Prepared by: Sabrina Rahman Archie

 The name ‘soft gelatin capsules’ is commonly abbreviated to ‘softgels’.  WHY SOFT GELATIN CAPSULE???  In the case of drugs for oral administration, it becomes more difficult to formulate poorly water soluble drugs into products from which the drug is fully released and absorbed.  One of the best method to overcome this problem is to make a liquid formulation containing the drug.  In order to convert this liquid formula into a solid dosage form, it may be encapsulated into soft gelatin capsules.

 Consist of a liquid or a semi-solid matrix inside a one-piece outer gelatin shell.  Ingredients that are solid at room temperature can also be encapsulated into soft gels providing they are at least semisolid below approximately 45 degree C.  The drug compound itself may be either in solution or in suspension in the capsule fill matrix.

 The characteristics of capsule fill matrix may be either  Hydrophilic (Polyethylene glycol)  Lipophilic (trigyceride vegetable oil) or  mixture of both.  available in a number of shapes and sizes, e.g. spherical, oval, cylindrical and tubes.

 The contents of soft capsules may vary from 0.1ml to 30ml  Composition of capsule shell: Gelatin + water+ plasticizer (glycerin, sorbitol, propylene glycol)  Can be transparent or opaque  Can be colored and flavoured

Swallowable softgel capsule: Orally administered softgels containing solutionsor suspensions that release their contents in the stomach in an easy-to- swallow, convenient unit dosage form.

Chewable soft gels: A highly flavoured shell is chewed to release the drug liquid fill matrix. Suckable soft gels: Consist of a gelatin shell containing the flavoured the to be sucked and a liquid matrix. Meltable soft gels: Designed for use as ‘patient-friendly’ pessaries or suppositories.

Twist-off soft gels:  Designed with a tag to be twisted or snipped off, thereby allowing access to the fill material.  Very useful for unit dosing of topical medication.

 Improved drug absorption:  Increased rate of absorption  Increased bioavailability  Decreased plasma variability  Patient compliance and consumer preference:  Easy to swallow  Absence of poor or undesirable taste  Convenient administration of a liquid drug dosage form.

 Safety for potent and cytotoxic drugs:  Avoids dust-handling problems during dosage form manufacture  Better operator safety  Environmental controls  Oils and low melting point drugs:  Overcomes problems with manufacture as compressed tablets or hard gelatin capsules.

 Dose uniformity for low dose drugs:  Liquid flow during dosage form manufacture is more precise than powder flow.  Drug solutions provide better homogeneity than powder and granule mixtures.  Product stability:  Drugs are protected against oxidative degradation by lipid vehicles and softgel capsule shells

 Before the encapsulation process takes place, 2 sub-processes are often carried out simultaneously. a. The gel mass which will provide the softgel shell. b. The fill matrix for the soft gel contents.  The gel mass is prepared by dissolving the gelatin in water at approximately 80 degree C and under vacuum followed by the addition of plasticizer (glycerol).

 Once the gelatin is fully dissolved then other components such as colors, opacifier, flavours and preservatives may be added.  The hot gel mass is then supplied to the encapsulation machine through heated transfer pipes by a casting method that forms two separate gelatin ribbons each with a width of approximately 150mm.  The 2 gel ribbons are then carried through rollers (at which a small quantity of vegetable oil lubricant is applied) and onwards to the rotary die encapsulation tooling.

 Each gel ribbon provides one half of the soft gel.  The Liquid gel matrix containing the active drug substance is manufactured separately from preparation the molten gel.  Manufacture of the active fill matrix involves dispersing or dissolving the drug substance in the non-aqueous liquid vehicle using conventional mixer-homogenizers.

 A number of different parameters are controlled during preparation of the active fill matrix, depending on the properties of the drug substance. - For example, oxygen sensitive drugs are protected by mixing under vacuum and/or inert gas; in some cases an antioxidant component may be added to formulation. - If the drug substance is present as a suspension in the liquid fill matrix then it is important to ensure that particle size of the drug does not exceed approximately 200 µm.

 Accurately metered volumes of the liquid fill matrix are injected from the wedge device into the space between the gelatin ribbons as they pass between the die rolls.  The injection of liquid between the gel ribbons forces the gel to expand into the pocket of the dies, which govern the size and shape of the soft gels.  The ribbon continues to flow past the heated wedge injection system and is then pressed between the die rolls.

 The two soft gel capsule halves are sealed together by the application of heat and pressure.  The soft gel capsules are then cut automatically from the gel ribbon by raised rims around each die on the rollers.

 After manufacture, the capsules are passed through a tumble dryer and then, to complete the drying process, they are spread onto trays and stacked in a tunnel dryer that supplies air at 20%relative humidity. The tunnel drying process may take 2-3 days or possibly as long as 2 weeks, depending on the specific soft gel formulation.  Finally the soft gels are inspected and packed into bulk containers in order to prevent further drying and for storage.

 3 parameters: Temperature: controls the heat available for capsule seal formation. Timing: the timing of the dosing of unit quantities of fill matrix into the softgel during its formation is critical. Pressure: the pressure exerted between the two rotary discs controls the softgel shape and the final cut-out from the gel ribbon.

