Capsule Technology

Hard Gelatin CapsulesSoft Gelatin Capsule Technology Capsule

Definition Capsules are solid dosage form that contains one or more medicinal or inert substances contained in a shell most properly made of gelatin.There are two types :

Soft gelatin capsules ( one piece).

Hard gelatin capsules ( two piece).

Studying of Capsules Hard Gelatin Capsules HGCAdvantages and disadvantages of HGC.Sizes and volumes of HGC.Manufacturing of Empty Hard Gelatin Capsules EHGC.Filling of EHGC.Formulation of fillManual capsule filling.Semiautomatic capsule filling.Automatic capsule filling.

Soft Gelatin Capsules Advantages and disadvantages.Sizes and shapes.Formulation of Gelatin sheet in manufacturing of soft gelatin capsulesFilling of SGC.Formulation of fill.Plate process.Rotary die machine.Bubble method

Stability and Quality Control for Capsules.

Hard Gelatin Capsules HGC HGC are composed of two parts:Shorter and wider is the capTaller and narrower is body.

Advantages of HGCThe use of capsules avoid many unit operations that associated with the manufacture of tablet.Beneficial for unpleasant taste and odour and attractive in appearance.Easy to swallow with water.Possibility of filling different system; granules, pellets, powders, tablets and liquid.The shells are physiologically inert and easily and quickly digested in the GIT.Better bioavailability than tablets.They are economical.Easily to handle and carry.If used titanium dioxide or colour it provides protection from light.Gives versatility to prepare any dose required for a variety of administration routes.Alternation of drug release is possible.

Disadvantages of HGCEasily tampered.Highly water soluble materials as iodides, bromides and chlorides should not be dispensed in capsules.Efflorescent materials softens the capsule and deliquescent materials make it brittle due to effect of humidity stability problems.Homogeneity of fill weight.More expensive than tablets.

Standard Sizes and Volumes of HGCSize numberVolume in mlSize in mm0001.3726.3000.9523.700.6821.810.519.220.3718.330.3015.340.2114.750.1511.9

Manufacture of EHGC Gelatin Production of Gelatin Why using gelatin?The ability of a solution of a gel to solidify just above the ambient temperature enabling the mold pin to solidify rapidly.Nontoxic and used in food.Readily soluble in biological fluid at body temperature.Produce strong flexible film.Homogeneous in structure giving good mechanical strength.Make a sol at 50 C.

Types of gelatin?- Type A : Produced by acid hydrolysis of bones, skin and connective tissues of pork ( bovine).- Type B : Produced by alkaline hydrolysis of bone, skin and connective tissues of animals.

Production Process of Gelatin

Differences between gelatin types for HGC characteristics of gelatin types for HGC Characteristic Type AType BProduction Acid hydrolysisAlkaline hydrolysisSource Pork skinOther animal & bonesIsoelectric point pHAt pH 7 - 9At pH 4.8 5Physical charactersPlastic and clearfirmGel strength240 300200 - 250Viscosity44 5545 60pH4.5 5.55.3 6.5Aerobic count-Max 1000 cfm/gE. Coli-NegativeSalmonella-NegativeYeast & molds-Max 1000 cfu/g

Type A may be suspected to Bovine spongiform encephalopathy.

Physiochemical properties of gelatinBloom test:Is to measure the strength of a gel or cohesive strength between gelatin molecules and it is proportional to the molecular weight of gelatin.It is defined as the weight in grams needed by specified plunger ( 0.5 inch diameter) to depress the surface of the gel at specified temperature to a distance of 4 mm without breaking. The result is expressed in bloom (grade) usually between 30 300. using 6.67% gelatin solution kept for 17 hours at 10 C prior to be tested.The higher the bloom value the higher the melting and gelling points and the shorter the gelling time.Range of 150 280 is considered suitable for capsules manufacturing.

Viscosity :Determined on 6.67% concentration of gelatin in water at 60 C in a capillary pipette. Viscosity range 30 60 millipose is considered suitable.As the viscosity lowered the capsule thickness will decrease.Microbiological tests:Total microbial counta- total aerobic bacteria.b- moldsc- preservative generally used preservative are propyl paraben, methyl paraben, sodium metabisulfite.

1- Preparation of solution for EHGC manufactureGelatin 30%Bloom 150 280Viscosity 30 -60 millposeVacuum is applied to remove the entrapped air.Water 65%Hot demineralizedDye 5%Water solublePigment As neededWater insolubleSurfactant 0.15% w/wSod. Lauryl sulphateEnhance wettability of gelatin to metal pin during production.Enhance wettability of capsule shell with aqueous medium. Preservative As neededSod. MetabisulfiteMethyl paraben- Propyl parabenGelatin is ideal growth medium at 55 C

2- Dipping - Pairs of stainless steel pins, lubricated are dipped into the solution. One for caps and the other for bodies. - Temperature of pins is ambient while that of the solution is 55 C kept constant by means of jacketed pan.Time for dipping is 22 seconds.3- SpinningPins are elevated and rotating in spinning manner to distribute the gelatin over the pins uniformly and to avoid formation of bead. Stream of cool air is then applied.

