SOFT GELATIN CAPSULES DEFINITION: Soft Gelatin capsules are one piece, hermetically sealed, soft gelatin shells

containing a liquid, a suspension, or a semisolid. The Nomenclature for this dosage form has now been changed to soft gel. They have long been preferred dosage form for those, taking Health & Nutritional supplements.

ADVANTEGES 1. Easy to administer 2. Easy to Manufacture 3. Liquids can be encapsulated ( non water soluble) 4. Small to large sizes possible 5. Elegance 6. Portability 7. Odour and taste masking 8. Ready availability of drug hence faster action. 9. Specialised dosage forms can be made e.g. chewable, extended release, captabs etc. 10. Can be used for ophthalmic preparations e.g. aplicaps(used for ophthalmic preparations), vaginal / rectal suppositories

DISADVANTEGES

Water soluble material are difficult to incorporate Highly Moisture sensitive Efflorescent material cannot be incorporated, they may cause softening / leaching Deliquescent materials cannot be incorporated, they may cause hardening or brittle capsules.

1. Preparation of the fill material This process is specific to each product 2. Shell-film formation The shell mass is heated and melted as required. The molten material is pressure-fed to extrusion dies via a metering pump, producing a film as the mass is extruded onto a casting drum. The film thickness is precisely controlled using electronic positioning of the extrusion dies.

3. Encapsulation -The resulting films are peeled from the casting drums and fed between a pair of rotating dies. A FORM, FILL, SEAL process is used that is identical to the one used to prepare traditional softgels. Capsule seals are formed by a combination of heat and pressure. The freshly formed soft gels are then transferred to drying device.

4. Drying -The first stage - a tumble drier -removes a significant portion of the water present in the shell. The semi-dried capsules are spread onto trays and kept under controlled temperature and humidity to complete the drying activity. 5. Inspection & Sorting - The dried capsules are inspected and sorted to ensure uniformity in weight, size and shape.

MANUFACTURING OF SOFT GELATIN CAPSULES Developing the Formulation and Selection of Capsule Size The goal is to prepare a capsule with accurate dosage, good bioavailability, ease of filling& production, stability and elegance The active and inactive components must be blended thoroughly to ensure a uniform powder mix for the fill Preformulation studies are performed to determine whether all of the formulations bulk powders may be effectively blended together. Diluent or filler may be added to produce the proper capsule fill volume - ex. LACTOSE, MICROCRYSTALLINE CELLULOSE and STARCH

Disintegrants are frequently included in a capsule formulation to assist the breakup and distribution of the capsules contents in the stomach - ex. PREGELATINIZED STARCH, CROSCARMELLOSE, SODIUM STARCH GLYCOLATE When necessary, particle size may be reduced by milling to produce particles ranging from 50 to 1000 m Drugs of lower dose or smaller particles are required, micronization is employed - 1 to 20 um particle size

Industrial Scale

The powder mix must be free-flowing to allow steady passage of the capsule fill from hopper and into the capsule shell Addition of lubricant or glidant - FUMED SILICON DIOXIDE, MAGNESIUM STEARATE, CALCIUM STEARATE, STEARIC ACID or TALC (about 0.25-1%) to the powder mix enhances flow properties Magnesium stearate as lubricant, the water proofing characteristics of this water-insoluble material can retard penetration by the gastrointestinal fluids and delay drug dissolution and absorption Selection of capsule size is done during product development The choice is determined by requirements of formulation, including the dose of the active ingredient and the density and compaction characteristics of the drugs. Hard gelatin capsules are used to encapsulate about 65 mg to 1 g of powdered material

Developing the Formulation and Selection of Capsule Size Gelatin capsules are unsuitable for aqueous liquids because water softens gelatin and distorts the capsules, resulting leakage of the content Some liquids or volatile oil do not interfere with the stability of the gelatin shells - may be placed in locking gelatin capsules to ensure retention of the liquid Eutectic mixtures of drugs - tends to liquefy - 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 Liquids are placed in soft gelatin capsules that are sealed during filling and manufacturing

1. Tetracycline Capsules Active Ingredient Filler Lubricant/glidant Capsule colorants Tetracycline hydrochloride 250 mg Lactose Magnesium stearate FD & C Yellow No.6, D & C Yellow no.10, D & C Red No.28, FD & C Blue No.1 Titanium dioxide

Capsule opaquant

2. Acetaminophen With Codeine Capsules Active ingredients Acetaminophen 325 mg, Codeine phosphate 30 mg Disintegrant Sodium starch glycolate Lubricant/glidants Magnesium stearate, stearic acid Capsule colorants D & C Yellow No. 10, edible Ink, FD & C Blue No.1 (FD & C Green No.3 and FD & C Red No. 40) 3. Diphenhydramine Hydrochloride Capsules Active ingredient Diphenhydramine HCl 25 mg Filler Confectioners sugar Lubricants/glidants Talc, colloidal silicon dioxide Wetting agent Sodium lauryl sulfate Capsule opaquant Titanium dioxide

