©上特 “-wls 国上人生 Capsule Solid dosage form in which the drug substance and excipients are enclosed within a hard or soft-elastic Capsules capsule ·Hard capsules ·Soft capsules School of Pharmacy Chen Jian 20123 Sustained release capsules chenjian@sjtu.edu.cn Controlled release capsules ·Enteric capsules 图上生一 Hard Capsules 国生一 ©Advantages ·Conceal the smell .Improve drug stability .Bioavailability is generally good Flexibility in formulation in comparison to tablets Solidify the liquid drug .Obtain sustained-release or targeted-release .Ideal or clinical trials and widely used for preliminary drug trials 国垫生 ©f达Manufacture of Hard Capsules Disadvantages ®Shell composition .Number of suppliers of shells is limited .Gelatin Filling equipment slower than tableting ·Plasticizer .Generally more costly than tablets ·Colorants Not suitable for some kinds of drugs ·Opaquing agents Water or alcohol solution of drugs ·Preservatives .Efflorescent materials ·Water .Hygroscopic materials Extremely soluble materials 1
1 Capsules School of Pharmacy Chen Jian 2012.3 chenjian@sjtu.edu.cn Shanghai Jiao Tong University Capsule Solid dosage form in which the drug substance and excipients are enclosed within a hard or soft-elastic capsule • Hard capsules • Soft capsules • Sustained release capsules • Controlled release capsules • Enteric capsules Shanghai Jiao Tong University Hard Capsules Shanghai Jiao Tong University Advantages • Conceal the smell • Improve drug stability • Bioavailability is generally good • Flexibility in formulation in comparison to tablets • Solidify the liquid drug • Obtain sustained-release or targeted-release • Ideal or clinical trials and widely used for preliminary drug trials Shanghai Jiao Tong University Disadvantages • Number of suppliers of shells is limited • Filling equipment slower than tableting • Generally more costly than tablets • Not suitable for some kinds of drugs • Water or alcohol solution of drugs • Efflorescent materials • Hygroscopic materials • Extremely soluble materials Shanghai Jiao Tong University Manufacture of Hard Capsules Shell composition • Gelatin • Plasticizer • Colorants • Opaquing agents • Preservatives • Water
图生 Gelatin 国上人生 Gelatin Although some other materials could be used. Type A gelatin contributes plasticity and clarity Manufactured from pork skin gelatin is the most popular component to prepare capsule shells. Produced by acid hydrolysis .Isoelectric point:7-9 Gelatin is prepared by the hydrolysis of collagen obtained from animal connective Type B gelatin contributes firmness Manufactured from bone tissue,bones,skin,and sinew. Produced by alkaline hydrolysis Isoelectric point:4.7-5.2 国生一 Manufacture of Hard Capsules Evaluation of gelatin Shell composition ·Gel strength冻力强度 Gelatin Plasticizer:glycerin ·Viscosity ·Thicker Opaquing agents ·Preservatives ·Colorants Water 国生一 Manufacture of Hard Capsules Manufacture of Hard Capsules ©Shell manufacture Properties of empty capsules ·Gelatin dissolution ·Appearance: ·Dipping ·Size ·Smel .Rotation Moisture content:13.0-16.0% ·Drying ·Friability ·Stripping ·Dissolution rate .Trimming ·Ash test ·Joining .Microbiological test 2
2 Shanghai Jiao Tong University Gelatin Although some other materials could be used, gelatin is the most popular component to prepare capsule shells. Gelatin is prepared by the hydrolysis of collagen obtained from animal connective tissue, bones, skin, and sinew. Shanghai Jiao Tong University Gelatin Type A gelatin contributes plasticity and clarity • Manufactured from pork skin • Produced by acid hydrolysis • Isoelectric point: 7-9 Type B gelatin contributes firmness • Manufactured from bone • Produced by alkaline hydrolysis • Isoelectric point: 4.7-5.2 Shanghai Jiao Tong University Evaluation of gelatin • Gel strength 冻力强度 • Viscosity Shanghai Jiao Tong University Manufacture of Hard Capsules Shell composition • Gelatin • Plasticizer: glycerin • Thicker • Opaquing agents • Preservatives • Colorants • Water Shanghai Jiao Tong University Manufacture of Hard Capsules Shell manufacture • Gelatin dissolution • Dipping • Rotation • Drying • Stripping • Trimming • Joining Shanghai Jiao Tong University Manufacture of Hard Capsules Properties of empty capsules • Appearance: • Size • Smell • Moisture content: 13.0–16.0% • Friability • Dissolution rate • Ash test • Microbiological test
图生_Manufacture of Hard Capsules ®i生_Manufacture of Hard Capsules ©Size ④Self-locking closure ·Eight size::000,00,0,1,2,3,4,5 Hard capsules are made self-locking by forming indentations or grooves 空数01234 on the inside of the cap 0750.550.400200.25015 and body portions 圈t生Manufacture of Hard Capsules Manufacture of Hard Capsules ©Storage of shells ©Rectification Avoid extremely temperature(s37C) Separation of caps from bodies Maintain a relative humidity of 50% Dosing of fill material ④Stability of shells Replacement of caps and ejection of filled capsules Moisture transfer between content and shell ·Trace aldehydes 8-ee-9-ggg-月-3 Manufacture of Hard Capsules 国生 Manual Filling Machines ®Powder filling ·Choice of shell ·Power filling Sealing 3