4- drying -The racks of gelatin coated pin passes through the upper and lower kilns of machine drying system. Gentle moving air of controlled temperature, humidity and volume removes the required amount of moisture from the two halves of capsule.5- Stripping- A series of bronze jaws strip out the caps and bodies from the pins and pass it to the trimming stage.

6- Trimming - The firmly held two portions of capsule rotates against knife blade which cut trim them to the required length.7- JoiningThe cap and body are then aligned concentrically in channels and slowly and smoothly pushed together.The and body are now joined to form the capsule which is then ejected.The entire cycle takes about 45 min , two thirds of which is in the drying chamber.

Properties of EHGC Should exhibit water content 13 16% w/w.Water act as plasticizer to ensure the mechanical properties of capsule.If lower water content , it will become brittle and crack.If excessive water content, it will undergo plastic flow upon exposure to stress and loose its shape, becoming soft.Water soluble at 37 C and insoluble below 30 C and absorb water.

Should be stored in a sealed container at room temperature at controlled humidity of 30% - 45%.

Properties of the Powder fillHomogeneity: The particle size distribution of various components should be similar to ensure homogeneous mixing and to minimize segregation.

The particle size distribution of the powder is preferable to be monomodal of low polydispersity to ensure predictable and reproducible flow during the filling process. Multimodal and polydispersity of powder mix tend to segregate with problems in homogeneity of the mix.

Irregular particle shape e.g needle shape, will result in flow problems and hence problems in the filling process and the product.

Assessment of Good flow propertiesAngle of repose:The angle that the powder makes with the horizontal plane. If the angle of repose exceeds 50 the flow properties is poor.Angle of repose 25 is suitable.Higher angle of repose requires the use of glidant.Torque rheometry:stress is applied to the powder and the rate of shear is determined to cause deformation. The powder of high cohesion requires high shear strength to initiate and maintain flow.Tap density: Hausner ratio- The density of the powder before shaking to the density after shaking. 1.2 is acceptable but if exceed 1.6 it will be unsuitable for capsule filling.

Formulation of the Powder FillExcipient functionExamples Diluent Provide powder massLactose monohydrateStarch Microcrystaline celluloseLubricant Reduce the adhesion to metal dossator and to metal of machine.- Mg StearateGlidant Reduce the interparticle attraction to provide powder flow.Talc Aerosil Disintegrant To break the powder mass following release into the stomach.Maize Starch crospovidoneMicrocrystaline celluloseSurface active agentTo enhance wettability- Sod lauryl sulphateProtective sorbentTo prevent absorption of moisture by hygroscopic materialsMg OxideCa CarbonateAntidusting To prevent dusting of powder- Inert edible oil

Filling Process Sequence

Manual Capsule Filling

Plate with rubber surfacePin platecapsule loading trayFiller unit Powder filling frame Powder spreader lever1- empty capsules are loaded into the capsule loading tray and put over the filler unit and lock.2-operate the lever and remove the loading tray to separate the caps from the bodies which are left into the filler unit.3- place the powder filling frame.4- fill the bodies by the weighed amount of powder using the spreader.5- use the pin plate to press the powder and refill the remaining powder.6- place the capsule filling tray which is holding the caps.7- press the caps with the plate with a rubber surface8. Release the lever to free the bodies which are holding the caps.9- remove the loading tray and collect the capsule.

Semiautomatic capsule filling

1- capsule orientation.2- capsule parts separation.3- capsule filling.4- capsule parts joining.5- capsules ejection.

Capsule orientation

Operation

Automatic Capsule FillingA- Dependent Method ( dosing system) - bodies of capsules are separated and placed in the slots that are located in the revolving turntable.Caps are housed above in the same turntable.The bodies is rotated under the hopper containing the powder.The powder falls into the capsules body cavities.The flow of the powder through the hopper and the homogeneity of the powder are maintained by the circular movement of an auger. then the caps and bodies brought together to form the finished product.The weight of the powder is dependent on the length of time that the hopper spends above the bodies which is dependent on the speed of turntable.Capsules are then ejected out of machine.

