. Medules Release is dependent on: 1. PH as (The coat is PH sensitive & disintegrates at intestinal pH) 2. The stomach emptying rate. A cationic drug is sorbed onto a cationic exchange resin Drug release depends on: Strasionic a. PH resins b. electrolyte in gastro-intestinal fluids Formed by reacting a drug possessing an amine group with tannic acid in an alcoholic solution After precipitation, washing & drying, the complex may be either encapsulated or Insoluble tableted. complex **** Complex dissolves in stomach (acidic) more than intestine (alkaline). Too rapid dissolution in the stomach is avoided by adding pectic or galacturonic acids for buffering effect.   Enteric Coated Capsules Capsules are coated to resist dissolution in gastric fluids but release their contents in the intestine. They are used when: 1. The drug is inactivated in gastric fluids. 2. The drug is irritating to the gastric mucosa. 3. When a high local concentration of the drug is required in the intestine (anthelmintic). ❖ Materials used for enteric coating 1. Shellac, cellulose acetate phthalate. 2. Fatty, waxy materials such as beeswax, carnauba wax and stearic acid. 3. Hard gelatine capsules may be rendered enteric by treatment with formaldehyde that forms methylene bridges and cross links with gelatine (hardening of gelatine) ❖ An alternative procedure for the enteric coating of capsules: Dip capsule into 10 % solution of cellulose acetate phthalate in acetone. Capsule is removed, held for a minute and then placed on gauze to finish drying. Three coats are applied. ❖ Advantages of this method 1. Avoids heat 2. Add less bulk to the capsules ❖ The dissolution rate of a drug from capsules depends on: 1. The dissolution rate of shell. 2. The rate of penetration of the dissolution medium into the powder. 3. The rate at which the powder mass deaggregate. 4. The nature of the primary particle. **** The dissolution of a drug is the essential step in the absorption process why? As the availability of a drug for absorption depends on the drugs dissolving in gastro- intestinal fluid. *Dissolution is the rate limiting step (i.e., the slowest step) in the over-all absorption process. ❖ Formulation Factors Affecting Drugs Availability from hard Capsules 1. Active ingredients Physicochemical properties of drug such as solubility, melting point, crystalline form The solution rate is proportional to the surface area of drug. The smaller the particle the greater the relative surface area. 2. Additives include diluents, lubricants & wetting agents. a. Diluents Inert materials added to a formulation to increase the volume of the mixture to a manageable quantity. Choice of diluent depends on the solubility & proportion of the active ingredient. Examples of diluents: Lactose, dicalcium phosphate, & microcrystalline cellulose (Avicel). b. Disintegrant: help the powder mass to break up without interfering with the solubility of the active ingredients (As starch grains). c. Lubricants & Glidants Added to improve the filling properties of the powder mixture. Can have an effect on drug release. Example of lubricants: magnesium stearate. d. Surfactants & wetting agents Enhance drug dissolution by increasing the wettability of the powder mixture. The hydrophobic effect of magnesium stearate could be overcomed by the addition of wetting agent to formula. ❖ Factors Affecting Bioavailability of Drugs in Soft Gelatine Capsules 1. Solubility of the drug in the vehicle. Acid-soluble drugs (dissolved or dispersed in water-miscible vehicles) are distributed quickly throughout the stomach. Suspended particles dissolve quickly & the bioavailability is good. 2. Particle size of the drug. 3. Nature of the vehicle: The vehicle is either hydrophilic or hydrophobic according to the nature of the drug. 4. Inclusion of suspending agent for insoluble drugs.  Evaluation of Commercial Capsules 1. Weight Variation The uniformity of dosage units may be demonstrated by determining weight variation and/or content uniformity. Weight variation may be taken as control for the uniformity of actual drug content if the dose of the drug is large and there is relatively little diluent or excipient present. In the case of more potent, low-dose drugs, the control of weight variation does not assure uniformity of drug content since sufficient blending may not have been achieved.  The weight variation method is as follows. Hard Capsules 10 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. 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. 2. Content uniformity Is defined as the degree of uniformity in the actual amount of the drug in the dosage units. In the official test 30 capsules are selected 10 of them are assayed individually. At least 9 of this fall within 85 and 115% of average specified in monograph potency definition. None may fall below 75% or above 125 % of the average If more than 1 but less than 3 of them fall outside of the 85 and 115 % limits, the remaining 20 capsules are individually assayed. The requirements are said to be met if not less than 27 capsules fall within range 85-115% of limits and not fall outside 75-125 % of limits. 3. Disintegration The capsules are placed in the basket rack, which is immersed 30 times per minute into a thermostatically controlled fluid at 37°C and observed over the time as per monograph. To satisfy the test, the capsules disintegrate completely into a soft mass having no palpably firm core and only some fragments of the gelatine shell. “Dissolution” The dissolution of a capsule shell does not imply complete dissolution of the active ingredient. 4. The dissolution test Carried out using the dissolution apparatus official in both the U.S.P. The capsule is placed in a basket (attached to a stirrer shaft) & caused to rotate at a specified speed. The dissolution medium (900 ml) is held in a covered 1000 ml. vessel made of glass or other transparent material. If the capsule floats on the surface of the dissolution fluid, a small, loose piece of nonreactive material, such as a few turns of a wire helix, may be attached to the dosage form to force it to sink to the bottom of the vessel. The dissolution medium is maintained at 37°C± 0.5 by means of a suitable constant- temperature water bath. Samples are withdrawn at certain time intervals, analysed for the dissolved drug, and dissolution rate is then calculated. 5. 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. 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 pre-test and post-test weight of the packaged unit.