Capsules

1.Introduction
2.Gelatin
3.Hard Gelatin Capsule (HGC)
4.Soft Gelatin Capsule (SGC)
5.Difference between HGC & SGC
6.Capsule shell
7.Evaluation of capsules
8.Package & storage of capsule

1. Presented By M. PRABAKARAN B.pharm ., Vinayaka Mission’s College of Pharmacy Vinayaka Mission’s Research Foundation CAPSULES 12 July 2018

2. CONTENTS 1.Introduction 2.Gelatin 3.Hard Gelatin Capsule (HGC) 4.Soft Gelatin Capsule (SGC) 5.Difference between HGC & SGC 6.Capsule shell 7.Evaluation of capsules 8.Package & storage of capsule 12 July 2018

3. INTRODUCTION: CAPSULES: Capsules are solid dosage forms in which the drug substance is enclosed within either a hard or soft soluble shell, usually formed from gelatin. The term capsule is derived from the Latin word capsula , meaning a small container. The medication may be a powder , a liquid or a semisolid mass . Capsules are usually intended to be administered orally by swallowing them whole. Occasionally, capsules may be administered rectally or vaginally . 1

4. HISTORY: • In 1730, the Pharmacist De PAULI from Vienna developed oval shaped capsules for covering up the unpleasant taste of the pure turpentine used for the treatment of gout • In 1834, the Pharmacist JOSEPH DUPLANC from FRONCOIS MOTHES were granted Patent which covered a method for the producing , single piece , olive shaped , gelatin capsules which were closed after filling by a drop of concentrated warm gelatin solution. • In 1846, the Frenchman JULES LEHUBY first to suggest Two- Piece Capsule produced by dipping silver coated metal pins into a gelatin solution and then drying them quickly • In 1931, the author COLTON designed a machine to manufacture bodies and caps and fitted them to form hard gelatin capsule. 2

5. ADVANTAGES OF CAPSULES: Capsules are tasteless, odorless and can easily be administered . Combination of powders we can use There are attractive in appearance. The drugs having un-pleasant odor and taste are enclosed in a tasteless shell . They can be filled quickly and conveniently. Physician can change the dose and combination of drug according to patient requirement. They are economical. They are easy to handle and carry . The ready solubility of gelatin at gastric pH provides rapid release of medication in the stomach. Packaged and shipped by manufacturers at lower cost less breakage than liquid forms. More stable and longer shelf life. 3

6. DISADVANTAGES OF CAPSULES: Capsules are not suitable for liquids that dissolve gelatin, such as aqueous or hydro alcoholic solutions. The concentrated solutions which require previous dilution are unsuitable for capsules because if administered as such lead to irritation into stomach. Not useful for efflorescent or deliquescent materials. Efflorescent cause capsules to soften & Deliquescent may dry the capsule shell to brittleness. 4

7. *The largest size of the capsule is No: 000. *The smallest size is No: 5. *The standard shape of capsules is traditional, symmetrical bullet shape. SHAPES OF CAPSULE: 5

8. Size Volume in ml Size in mm 000 1.37 26.3 00 0.95 23.7 0.68 21.8 1 0.50 19.2 2 0.37 18.3 3 0.30 15.3 4 0.21 14.7 5 0.15 11.9 SIZE OF CAPSULE: 6

9. RAW MATERIALS: 1. Gelatin 2. FD & C and D & C colorant 3. Sugar 4. Water - 12 to 16 % (may vary depending on the storage condition ) 5. Sulfur dioxide (15%) - prevent decomposition during manufacture 6. Colorants / Opacifying agent : There are two types A) water soluble dyes – e.g. erythrosine B) pigments – e.g. iron oxides , titanium dioxide (make the capsule opaque to provide protection against light) 7