B- Independent Method ( dosing system)This method involves a physical transfer of a plug of powder from the powder mix bed into the capsule body.A tube containing a spring-loading-piston, is depressed into the powder bed enabling a pre-adjusted volume of powder ( plug) into the tube.The tube containing the powder is then elevated out of the powder bed , rotated and located above the capsules body.The piston depressed and push the powder into the capsule body.Then the caps and bodies came together and joined then ejected.

Finishing of HGCSalt polishing.Cloth dedusting.Brushing. Sorting Unfilled capsules.Filled unfitted capsule.Loose capsSealing or lockingApplication of moisture and slipping.Coloured band of gelatin.Interlocking ringsHeat spot welding by a heated needle.

Soft Gelatin Capsules softgelsSoft gelatin capsules are capsules in which the mechanical properties of gelatin have been manipulated by addition of a plasticizer ( glycerol, polyhydric alcohols as sorbitol) resulting in more flexible capsule.Soft gelatin capsules SGC may have a various shapes and sizes.

Advantages of softgelsPatient compliance: easy to sallow, no taste, tamper proof, unitdose delivery.Versatile: filled as semisolid, liquid, gel or paste. Various colours, shapes, sizes.Improved bioavailability: immediate or delayed by delivering drug in solution.Improve stability: drug is protected by lipophilic vehicle and capsule shell.Liquid flow in filling is more precise than powder flow. No dust. Homogeneity.Can be enteric coated for delayed release.Popular for pharmaceutical and nutritional products.

Disadvantages of SoftgelsRequires special manufacturing equipment.Stability issues for water soluble drugs.Possibility of interactions between liquid and gelatin shell.Limited choices for excipients.Highly moisture sensitive.

Composition of Softgel shellGelatin type B alkali processed, constitutes 40% of melt gel.Plasticizer Water.Other additives which may be added as colorants, opacifier, preservative or flavouring agents.

Plasticizer in SoftgelsIncorporated to provide flexibility of the shell.20 -30 % of the wet gel formulation.The compatibility with the fill formulation determine the plasticizer.The mechanical properties of the capsule determine the concentration. Above 30% result in too flexible capsules and below 20% will result in too brittle capsules.Glycerol, Sorbitol, propylene glycol or mixtures are frequently used.

Water in SoftgelWater accounts for 30 40% of the wet gel to facilitate proper processing during gel preparation.Excess water is removed by controlled drying.Water content in the finished capsule should be 5 8%, to keep the physical stability .Improper storage conditions may make the capsules too soft or too hard and embrittled.

Other additives in gel formulationInsoluble pigments, soluble pigments with or without opacifier can be used.Opacifier Titanium dioxide isgenerally used for suspension or to guard against light.Methy paraben, propyl paraben, sod sulfite may be used as preservative.

Formulation of the Fill for SoftgelThe liquid-phase fill matrix is selected according to the following criteria:Capacity to dissolve the drug.Rate of dispersion in the GIT after softgel shell rupture.Capacity to retain the drug in solution in the GIT fluid.Compatibility with the gelatin shell.Ability to optimize the rate, extend and consistency of drug absorption.

Types of softgel matricesLipophilic liquid oils. Soya bean oil can be used for encapsulation of Vit D analoques, steroids as oestradiol.Hydrophilic liquids as PEG 400, ethanol on a concentration below 10%.Self-emulsifying oils: oil + tween, the fill rapidly emulsified in the GIT fluid in small droplets, so enhancing absorption.Microemulsion and nanoemulsion systems: lipid-surfactant-polar liquid system. Droplets of submicrometre scattering light results in blue coloration= Tyndal effect.Preconcentrate softgel matrix fill contain lipid + surfactant form micro and nan emulsion with the GIT fluid.Suspension using fine particle size passing mesh 80.Lipolysis Base adsorption.

Effect of pH of the fillThe matrix fill should have pH 2.5 7.5. More acidic cause hydrolysis of gelatin and leakage of shell.More alkaline cause tanning of gelatin decreasing its solubility.

Manufacture of Soft Gelatin CapsulesPlate processRotary die process.AccogelBubble method .The most common used is the rotary die process.

Rotary Die Process

The two roller dies have cavities.Gelatin ribbons come from two sides made by means of the cooling drum.The fill come from the pump above the rollers.The injection wedge inject the required amount of fill when the cavities of the two die rolls come together.By means of pressure and controlled temperature ( 37 -40 C ) the two sides of ribbons welded together forming the capsule in the shape of die cavities.By means of conveyor the capsules transferred to the drying chamber.Drying conditions is 20 30% RH at 21 24 C.

Filling theory

Quality Control Tests for Capsules Visual inspectionAppearance : shape, colour, size , thickness of the shell, leakage test for softgels.Weight variationDisintegration test.Dissolution test.Content uniformitytestMicrobiological Testing

Vegetarian Capsules

End of capsules good luck