1. capsules

2. Capsules - definition
Capsules are solid preparations with hard or soft shells of various shapes and capacities, usually containing a single dose of active substance(s). They are intended for oral administration.
The capsule shells are made of gelatin or other substances, the consistency of which may be adjusted by the addition of substances such as glycerol or sorbitol.
Excipients such as surface-active agents, opaque fillers, antimicrobial preservatives, sweeteners, colouring matter authorised by the competent authority and flavouring substances may be added. The capsules may bear surface markings.
The contents of capsules may be solid, liquid or of a paste-like consistency.
They consist of one or more active substances with or without excipients such as solvents, diluents, lubricants and disintegrating agents.
The contents do not cause deterioration of the shell. The shell, however, is attacked by the digestive fluids and the contents are released.

3. Capsules - categories
Several categories of capsules may be distinguished:
hard capsules;
soft capsules;
gastro-resistant capsules;
modified-release capsules;
cachets.

4. Hard capsules
Hard capsules have shells consisting of 2 prefabricated, cylindrical sections, each of which has one rounded, closed end and one open end.
They are manufactured in one procedure and packed in another totally separate operation
The active substance(s), usually in solid form (powder or granules), are filled into one of the sections that is then closed by slipping the other section over it.
The security of the closure may be strengthened by suitable means.

5. HARD CAPSULES
They can be made self - locking by forming indentations or grooves on the inside of both parts so that when they are engaged

6. Soft capsules
Soft capsules have thicker shells than those of hard capsules. The shells consist of a single part and are of various shapes.
Soft capsules are usually formed, filled and sealed in one operation, but for extemporaneous use the shell may be prefabricated. The shell material may contain an active substance.
Liquids may be enclosed directly; solids are usually dissolved or dispersed in a suitable vehicle to give a solution or dispersion of a paste-like consistency.
There may be partial migration of the constituents from the capsule contents into the shell and vice versa because of the nature of the materials and the surfaces in contact.

7. Modified-release capsules
Modified-release capsules are hard or soft capsules in which the contents or the shell or both contain special excipients or are prepared by a special process designed to modify the rate, the place or the time at which the active substance(s) are released.
Modified-release capsules include prolonged-release capsules and delayed- release capsules.

8. Gastro-resistant capsules
Gastro-resistant capsule are delayed-release capsules that are intended to resist the gastric fluid and to release their active substance or substances in the intestinal fluid.
Usually they are prepared by filling capsules with granules or with particles covered with a gastro-resistant coating, or in certain cases, by providing hard or soft capsules with a gastro-resistant shell (enteric capsules).

9. cachets
Cachets are solid preparations consisting of a hard shell containing a single dose of one or more active substances.
The cachet shell is made of unleavened bread usually from rice flour and consists of 2 prefabricated flat cylindrical sections.
Before administration, the cachets are immersed in water for a few seconds, placed on the tongue and swallowed with a draught of water.

10. advantages
Capsules are tasteless, odourless and can easily be administered
Combination of powders can be use
There are attractive in appearance
The drugs having un-pleasant odour and taste are enclosed in a tasteless shell
They can be filled quickly and conveniently
Easy to handle and carry
Economical
Physician can change the dose and combination of drug according to patient requirement

11. disadvantages
Hygroscopic drugs are not suitable for filling into capsules, because they absorb water present in capsule shell make shell very brittle and ultimately lead to crumble into pieces
The concentrated solutions which require previous dilution are unsuitable for capsules because if administered as such lead to irritation into stomach

12. Capsule size
For human use, empty capsules ranging in size from 000 the largest to 5 the smallest are commercially available.
Generally, hard capsule are used to encapsulate between 65 mg to 1 gram

14. recaps
Capsules - definition
Capsules are solid dosage forms in which one or more medicinal and or inert substances are enclosed within a small shell or container generally prepared from a suitable form of gelatin

15. 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
Types of gelatin
Type A
Type B

16. two basic types of gelatin
Type A
Derived from acid treated precursor that exhibits an iso-electric point ph-9. It is manufactured mainly from pork skin
Type B
Derived from alkali treated that exhibits an iso-electric point at ph-4.7. It is manufactured mainly from animal bones

17. Preparation of gelatin

18. Extraction and purification of gelatin
Bone
Degreasing
Grading
Demineralization
Washing
Liming; Deliming / Acidification
Extraction
Filtration
Characterization
Deionization
Concentration
Sterilization
Chilling & dryring
Grinding
Seiving
Blending

20. Manufacturing of hard gelatin capsules

21. Manufacturing of hard gelatin capsules
Steps involed in making empty gelatin capsules.
Dipping
Spinning
Drying
Stripping
Trimming and joining
Polishing

22. 1) Once raw material have been received and released by quality control, the gelatin and hot demineralized water are mixed under vacuum in Stainless Stain Gelatin Melting System
2) After aging in stainless steel receiving tanks, the gelatin solution is transferred to stainless steel feed tanks