Compendial Requirements for Capsules

1. Added Substances Harmless in the quantities used Do not exceed the minimum amounts required to provide their intended effect Do not impair the products bioavailability, therapeutic efficacy or safety Do not interfere with requisite compendial assays & test 2. Containers for dispensing Tight, well closed & light resistant containers depending on the item 3. Disintegration Test for Capsules The capsules are placed in the basket rack assembly, which is immersed 30 times per minutes into a thermostatically controlled fluid at 37 0C and observed over the time described in the individual monograph 4. Dissolution Test for capsules

5. Weight Variation Hard Capsules - 10 capsules are individually weighed & the content removed. Empty shells are individually weighed & the net weight of the contents calculated by subtraction. Soft Gelatin - the gross weight of 10 intact capsules is determined individually. Then each capsule is cut open & the contents removed by washing with suitable solvent. The solvent is allowed to evaporate at room temperature over about 30 minutes. The individual shells are weighed and net contents calculated.

6. Content Uniformity 85-115% of the label claim for 9 of 10 dosage units assayed with no unit outside the range of 70-125% of label claim 7. Content Labeling Requirement All official capsules must be labeled to express the quality of each active ingredient in each dosage unit 8. Stability Testing To determine the appropriate conditions for storage and the products anticipated shelf life 9. Moisture Permeation Test Determined by packaging the dosage unit together with a color-revealing dessicant pellet, exposing the packaged unit to known relative humidity over a specified time, observing the dessicant pellet for color change (indicating absorption of moisture) & comparing the pretest & posttest weight of the package unit.

Inspecting, Counting, Packaging, and Storing Capsules Should have a uniform in appearance Defective capsules should be rejected Capsules may be counted manually or automated equipment Containers are then mechanically capped, inspected visually or electronically, labeled, and inspected once more. packaged in glass or in plastic containers

Oral Administration of Solid Dosage Forms

Placing the dose upon tongue & swallowing it w/ a glassful of wateror beverages Without water is dangerous because of the possibility that will lodge in the esophagus. Esophageal ulceration can occur with dry ingestion of tablets and capsules, particularly taken just before bedtime Example of drugs of greatest concern are: ALENDRONATE SODIUM, ASPIRIN, FERROUS SULFATE, NSAID, POTASSIUM CHLORIDE, & TETRACYCLINE The proper administration of alendronate sodium tablets (FOSAMAX) calls for tablets to be taken with full 6 or 8 ounce glass of plain water upon rising in the morning or half an hour before taking any food - to prevent local irritation of esophagus

Some Medications Commercially Prepared Into Soft Gelatin Capsule 1. Acetazolamide - Diamox = Carbonic anhydrase inhbitor 2. Cyclosporine - Sandimmune = Immunosuppressive 3. Cyclosporine - Neoral =Immunosuppressive 4. Digoxin - Lanoxicaps = Cardiac glycoside 5. Ethosuximide - Zarontin = Anticonvulsant 6. Ranitidine HCl - Zantac GELdose = Histamine H2 receptor inhibitor

Process Capsule Filling 1. Milling /Sieving of all Ingredients 2. Blending 3. Capsule Filler 4. Capsule cleaner/deduster 5. Capsule injection screen 6. Capsule check-weighing system/reject 7. Finished capsules 8. Packaging

Advantages of Coni-Snap 1. The tapered rim avoid telescoping 2. The indentations prevent premature opening 3. The grooves lock the two capsule parts together after the capsule has been filled Preparation of Filled Hard Gelatin Capsules 1. Developing & preparing the formulation & selecting the size of capsule 2. Filling the capsule shell 3. Cleaning and polishing the filled capsules

Methods For commercial Manufacture of Soft Gelatin Capsule 1. Plate-Process. A warm sheet of prepared gelatin is laid over the lower plate and the liquid is poured on it. A second sheet of gelatin is carefully put in place and this is followed by the top plate of the mold. The set is placed under the press where pressure is applied to form the capsule which is washed off with a volatile solvent to remove any trace of oil from exterior. 2. Rotary Die Process. The rotary die machine is a selfcontained unit capable of continuously & automatically producing finished capsules from a supply of gelatin mass and filling material which may be any liquid, semiliquid, or paste that will not dissolve gelatin. Two continuous gelatin ribbons, which the machine forms, are brought into convergence between a pair of

Methods For commercial Manufacture of Soft Gelatin Capsule 1. Plate-Process. A warm sheet of prepared gelatin is laid over the lower plate and the liquid is poured on it. A second sheet of gelatin is carefully put in place and this is followed by the top plate of the mold. The set is placed under the press where pressure is applied to form the capsule which is washed off with a volatile solvent to remove any trace of oil from exterior. 2. Rotary Die Process. The rotary die machine is a selfcontained unit capable of continuously & automatically producing finished capsules from a supply of gelatin mass and filling material which may be any liquid, semi- liquid, or paste that will not dissolve gelatin. Two continuous gelatin ribbons, which the machine forms, are brought into convergence between a pair of

3. Norton Capsule Machine. This machine produces capsule completely automatically by leading two films of gelatin between aset of vertical dies. These dies as they close, open, and close, are in effect a continual vertical plate forming row after row of pockets across the gelatin film. These are filled with medicament and as they progress through the dies, are sealed, shaped, and cut out of the film as capsules which drop into a cooled solvent bath. 4. Accogel Capsule Machine. Or Stern machine, uses a system of rotary dies but is unique in that it is the only machine that can successfully fill dry powder into a soft gelatin capsule.

