Soft Gelatin Capsules

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1 Seminar On Soft gelatin capsules Manufacturing and quality control Department of pharmaceutics Balaji institute of pharmaceutical sciences Kakatiya university warangal Presented By n.raju sem

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2 Contents 1.Introduction 2.Production of soft gels Formulation development Product development Method of manufacture Therapeutic performance Product quality considerations 3.Conclusion References

Soft Gelatin Capsules : 

Soft Gelatin Capsules 3 Definition: Soft Gelatin Capsules are one-piece forms that encase a predetermined dose of liquid or semi liquid fill. Filled and hermetically sealed in a single operation Fresh and potent for a prolonged period of time.

Advantages: : 

Advantages: Improved bioavailability Enhanced drug stability Superior patient compliance Product differentiation by colour, size and shape Portability and easy to swallow Better tamper evidence and cloaks bad taste Uniformity and precision dosage 4

Limitations : 

Limitations Equipment Higher manufacturing cost as compared to tablets Stability concerns with compounds susceptible to hydrolysis 5

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Hard Vs soft gelatin Capsules 6

Frequently used capsule sizes : 

Frequently used capsule sizes Oblong-20minim Oval-16minim Round-9minim 7

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PRODUCTION OF SOFTGELS FORMULATION DEVELOPMENT Shell formulation Fill formulation PRODUCT DEVELOPMENT Fill formulation development Shell compatibility Prototype development Process development Clinical supply Product performance review METHOD OF MANUFACTURE THERAPEUTIC PERFORMANCE Rate of absorption Increased bioavailability Decreased plasma variability PRODUCT QUALITY CONSIDERATIONS Ingredient specifications In-process testing Final product testing 9

Formulation development: : 

Formulation development: Shell development: Constituents of shell: 10 1 part gelatin,1 part water and 0.4 to 0.6 part plasticizer

Category I : 

Category I Additional components of gelatin mass 11

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Category II 12

Gelatin : 

Gelatin non-toxic. soluble in biological fluids at body temperature. strong flexible film homogeneous in structure Structure of gelatin Gelatin contains mainly glycine (almost 1 in 3 residues, arranged every third residue), proline and 4-hydroxyproline residues. A typical structure is -Ala-Gly-Pro-Arg-Gly-Glu-4Hyp-Gly-Pro- 13

Gelatin USP grade: : 

Gelatin USP grade: Bloom or Gel strength………150-250 g Viscosity………………………25-45 milli poise Iron.……………………………NMT 15 ppm Microbial content…………NMT 1000 organisms/gram and total absence of Salmonella and E.coli 14

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15 Source and types

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Gelatin Manufacture 1. Pre-treatment: Size reduction, washing, removing hair from the hides and degreasing 2. Extraction: With Hot water, Acid treatment Reducing cross linkages between collagen Removing impurities like fat and salts 3. Recovery: Filtration, Evaporation, Drying, Grinding, Sifting. 16

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Flow chart for gelatin production 17

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PLASTICIZERS: Examples: Glycerin Sorbitol USP Propylene glycol USP Dry Plasticizer:Gelatin=hardness of the shell 19

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Importance of plasticizers: Plasticizer α softness Determines disintegration and dissolution characters Must be compatible with fill formulation with minimum migration. 20

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WATER: To ensure proper processing during gel preparation and soft gel encapsulation. Excess-capsules become soft and fuse Insufficient-hard and embrittle Equilibrium moisture content-5-8%w/w 21

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COLORS: An important aspect The color of the capsule shell should never be lighter in hue than capsulated material. Test for any reaction with the compound Dark spots with iron compounds Clear colors –clear type fill Opaque –suspensions Titanium dioxide- As an opaquant and also to protect light sensitive ingredients In combination with different dyes produces different colors FD&C,D&C approved colors must be used 22

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PRESERVATIVES Microbial growth occurs due to presence of moisture. Examples: Methyl paraben Propyl paraben Humectants-glycerin 23

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FILL FORMULATION: To dispense active compounds formulated as Liquids Semisolids Suspensions Micro emulsion preconcentrate(nanoemulsions) Dry powders They are formulated such that Smallest possible capsule consistent with maximum amount of ingredient and it is physically stable. (ii) Therapeutically effective (iii)Production efficiency 24

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Liquids: Determine the solubility of drug in range of pharmaceutically acceptable solvents. Water-miscible liquids: PEG-400 Polysorbates(non-ionic surfactants) 5-10% of propylene glycol, ethanol, glycerin Water-immiscible liquids: Vegetable oils Aliphatic & Aromatic chlorinated hydrocarbons Esters Ethers 25

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Liquids which can not be incorporated: Water-in more than 5% of total formulation Ethyl alcohol Aldehydes Liquids with extremes of pH 26

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SUSPENSIONS: Drugs that are insoluble in a liquid are formulated as suspensions Suspending Agents: Water miscible vehicles Solid glycol ester High molecular weight PEGs Water immiscible vehicles Paraffin wax Bees wax Hydrogenated vegetable oils Microemulsions/nanoemulsions 27