10. 7. Preservatives: To prevent microbial growth during manufacture. 8. Diluents: lactose, mannitol, sorbitol, starch, etc 9. Lubricants and Glidants : talc, magnesium stearate & calcium stearate 10. Wetting agents: sodium lauryl sulphate 11. Disintegrants 12. Anti – dusting agent : inert edible oils 8

11. GELATIN: Gelatin is heterogeneous product derived by hydrolytic extraction of animal's collagen. The sources of gelatins including animal bones, hide portions and frozen pork skin. It is the major component of the capsule. The reason for this is that gelatin possesses five basic properties: A- Non-toxic. B- Soluble in biological fluids at body temperature. C- It is a good film-forming material. D- Solutions of high concentration, 40% w/v, are mobile at 50°C. E- A solution in water changes from a sol to a gel at temperatures only a few degrees above ambient 9

12. Preparation of Gelatin: 10

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14. TYPES OF GELATIN: There are two basic types of gelatin 1. Type - A 2. Type - B 1.TYPE - A Derived from acid treated precursor that exhibits an iso electric point at pH-9. It is manufactured mainly from pork skin. 2.TYPE - B Derived from alkali treated precursor that exhibits an iso electric point at pH-4.7. It is manufactured mainly from animal bones 12

15. GENERAL CHARACTERISTICS OF GELATIN: 1 Bloom value; Is a measurement of the gelling power and the strength of the resulting gel. Gelatin generally falls between 50 and 300 bloom strength. 2 Gelling power; The key function of gelatin. The gelling power varies depending on the grade of gelatin Its measured in terms of bloom value. The higher the bloom value, the greater the ability to form gels & the stronger the gel strength. 13

16. 3. Viscosity; In general the higher the bloom, the greater the viscosity. Beef bone grades tend to have higher viscosity. Viscosity is determined by measuring the flow time of a 6.67% solution of gelatin through a U-tube viscometer at 60 °C. Viscosity measurement is given in millipoise units and varies between 20 and 70mps. 4. Foamability; In general pigskin grades tend to have better foaming properties. Gelatin lowers the surface tension, allowing for the incorporation of air, and stabilizes the foam once aerated. Gelatin will also prevent crystal formation of sugars in the foam and maintain smoothness in texture. 14

17. 5. Melting point; Lower melting point gelatins dissolve faster in the mouth, therefore releasing the flavors more quickly for an instant taste sensation. Lower bloom grades tend to have lower melting points. 6. Color and odor; The gelatin should be as clear as possible in solution. Clarity is measured using a turbidimeter . The gelatin should be without odor. 7. Conductivity; is a key parameter in photographic applications and grades of the highest purity with minimal or no conductivity are required. De-ionized grades have an advantage because of their low conductivity. 8. pH; pH is measured using a pH meter on a 1% solution and typically for gelatin solutions falls between ph 4.5 and 6.5. 15

18. TYPES OF CAPSULES: Capsules are available in two types: 1.Hard gelatin capsules 2.Soft gelatin capsules. 1.Hard gelatin capsule 2.Soft gelatin capsule 16

19. 1.HARD GELATIN CAPSULES: The hard gelatin capsule consists of two pieces in the form of cylinders closed at one end. The shorter piece is called the cap. This cap fits over the open end of longer piece called body. Hard gelatin capsules are also known as dry-filled capsules or two piece capsules. The drug substance placed in the body and the caps are slided over it, hence enclosing the drug substance. 17

20. Manufacturing of Hard gelatin capsules Steps involved in making empty gelatin capsules… 1.Dipping 2.Spinning 3.Drying 4.Stripping 5.Trimming and Joining 6.Polishing 18

21. 1.DIPPING: Pairs of the stainless steel pins are dipped into the dipping solution to simultaneously form the caps and bodies. The dipping solution is maintained at a temperature of about 500C in a heated, jacketed dipping pan. 2.SPINNING: The pins are rotated to distribute the gelatin over the pins uniformly and to avoid the formation of a bead at the capsule ends. 19