 Gelatin:  Most commonly used type-B gelatin.  Plasticizer:  To make the soft gel shell elastic and pliable.  They usually account for 20-30% of the wet gel formulation.  Commonly used plasticizer: Glycerol  Frequently used plasticizer: Sorbiltol and PG in combination with Glycerol.  The amount and choice of the plasticizer contribute to the hardness of the final product and may even affect the final product’s dissolution or disintegration characteristics as well as physical and chemical stability.

 Plasticizers are selected on the basis of- their compatibility of the fill formulation ease of processing desired properties of the final softgels including: -hardness -appearance -handling characteristics -physical stability

 Water:  Usually accounts for 30-40% of the wet gel formulation and its presence is important to ensure proper processing during gel preparation and softgel encapsulation.  Following encapsulation, excess water is removed from the softgels through controlled drying.  In dry softgels, the equilibrium water content is typically in the range 5-8% w/w which represents the proportion of water that is bound to the Gelatin in the softgel shell.

 This level of water is important for good physical stability of softgels because in harsh storage conditions, softgels will become either too soft and fuse together or too hard and embrittled.

 Colorants:  Soluble dyes or insoluble pigments  Colorants can be synthetic or natural and are used to impart desired shell color for product identification.  Opacifiers at low concentrations (Titanium dioxide)  Opacifiers may be added to produce an opaque shell when the fill formulation is a suspension or to prevent photodegradation of light-sensitive fill ingredients.

 Titanium dioxide can either be used alone to produce a white opaque shell or in combination with pigments to produce a colored opaque shell.

 Oxygen Permeability: The gelatin shell provides a good barrier against the diffusion of oxygen into the contents of the product. The quantity of Oxygen(q) that passes through the gelatin is governed by the permeability coefficient(P), the area(A), the thickness(h) of the shell particle, the pressure difference (P1-P2) and the time of diffusion (t) by the following equation: q=PAt (P1-P2)/ h

 Residual water content: Soft gel contains 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 a soft gelatin capsule.

 The softgel can be considered as a biphasic dosage form: a solid-phase capsule shell Liquid phase capsule-fill matrix  Liquid phase capsule fill matrix is selected from components with a wide range of different physicochemical properties.

 The choice of components is made according to one or more of a number of criteria: Capacity to dissolve the drug Rate of dispersion in the GIT after the soft gel shell ruptures and releases the fill matrix Capacity to retain the drug in solution in the GIT fluid Compatibility with the soft gel shell Ability to optimize the rate, extent and consistency of drug absorbed.

1. Lipophilic liquids/oils:  Triglyceride oils such as soya bean oil, are commonly used in softgels  Limited capacity to dissolve drug when used alone  Hydroxycholecalciferol and other Vitamin D analogues, steroids (oestradiol) can be formulated into simple oily solution for encapsulation in softgels.

2. Hydrophilic Liquids:  Polar liquids with a sufficiently high molecular weight  Most commonly used PEG (ex. PEG 400)  Smaller hydrophilic molecules, such as ethanol can be incorporated in the softgel matrix in low levels, typically below 10% by weight.

3. Self-emulsifying oils:  A combination of pharmaceutical oil and a non-ionic surfactant such as poly- oxyetylene sorbitan monooleate can provide an oily formulation which disperses rapidly in the GIT fluid.  The resulting oil/surfactant droplets enable rapid transfer of the drug to the absorbing mucosa and subsequent drug absorption.

4. Microemulsion and nanoemulsion system:  A microemulsion of a lipid surfactant-polar liquid system is characterized by its translucent single-phase appearance.  The droplet size is in the submicron range  A nanoemulsion describes a similar system but containing emulsion droplets in the 100 nm size range.  Microemulsion and nanoemulsion systems have the advantage of a high capacity to solubilize drug compounds and to retain the drug in the solutioneven after dilution in GIT fluid.

5. Suspension:  Drugs that are insoluble in soft gel fill matrices are formulated as suspensions.  This formulation provides significant advantages for certain low solubility drugs which are very poorly absorbed after oral administration.

 Ingredient specifications:  All the ingredients of a softgel are controlled and tested to ensure compliance with pharmacopoeial specifications.  It is important to limit certain trace impurities such as aldehydes and peroxides that may be present in PEG.  The presence of high level of these impurities gives rise to cross-linking of the gelatin polymer leading to insolubilization through further polymerization.

 On prolonged storage, this can lead to slow dissolution of the capsule shell and subsequent retarded drug release.  Once a particular grade of gelatin is used in the softgel formulation, the quality is controlled using parameters such as viscosity and Bloom strength.

 In-process testing:  4 more important tests are: 1. The gel ribbon thickness 2. Softgel seal thickness at the time of encapsulation 3. Fill matrix weight and capsule shell weight. 4. Softgel shell moisture level and softgel hardness at the end of the drying stage.

 Finished product testing:  Capsule appearance  Active ingredient assay  Fill weight test  Content uniformity test  Microbiological test

Characteristics Hard gelatin Capsule Soft gelatin capsule ShapeUsually cylindricalSpherical, Oval, Cylindrical and tube Filled medicaments Usually solidLiquid or semi-solid matrix Boundary wallFirm and rigidSoft and flexible Formulation process Two step process, first the shell formation and then the filling process is completed. One continuous process, e.g. filling & formulation in same time. StructureThe body and the capOnly the body Gelatin strength. High bloom gelatin usedLow bloom gelatin used ExampleOmeprazole  - tocophrol acetate 100mg

 Reference: Aulton’s Pharmaceutics