3 Shanghai Jiao Tong University Manufacture of Hard Capsules Size • Eight size: 000, 00, 0, 1, 2, 3, 4, 5 Shanghai Jiao Tong University Manufacture of Hard Capsules Self-locking closure • Hard capsules are made self-locking by forming indentations or grooves on the inside of the cap and body portions Shanghai Jiao Tong University Manufacture of Hard Capsules Storage of shells • Avoid extremely temperature(≤ 37℃) • Maintain a relative humidity of 50% Stability of shells • Moisture transfer between content and shell • Trace aldehydes Shanghai Jiao Tong University Manufacture of Hard Capsules Rectification Separation of caps from bodies Dosing of fill material Replacement of caps and ejection of filled capsules Shanghai Jiao Tong University Manufacture of Hard Capsules Powder filling • Choice of shell • Power filling • Sealing Shanghai Jiao Tong University Manual Filling Machines
Powder filling ®生Design of Powder Formulation 柱塞 General Considerations ·Lubricity 1防 ·Compactibility 。Fluidity 填充管 ]T仔单位重药指块 放表 @卢t生Design of Powder Formulation Manufacture of Hard Capsules ©Excipients ©Nonpowder filling ·Fillers ·Beads/pellets ·Glidants ·Microtablets 。Lubricants ·Liquid ·Disintegrants 国垫生 ©f达Soft Gelatin Capsules(softgels) Alternatives to Gelatin Capsules ·Starch capsules The moisture content of the capsules is 14%. ·HPMC capsules Lower moisture content than gelatin capsules The moisture is tighter bound 4
4 Powder filling Shanghai Jiao Tong University Design of Powder Formulation General Considerations • Lubricity • Compactibility • Fluidity Shanghai Jiao Tong University Design of Powder Formulation Excipients • Fillers • Glidants • Lubricants • Disintegrants Shanghai Jiao Tong University Manufacture of Hard Capsules Nonpowder filling • Beads/pellets • Microtablets • Liquid Shanghai Jiao Tong University Alternatives to Gelatin Capsules • Starch capsules • The moisture content of the capsules is 14%. • HPMC capsules • Lower moisture content than gelatin capsules • The moisture is tighter bound Shanghai Jiao Tong University Soft Gelatin Capsules (softgels)
国必生 Soft Capsules 国上生 Soft Capsules Capsule filling material Advantages of soft capsule ·Single liquid Solidify the liquid drug ·Liquid blends Improved bioavailability ·Drug solution Enhanced drug stability ·Suspensions .Pharmaceutical elegance Superior patient compliance ·Semisolids Excellent dose uniformity 国生一 Soft Capsules 国生 Soft Capsules Disadvantages of soft capsule ©Plasticizer Not suitable for some kinds of drugs Glycerin,sorbitol,propylene glycol Specialized manufacturing equipment requirements ·Ratio:0.4-0.6 Higher manufacturing cost as compared to tablets .Stability concers with compounds susceptible to hydrolysis. 国坠生 Soft Capsules 国生 Soft Capsules Requirements of filling material ©The types of vehicles Water content lower than 5% .Water-immiscible liquids No low MW water soluble and volatile ·Vegetable oils organic compounds .Aliphatic and aromatic hydrocarbons No aldehyde .Water-miscible,nonvolatile liquids ·PEG The pH of the liquids can be between 2.5 and 7.5 All liquids used for filling must flow by gravity at a temperature of 35'C or less. 5
5 Shanghai Jiao Tong University Soft Capsules Capsule filling material • Single liquid • Liquid blends • Drug solution • Suspensions • Semisolids Shanghai Jiao Tong University Soft Capsules Advantages of soft capsule • Solidify the liquid drug • Improved bioavailability • Enhanced drug stability • Pharmaceutical elegance • Superior patient compliance • Excellent dose uniformity Shanghai Jiao Tong University Soft Capsules Disadvantages of soft capsule • Not suitable for some kinds of drugs • Specialized manufacturing equipment requirements. • Higher manufacturing cost as compared to tablets • Stability concerns with compounds susceptible to hydrolysis. Shanghai Jiao Tong University Soft Capsules Plasticizer • Glycerin, sorbitol, propylene glycol • Ratio: 0.4-0.6 Shanghai Jiao Tong University Soft Capsules Requirements of filling material • Water content lower than 5% • No low MW water soluble and volatile organic compounds • No aldehyde • The pH of the liquids can be between 2.5 and 7.5 Shanghai Jiao Tong University Soft Capsules The types of vehicles • Water-immiscible liquids • Vegetable oils • Aliphatic and aromatic hydrocarbons • Water-miscible, nonvolatile liquids • PEG All liquids used for filling must flow by gravity at a temperature of 35℃ or less