22. 3.DRYING : The gelatin is dried by a blast of cool air to form a hard shells. The pins are moved through a series of air drying kilns to remove water 4.STRIPPING : A series of bronze jaws strip the cap and body portions of the capsules from the pins. 20

23. 5.TRIMMING AND JOINING: The stripped cap and body portions are trimmed to the required length by stationary knives. The cap and body lengths are precisely trimmed to a ±0.15 mm tolerance. After trimming to the right length, the cap and body portion are joined. Finished capsules are pushed onto a conveyer belt which carries them out to a container. Capsule quality is monitored throughout the production process including size, moisture content, single wall thickness, and color. Capsules are sorted and visually inspected on specially designed Inspection Stations. Perfect capsules are imprinted with the client logo on high-speed. 21

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25. 6.POLISHING : a)Pan Polishing : Acela-cota pan is used to dust and polish. b)Cloth Dusting : Capsule are rubbed with cloth. c)Brushing : Capsule are feed under soft rotating brush. Fig : Capsule polishing machine 23

26. STORAGE : Finished capsules normally contain an equilibrium moisture content of 13-16%. To maintain a relative humidity of 40-60% when handling and storing capsules. 24

27. FILLING OF HARD GELATIN CAPSULES : Hand Operated methods or Semi Automatic Capsules Devices. Punch Method or Manual Filling. Automatic filling machine. ex: osaka capsule filling machine , macofar capsule filling machine HAND OPERATED METHOD; 25

28. • It consists of: 1.A bed having 200-300 holes 2.A loading tray having 200-300 holes 3.A powder tray 4.A pin plate having a rubber top 5.A lever 6. A cam handle. 26

29. The empty capsules are filled in the loading tray . ↓ and it is placed over the bed ↓ The cam handle is operated to separate the capsule caps from their bodies. ↓ The powder tray is placed in a proper position and filled with an accurate quantity of powder with scraper. ↓ The excess of powder is collected on the plat for of the powder tray ↓ The pin plate is lowered and the filled powder is pressed by moving the pin downwards ↓ 27

30. After pressing ,the pin plate is raised and the remaining powder is filled into the bodies of the capsules ↓ The powdered tray is removed after its complete filling ↓ The cap holding tray is again placed in position ↓ The plate with the rubber top is lowered and the lever is operated to lock the caps and bodies ↓ The loading tray is then removed and the filled capsules are collected 28

31. PUNCH METHOD: Powder is placed on a sheet of a clean paper or porcelain plate using spatula which is formed into a cake having a depth of approximately one-fourth to one-third the length of the capsule body. Then empty capsule body is held between the thumb and forefinger and punched vertically into the powder cake repeatedly until filled.   29

32. FILLING OF HARD CAPSULE SHELL The process of working: Rectification Separating the caps from empty capsules Filling the bodies Scraping the excess powder Replacing the caps Sealing the capsules Cleaning the outside of the filled capsules 160,000 capsules per 8hour shift Fig : OSAKA MODEL R-180 SEMI AUTOMATIC CAPSULE FILLING MACHINE 30

33. Rectification ; • The empty capsules are oriented so that all point the same direction i.e. body end downwards. • In general, capsule pass one at a time through a channel just wide enough to provide grip at cap end. • The capsules will always be aligned body end downwards, regardless of which end entered the channel first with the help of specially designated blades. 31

34. Separation of caps from body ; • The rectified capsules are delivered body end first into the upper portion of split bushings or split filling rings • A vacuum applied from below pulls the body down into the lower portion of the split bushing • The diameter of the bush is too large to allow them to follow body • The split bushings are separated to expose the bodies for filling 32