Application of Soft Gelatin Capsule Liquid which may be encapsulated into soft gelatin capsules include: 1. Water immiscible, volatile & nonvolatile liquids such as vegetable & aromatic oils, aromatic and aliphatic hydrocarbons, chlorinated hydrocarbons, ethers, esters, alcohol & organic acids. 2. Water miscible, nonvolatile liquids such as polyethylene glycols, and nonionic surface active agents as polysorbate 80 3. Water miscible and relatively nonvolatile compounds, as propylene glycol and isopropyl alcohol, depending upon factors as concentration used and packaging conditions.

Drugs commercially prepared in Soft Gelatin capsules: 1. Ethychlorvynol (Placidyl) 2. Demeclocycline HCl ( Declomycin ) 3. Chlortrianisene (TACE) 4. Digoxin (Lanoxicaps) 5. Docusate calcium (Surfak) 6. Vitamin E

Method for commercial manufacturing Soft Gel Capsules 1. Globex Method Filling is pumped through the inner capillary of a concentricdouble capillary Shell forming solution is pumped through the outer capillary ofthe concentric double capillary The soft capsules are then immersed in a cooling bath of about4oC (usually liquid paraffin) Cooling bath ensures immediate sol-gel transformation, henceformation of flexible yet firm robust outer film. Soft capsules are collected, washed with organic solvent toremove residues of cooling liquid & gently dried at a relativehumidity of 20% in infrared tunnels. Advantage: production of seamless capsules which are tamper-evident and free of contamination or entrapped air.

2. Rotary Die Method Shell materials are converted into liquid state. Plasticizers and other additives are added to the liquid shell materials. Shell ribbons are formed and passed through cooling bath. This transforms sol state to gel state. After cooling bath, capsules are lubricated on either side with liquid paraffin or vegetable oil. The ribbons are guided to counter-rotating rolls containing sharp- edged dies Each die cavity has the size and shape of half of the capsule Die rolls are pressed together with pressure two ribbons can be sealed and cut along the slightly raised rims of the dies for filling The capsule is washed with organic solvent and pre-dried

Advantages: - Capsules can have all kinds of shapes & sizes - Different colors for both sides - Wide variety of fills Disadvantages: - High amount of shell waste material - Longer drying time compared to Globex Method

Check-weighing Based on Gravity Flow The capsules are fed from the hopper by means of a drive mechanism and size-dependent guiding plate onto the weighing cell. After check weighing, the capsules are classified into correctly and incorrectly filled ones Cleaning and Polishing On a small scale, capsules maybe cleaned individually or in small numbers by rubbing them with a clean gauze or cloth. On a large scale, many capsule-filling machines are affixed with a cleaning vacuum that removes any extraneous material from the capsules as they exit the equipment. Or using Accela-Cota apparatus.

Inspecting, Counting, Packaging, and Storing Capsule 1. Using Sanitary Counting Tray (a) placing units from stock package onto tray, (b) counting and transferring units to trough, (c) returning excess units to stock container, (d) placing counted units into prescription container. 2. Using Mini-Counter II - Small automatic tablet and capsule counting and filling apparatus. 3. Using Versacount Model - Automatic tablet and capsule counting and filling apparatus. 4. Using large Merill filling machine - fills 16 bottles with 200 tablets each at one time, a flipper gate in the upper manifold directs the tablets into one row of bottles while the other filled row is evacuated and a new row of bottles moves into place.

PRODUCT QUALITY CONSIDERATIONS Ingredient specifications All ingredients of a soft gel are controlled and tested to ensure compliance with pharmacopoeial specifications. E.g. Impurities such as aldehydes & peroxides which may be present in polyethylene glycols. Presence of high levels of these impurities gives rise to crosslinking of the gelatin polymer, leading to insolubilization through further polymerization.

IN-PROCESS TESTING During the encapsulation process the four most important tests are:The gel ribbon thickness; Soft gel seal thickness at the time of encapsulation; Fill matrix weight & capsule shell weight; Soft gel shell moisture level and soft gel hardness at the end of the drying stage.

FINISHED PRODUCT TESTING These normally includes Capsule appearance, active ingredient assay & related substances assay Fill weight Content uniformity and Microbiological testing.