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PRODUCT DEVELOPMENT Fill formulation development Rheology Fill type liquid-solution or suspension Solutions-most preferable Must be robust enough to remain in solution throughout manufacturing and shelf life. Physically stable Good IVIV correlation Suspensions Drug-solubility in solvents -Insolubility in excipients Controlled particle size 28

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Excipients used must be compatible Check for immediate and long term migration effects Shell compatibility immediate effects After encapsulation Shelf life 29

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Prototype development (Lab Scale Encapsulation) Especially for NCEs To evaluate whether the Softgel dosage form is viable for a particular drug 30

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Process Development: Information obtained in process development batches will provide suitable information for later process ranging and validation studies. Includes: Selection of equipment Investigating critical process parameters- Order of addition Temperature Mixing condition Speed 31

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Clinical supply: Manufacture of clinical batches will be performed according to the need for clinical studies Product Performance Review/Preparation for Process Validation: Performed at the end of product development phase and prior to process validation To ensure development process is complete 32

METHOD OF MANUFACTURE:Gelatin preparation department : 

METHOD OF MANUFACTURE:Gelatin preparation department 33

Material preparation department: : 

Material preparation department: 34

Requirements in manufacturing area: : 

Requirements in manufacturing area: Air-conditioned Temperature-20-220C Humidity Operating areas-40% Drying areas-20-30% 35

Methods of manufacture:1.Plate press method: : 

Methods of manufacture:1.Plate press method: Semi-automatic batch process Procedure: Place the upper half of a plasticized gelatin sheet over a die plate containing numerous die pockets Application of vacuum to draw the sheet into die pockets Filling the pockets with liquid or paste Folding the lower half of the gelatin sheet back over the filled pockets Inserting the sandwich under a die press where the capsules are formed and cut out. 36

2.Rotary die process : 

2.Rotary die process Patented by Robert.P.Scherer in 1933 Principle: Two independent processes take place, often simultaneously,yielding two different materials.Both are united in the encapsulation process that produces wet soft gels. 37

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Encapsulation Process Gelatin ribbons are brought together and the medicine is injected from the segment(S) into the die pocket from the pump(P). The necessary temperature for sealing is provided by the segment(S) and pressure provided by the die rolls(D). 39

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Typical parts of the machine: 01. Spreader Box 02. Cooling Drum 03. Oil Lubrication Roller 04. Gelatin Ribbon Guide Roller 05. Die Roll 06. Injection Wedge 07. Capsule Stripper 08. Conveyor 09. Medicine Filling Hopper 10. Medicine Filling Pump 40

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Change gear Injection segment Die rolls Distribution plate 42

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The soft gelatin capsule encapsulation machine wedge heater/ heating element is very important for making good quality softgels 43 Spreader box

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44 Rotary die encapsulation machine

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Drying: Tumble dryer Tray drying Moisture content-toluene distillation method Bulk holding container Washing Offline printing Inspecting packaging Tray dryer 45

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46 Tumble dryer

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3.Accogel process Developed by Lederle labs Continuous process for manufacturing of softgels with powders or granules Measuring roll rotates directly over the die roll, and the pockets in the 2 rolls are aligned each other. Measuring roll-powder or granular fill material under vacuum. Die roll-plasticized sheet under vacuum Sealing roll-second gelatin sheet applied to form other half of capsule Pressure developed between die roll and sealing roll seals and cuts out the capsules. 48

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49 Schematic representation of Accogel process

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4.Bubble method: 51

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Schematic representation of bubble method 52

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53 THERAPEUTIC PERFORMANCE: Rate of absorption Increased bioavailability Decreased plasma variability

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54 Product quality considerations: Ingredient specifications Adequate quality of ingredients and excipients To meet all the specifications especially in case of gelatin In-process testing Determination of fill materials and shell Thickness of the seals Fill moisture ,hardness measurements during drying process Final product testing Microbiological testing Assay and identity of activities Physical appearance Fill weight Dissolution & disintegration Dosage uniformity

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55 Conclusion: Recent developments: Development of gelatin substitutes VegiCap soft- a non-gelatin based capsule Delayed release forms Enteric release forms

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56 References: Bentley’s Text book of Pharmaceutics, eighth edition Encyclopedia of Pharmaceutical Technology, edited by James Swarbrick, third edition Volume I Handbook of hydrocolloids By Glyn O.Philips, Peter.A.Williams Modern pharmaceutics, fourth edition, edited by Gilbert S.Banker,Christopher Rhodes Pharmaceutics – The Science of Dosage form Design by M.E. Aulton, 2nd Edition Pharmaceutical Dosage Forms and Drug Delivery Systems By Howard.C.Ansel,Loyd V.Allen,Jr.Nicholas G.Popovich Remington:The Science and Practice of Pharmacy Vol II 20th edition The Theory and Practice of Industrial Pharmacy By Leon Lachmann Water insoluble drugs By Rong Liu 681247_DY-SG150_PT_ENGLISH[1].pdf

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