35. Principles of capsule Filling: Auger Fill principle: empty capsules – rectifying unit Rectifier descends the capsules such that caps are turned up and bodies down. From rectifying unit these are placed one by one in filling ring kept on rotating mode. The lower ring is rotated with a suitable speed and the hopper containing powdered drug is held over this ring. The auger drives the drug into bodies. Vibratory Fill Principle: The feed is placed in the feed hopper and the capsule bodies are passed under it. A perforated resin plate is placed in the feed hopper. Due the vibrations of the resin plate, the powder flows freely through the pores into bodies. - Osaka machines follows this principle. 33

36. Piston – Tamp principle : These piston tamps alter the shape of powder by compressing the powder to form slugs. These plugs are transferred into the empty capsule bodies with the application of slight pressure. Finally the bodies are ejected from the machine. Compression force 50-200N a) Dosator machine b) Dosing Disc Vacuum Fill principle: It consists of an open ended cylinder. The upper end of this is fitted with a piston. The open end is placed in bulk powder. Vacuum is applied & the piston is moved upward by sucking the predetermined amount of powder which results in filling of the cylinder. 34

37. HOFLIGER KARG AUTOMATIC CAPSULE FILLING MACHINE ZANASI AUTOMATIC CAPSULE FILLING MACHINE 35

38. Various Filling Machine Available… Eli-lily Farmatic Hofliger and Karg Zanasi Nigris Parke-Davis Osaka Macofar SAS (These machine differ in there design and output ) 36

39. Locking and Sealing of Capsules : Banding – Placing gelatin color bands at the meeting point of caps and the bodies. Moistening – Moistening the inner surface of caps with lukewarm gelatin solution. Spot Welding – Spot welding the joints which leaves a ring like appearance at the point of sealing Thermal welding – Applying wetting sol. At the meeting points which causes lowering of M.P at applied area. Finally they are sealed at a temp. 40-45ºc.   By using Coni -snap capsules – Grooves help to lock the caps with the bodies. 37

40. FINISHING OF CAPSULES: Cloth dusting: Capsule are rubbed with cloth. Polishing Pan Polishing : Acela-cota pan is used to dust and polish which is lined with cheese or a polyurethane cloth. Brushing : Capsule are feed under soft rotating brush SORTING: Rotosort – 1,50,000 capsules/hr. 38

41. Storage, packaging, and stability: • Finished capsules normally contain an EMC of 13-16%. • < 12% MC, the capsule shells become brittle. • >18% make them too soft. • To maintain a relative humidity of 40-60% when handling and storing capsules. • QUALI-V, developed by Shionogi Qualicaps , is the first HPMC capsule developed for eventual use in pharmaceutical products. 39

42. SOFT GELATIN CAPSULE: Definition:- Soft Gelatin capsules are one piece, hermetically sealed, soft gelatin shells containing a liquid, a suspension, or a semisolid. Soft gelatin is mainly composed of gelatin, plasticizers, preservative, colouring and opacifying agents, flavoring agents and sugars. APPLICATION OF SOFT GELATIN CAPSULE: The pharmaceutical applications of soft gelatin capsules are: As an oral dosage form As a suppository dosage form As a specialty package in tube form, for human and veterinary use, single dose application for topical, ophthalmic, and rectal ointments. 1 40

43. ADVANTAGES OF SOFT GELATIN CAPSULES: Easy to administer. Easy to manufacture. Liquids can be encapsulated (non water soluble) Small to large sizes possible. Elegance. Portability Ready availability of drug hence faster action. Odour and taste masking. Specialised dosage forms can be made. e.g. chewable, extended release, captabs , etc Can be used for ophthalmic preparations. e.g. aplicaps , vaginal/ rectal suppositories. 41

44. SHAPE OF CAPSULE: The shape of soft gelatin capsule are round, oval, oblong, tube. 42

45. soft gelatin capsules composition: • A typical gel mass formula for making soft gelatin capsules would be: • Gelatin 35-45% • Plasticizer 15-25% (glycerin or sorbitol ) • Water ~40% • Dye / Pigment as needed • Opacifier as needed • Other ( flavour , sugar,) as needed 43