23. 3) Dyes, opacifants, and any needed water are added to the gelatin in the feed tanks to complete the gelatin preparation procedure. The feed tanks are then used to gravity-feed gelatin into Capsule Machine
4) From the feed tank the gelatin is gravity fed into Dipper section. Here, the capsules are molded onto stainless steel Pin Bars which are dipped into the gelatin solution

24. 5) Once dipped, the Pin Bars rise to the upper deck allowing the cap and body to set on the Pins
6) The Pin Bars pass through the upper and lower kilns of Capsule Machine Drying System. Here gently moving air which is precisely control for volume, temperature, and humidity, removes the exact amount of moisture from the capsules halves

25. 7) Once drying is complete, the Pin Bars enter the Table section which position the capsules halves for stripping from the Pins in the Automatic Section.
8) In the Automatic section, capsules halves are individually stripped from the Pins

26. 9) The cap and body lengths are precisely trimmed to a 0
9) The cap and body lengths are precisely trimmed to a 0.15mm tolerance.
10) The capsules body and caps are joined automatically in the joiner blocks

27. 11) Capsule quality is monitored throughout the production process including size, moisture content, single wall thickness and colour
12) Capsules are sorted and visually inspected on specially designed Inspections Stations

29. Filling operation of hard gelatin capsules

30. Preparation of filled hard gelatin capsules
In large scale or small preparations of filled hard gelatin divided into the following general steps:
Developing and preparing formulation
Filling the capsule shell
Capsule sealing
Cleaning and polishing the filled capsules

31. RAW MATERIALS OF HARD GELATIN CAPSULES
S.No.
Raw Materials used
Properties
Example 1
Gelatin
Is the major component of the capsule
Non-toxic
Readily soluble in biological fluids at body temperature
Good film –forming material
Pharmagel-A
Pharmegel-B 2
Colourants / Pigments
Used to impart colour
Indigo carmine
Quinoline yellow
Iron oxide 3
Diluents
To be added to bring the medicament up to a desired bulk
Lactose
Mannitol
Sorbitol 4
Protective Sorbents
to prevent absorption of moisture by hygroscopic substances
Inert materials 5
Glidants
To maintain regular flow to the capsule
Talcum
Stearates 6
Anti-dusting compounds
To prevent dust in the potent drugs
Inert edible oils

32. Filling of hard gelatin
Hand operated methods
Ex: feton capsule filling machine
Semi automatic capsules devices
Automatic filling machine
Ex: osaka filling machne, macofar capsule filling machine

33. Filling operation of hard gelatin capsules
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

34. I. 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

35. II. 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

36. III. FILLING THE BODY
Direct filling method
Indirect filling method

37. Direct filling methods:
The punch method
Powder is placed on a sheet of a clean paper or porcelain plate.
It 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

38. Feton capsule filling
With empty capsules in the loader tray, the tray placed on top of the filler unit
The loader inserts the capsules into the filling unit and is removed and the top plate is lifted to separate the caps from the bodies
The powder is placed on the unit and the capsules bodies filled
The top plate is returned to the unit and the caps placed on filled capsule bodies
Eg: ProFill 100

39. ProFill 100- the ProFill 100 capsule filling machine utilizes an advanced design for fool-proof manual filling of two-piece capsules. With the ProFill 100 machine, there is no need for expensive capsule filling equipment and electrical/vacuum connections

41. INDIRECT FILLING METHODS: Auger-Filling Principle
Powder or granules are contained in mass flow hoppers with rotating augers
Powder is fed continuously out of the hopper outlet due to the rotation of the auger
Amount of powder fed into the body depends on the time capsule body spends underneath on the hopper outlet and auger speed
Slower rotation increases the fill weight

42. Auger-filling equipments

43. INDIRECT FILLING METHODS: Vibratory Fill Principle
Vibratory fill principle: in the powder, a perforated resin plate is positioned and connected to a vibrator
The powder blend tends to be fluidized by the vibration of plate and assists the powder to flow into the bodies through the holes in resin plate

45. INDIRECT FILLING METHODS: Piston Tamp Principle
In this pistons or tamping pins lightly compress the individual doses of the powders into plugs (also called as slugs) and eject the plugs into empty capsule bodies
Dosator principle
Dosing disc principle

46. Dosing disc principle: A solid ‘stop’ brass plate is sliding down the dosing disc to close off the hole. Five sets of pistons compress the powder into cavities to form plugs
Dosator principle: It consists of cylindrical dosing tube fitted with movable pistons. The positions of the piston is preset to a particular height to define a volume. Powders enters the open end of dosator and is slightly compressed against the piston into a plug

47. VI. Capsule sealing Sealing the joint between the 2 capsules parts
Sealing them with coloured band of gelatin (Kapseals)
Through a heat welding process that fuses the capsule cap to the body through the double wall thickness at their juncture-distinctive ring around the capsules where heat welded
Example: weld’s gelatin seal
Liquid wetting agent that lowers the melting point in the contact areas of the capsule’s cap and the body using low temperatures (40-45C)
Lightly coating the inner surface of the cap with a warm gelatin solution immediately prior to placement on the filled capsule body.