46. Formulation : Formulation for soft gelatin capsules involves liquid, rather than powder technology. Materials are generally formulated to produce the smallest possible capsule consistent with maximum stability, therapeutic effectiveness and manufacture efficiency. The liquids are limited to those that do not have an adverse effect on gelatin walls. Emulsion can not be filled because water will be released that will affect the shell. The pH of the liquid can be between 2.5 and 7.5. 44

47. Vehicles used in soft gelatin capsules: Two main groups : 1.Water immiscible, volatile or more likely more volatile liquids such as vegetable oils, mineral oils, medium-chain triglycerides and acetylated glycerin. 2.Water miscible, nonvolatile liquids such as low molecular weight PEG have come in to use more recently because of their ability to mix with water readily and accelerate dissolution of dissolved or suspended drugs. All liquids used for filling must flow by gravity at a temperature of 350ºC or less. The sealing temperature of gelatin films is 37-400ºC 45

48. MANUFACTURE OF SOFT GELATIN CAPSULE: Is manufactured by four methods, 1)Plate process 2)Rotary die process 3) Accogel machine 4) Reciprocating die 46

49. 1.PLATE PROCESS: •Place the gelatin sheet over a die plate containing numerous die pockets. •Application of vacuum to draw the sheet in to the die pockets. •Fill the pockets with liquid or paste. •Place another gelatin sheet over the filled pockets. •Sandwich under a die press where the capsules are formed and cut out. 47

50. 2.ROTARY DIE PROCESS: 1) In this machine the soft gelatin capsules are prepared & then filled immediately with liquid medicaments it is having two hoppers & two rotating dies. 2) Liquid mixture is placed in one hopper & the liquid medicament in other Hooper. 3) The two rotating dies rotate in opposite directions when the fluid gelatin mixture enters the machine from the hopper it produces two continuous ribbons . 4) These half shell of the capsule is formed. 5) At this stage the measured quantity of the medicament is filled in to it with the stroke of a pump with the subsequent movement of the dies the other half capsule is formed. 6) The two halves' of the capsules are sealed together by the heat & pressure of the rotating dies. 7) As the die rolls rotate, the convergence of the matching die pockets seals and cuts out the filled capsules. 48

51. Figure 3.8 Schematic drawing of a rotary-die soft gelatin capsule filler (R.P. Scherer: Detroit, MI). 49

52. 3.ACCOGEL CAPSULE MACHINE: It consists of mainly 3 parts: Measuring roll Die roll Sealing roll As the measuring roll and die rolls rotate, the measured doses are transferred to the gelatin-linked pockets of the die roll. The continued rotation of the filled die converges with the rotating sealing roll where a second gelatin sheet is applied to form the other half of the capsule. Pressure developed between the die roll and sealing roll seals and cuts out the capsules. 50

53. DIFFERENCE BETWEEN HARD GELATIN CAPSULES AND SOFT GELATIN CAPSULES 51

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55. CAPSULE SHELL: The capsule shell is basically composed of Gelatin, a plasticizer & water, it may contain additional ingredients such as preservative, coloring & opacifying agents, flavourings , sugars, acids & medicaments to achieve desired effects. Composition of the capsule shell: The basic component of soft gelatin shell is gelatin; however, the shell has been plasticize The ratio of dry plasticizer to dry gelatin determines the “hardness” of the shell and can vary from 0.3-1.0 for very hard shell to 1.0-1.8 for very soft shell. Up to 5% sugar may be included to give a “chewable” quality to the shell. The residual shell moisture content of finished capsules will be in the range of 6-10%. 53