50. VII. CLEANING AND POLISHING CAPSULES
Small amount of powder may adhere to the outside of capsule of capsules after filling
Salt polishing-cloth dusting
Brushing
Pan Polishing-Acela-Cota pan is used to dust and polish

51. CAPSULE POLISHIG AND CAPSULE INSPECTION MACHINE

52. STORAGE, PACKAGING AND STABILITY
Finished capsules normally contain an EMC of 13-16%
< 12% MC, the capsules shells become brittle
> 18% make them too soft
To maintain a relative humidity of 40-60% when handling a storing capsules
QUALI-V, developed by Shionogi Qualicaps, is the first HPMC capsule developed foR eventual use in pharmaceutical products

53. INSPECTING Visual or electronic inspection uniform in appearance
Counting
Counting tray
Counting or filling machine
Packaging
Unit dose and strip packaging (sanitary, identifiable, safe)
Storing
In a tightly closed container in a cool dry place

54. RECENT FILLING EQUIPMENTS
Roto-fill :- 2 lakh capsules/day
Acco-fill : capsules/hr
Roto-weigh
Roto-sort : capsules/hr

55. Manufacturing soft gel capsules
Soft capsules are usually formed, filled and sealed in one operation, but for extemporaneous use the shell may be prefabricated. The shell material may contain an active substance.
recaps
Method
1. Plate Process
2. Globex Method
3. Rotary Die Method
Important characteristic
1. Composition of the shell
2. Formulation

56. 1. Composition of the shell
The basic component of soft gelatin shell is gelatin; however, the shell has been plasticize
The ration of dry plasticizer to dry gelatin determine the ‘hardness’ of the shell and can vary from for very hard shells to 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%

57. 2. formulation
Formulation for soft gelatin capsules involves liquid, rather than powder technology
Materials are generally formulated to produce the smallest possible consistent with maximum stability, therapeutic effectiveness and manufacture efficiency
The liquids are limited to those that do not have and 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

58. Methods For Commercial Manufacture Of Soft Gelatin Capsule: 1
Methods For Commercial Manufacture Of Soft Gelatin Capsule: 1. Plate process
A warm sheet of prepared gelatin is laid over the lower plate and the liquid is poured on it
A second sheet of gelatin is carefully put in place and this is followed by the top plate of the mold
The set is placed under the press where pressure is applied to form the capsules which are washed off with a volatile solvent to remove any trace of oil from exterior

59. 2. Rotary die method
Liquid gelatin flowing from an overhead tank is formed into two continuous ribbons by the rotary die machine and brought together between twin rotating dies.
At the same time, metered fill materials is injected between the ribbons precisely at the moments that the dies form pockets of the gelatin ribbons.
These pockets of fill-containing gelatin are sealed by pressure and heat and then severed from the ribbon.
The capsules is washed with organic solvent and pre-dried.

60. Advantages:
Capsules can have all kind of shapes and sizes
Different colors for both sides
Wide variety of fills
Disadvantages
High amount of shell waste material
Longer drying time compared to Globex Method

62. 3. Globex method
Filling is pumped through the inner capillary of a concentric double capillary
Shell forming solution is pumped through the outer capillary of the concentric double capillary
The soft capsules are then immersed in a cooling bath of about 4C (usually liquid paraffin)
Cooling bath ensures immediate sol-gel transformation, hence formation of flexible yet firm robust outer film

63. Soft capsules are collected, washed with organic solvent to remove residues of cooling liquid, and gently dried at a relative humidity of 20% in infrared tunnels
Advantage : production of seamless capsules which are temper-evident and free of contamination or entrapped air

64. Evaluation of capsules
Weight variation test
In which 20 capsules are individually weighed and standard deviation from mean weight was measured that should not be < 90% or > 110%
Content uniformity
The amount of active ingredients should be within the range of 85% to 115% of the label amount for 9 of 10 capsules, with no unit outside the range of 70% to 125% of label amount
Dissolution test
Disintegration test

65. Hard Gelatin Capsules
Soft Gelatin Capsules
Two piece (large body & short cap)
One piece & hermetically sealed
2. Cylindrical shape
Available in round, oval & tube like shape
3. Powder drug or pallets coated with drug are encapsulated
Liquid & Semi liquid fill & unstable substances are encapsulated
4. Gelatin in hard form is used
Molten gelatin are used
5. Capsules are sealed after they are filled to ensure that the medicaments may not come out of the capsule due to rough handling
Filling & sealing of soft gelatin capsules are done in a combined operation on machine
6. 8 different type of sizes are available
No specific sizes are available

66. Extra reading