56. Constituents of Capsule Shell: Constituents Examples Function Gelatin Type A, Type B Plasticizers Glycerine USP, glycerol (85% & 98%) Imparts s oftness, Elasticity & hardness Preservatives Methyl paraben, Sorbic acid (0.2%) Retard growth of microorganisms Solvents Oils Elegance Opacifying agents Tio2(0.2-1.2%) Minimize transparency Colours Veg. colours,FD&C D&C water soluble dyes, certified lakes Gives pleasant appearance to the shells. Flavours Ethyl vanillin(0.1-2%) Good flavour Sugars Sucrose( up to 5%) Sweet taste Acids Fumaric acid(up to 1%) Lessen aldehydic tanning of gelatin Thickening agents Methyl cellulose Adjust viscosity of gelatin Water 54

57. QUALITY CONTROL OF CAPSULES: Whether capsules are produced on a small scale or large scale all of them are required to pass through certain tests i.e., quality control tests to test the quality of the finished product. Quality control tests are divided into; PHYSICAL TEST • Disintegration test • Weight variation CHEMICAL TEST • Dissolution test • Assay • Content uniformity • Stability testing • Moisture permeation test 55

58. EVALUATION OF CAPSULES: Weight variation test Moisture permeation test Content uniformity Dissolution test Disintegration test 56

59. Weight variation test: 20 capsules are taken at random and weighed. Their average weight is calculated, then each capsule is weighed individually and their weight is noted. The capsule passes the test if the weight of individual capsule falls with in 90-110% of the average weight. Moisture permeation test: According to U.S.P the unit dose container is packed along with dehydrated pellets, which have the property of changing color in the presence of moisture. The weight of test capsule is compared with the under test capsules. Diff. in weights gives the amount of moisture absorbed. 57

60. Content Uniformity Test: This test is applicable to all capsules which are meant for oral administration. For this test a sample of the contents is assayed as described in individual monographs and the values calculated which must comply with the prescribed standards. Content uniformity: 30 Capsules are selected and 10 of these are assayed individually. At least 9 of these contain 85-115% of drug and none contain below 75-125% of drug. If 1 to 3 of them fall outside of 85 -115% limits , the remaining 20 capsules are individually assayed and the requirements are met if no few than 27 contain 85-115% of drug and none contain less than 75-115% of drug. 58

61. Dissolution Test: Place 1000 ml of water free from disolevied air having temperature of 36.5ºC to 37.5ºC Place specified number of capsules in each basket. Start motor and adjust speed 100 rpm as per monograph. Withdraw the required volume of solution after 45 minutes or as specified in the monograph Filter and weigh the amount of active ingredients by the method specified in the monograph. Repeat four times. The test is said to pass if the amount of active ingredient is not less than 70% of the stated amount given in the monograph. 59

62. Disintegration Test: Place one capsule in each basket. Set the temperature of water to 37 +/- 2 Use disc if HGC floats whereas for soft gelatin use the disc. Operate the apparatus for 30 mins for HGC and 60 minutes for SGC. The test is said to pass if no residue is left on the screen of the apparatus. Repeat the test for 12 capsules if more than 1 or 2 capsules fails to disintegrate The test passes if 16 out of 18 capsules disintegrate or else fail. 60

63. PACKING & STORAGE OF CAPSULES: Capsules should be packed well closed glass & plastic container & stored at temperature not exceeding 30 º c. Capsules are individually protected by enclosing in strip & blister packaging. In strip packing the capsule is hermetically sealed within the strips of an aluminum or plastic film. In blister packs, a press on the blister forces the capsule through the backing strip. Capsules have a larger shelf life in unopened glass bottles than in strip pack & but this is reversed.  61

64. • Now a days capsules are strip packaged which provide sanitary handling of medicines, ease in counting and identification. • Plastic bottle with screw cap. ( most popular package in USA ) Clam shell blister (one piece plastic that folds over and locks itself; no heating required) 62

65. • Blister pack (heat sealed blister on a cardboard) • Plastic pail/bucket ( economical bulk package) • Plastic pouch zip locked (for sale via retail stores or route trucks must be packed in outer case for shipping ) 63

66. 12 July 2018