hard and soft gelatin capsule shell manufacturing. preparation of shell fluid, preparation of fill material and manufacturing process. machineries and equipment for capsule manufacturing. stability and quality control

1. Hard Gelatin Capsules Soft Gelatin Capsule
TechnologyCapsule

2. 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).

3. Studying of Capsules
Hard Gelatin Capsules HGC
• Advantages and disadvantages of HGC.
• Sizes and volumes of HGC.
• Manufacturing of Empty Hard Gelatin
Capsules EHGC.
• Filling of EHGC.
- Formulation of fill
- Manual 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 capsules
• Filling of SGC.
- Formulation of fill.
- Plate process.
- Rotary die machine.
- Bubble method
 Stability and Quality Control for Capsules.

4. Hard Gelatin Capsules HGC
 HGC are composed of two parts:
- Shorter and wider is the cap
- Taller and narrower is body.

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

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

7. Standard Sizes and Volumes of HGC
Size number Volume in ml Size in mm
000 1.37 26.3
00 0.95 23.7
0 0.68 21.8
1 0.5 19.2
2 0.37 18.3
3 0.30 15.3
4 0.21 14.7
5 0.15 11.9

8. 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.

9. Production Process of Gelatin

10. Differences between gelatin types for HGC
• characteristics of gelatin types for HGC
Characteristic Type A Type B
Production Acid hydrolysis Alkaline hydrolysis
Source Pork skin Other animal & bones
Isoelectric point pH At pH 7 - 9 At pH 4.8 – 5
Physical characters Plastic and clear firm
Gel strength 240 – 300 200 - 250
Viscosity 44 – 55 45 – 60
pH 4.5 – 5.5 5.3 – 6.5
Aerobic count - Max 1000 cfm/g
E. Coli - Negative
Salmonella - Negative
Yeast & molds - Max 1000 cfu/g
Type A may be suspected to Bovine spongiform encephalopathy.

11. Physiochemical properties of gelatin
• Bloom 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.

12. • 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 count
a- total aerobic bacteria.
b- molds
c- preservative
• generally used preservative are propyl paraben, methyl paraben,
sodium metabisulfite.

13. 1- Preparation of solution for EHGC manufacture
Gelatin 30% • Bloom 150 – 280
• Viscosity 30 -60 millpose
Vacuum is applied to
remove the entrapped air.
Water 65% Hot demineralized
Dye 5% Water soluble
Pigment As needed Water insoluble
Surfactant 0.15% w/w Sod. Lauryl sulphate - Enhance wettability of
gelatin to metal pin
during production.
- Enhance wettability of
capsule shell with
aqueous medium.
Preservative As needed - Sod. Metabisulfite
- Methyl paraben
- Propyl paraben
Gelatin is ideal growth
medium at 55 ˚C

14. 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- Spinning
Pins 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.

15. 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.

16. 6- Trimming
- The firmly held two portions of capsule rotates against knife blade which cut
trim them to the required length.
7- Joining
- The 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.

19. 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%.

20. Properties of the Powder fill
• Homogeneity: 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.

21. Assessment of Good flow properties
• Angle 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.

22. Formulation of the Powder Fill
Excipient function Examples
Diluent Provide powder mass - Lactose monohydrate
- Starch
- Microcrystaline cellulose
Lubricant Reduce the adhesion to metal dossator
and to metal of machine.
- Mg Stearate
Glidant Reduce the interparticle attraction to
provide powder flow.
- Talc
- Aerosil
Disintegrant To break the powder mass following
release into the stomach.
- Maize Starch – crospovidone
- Microcrystaline cellulose
Surface active
agent
To enhance wettability - Sod lauryl sulphate
Protective sorbent To prevent absorption of moisture by
hygroscopic materials
- Mg Oxide
- Ca Carbonate
Antidusting To prevent dusting of powder - Inert edible oil

23. Filling Process Sequence

24. Manual Capsule Filling
Plate with rubber surface
Pin plate
capsule loading tray
Filler unit
Powder filling frame
Powder spreader
lever
1- 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 surface
8. Release the lever to free the
bodies which are holding the caps.
9- remove the loading tray and
collect the capsule.

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

27. Capsule orientation

28. Operation

29. Automatic Capsule Filling
A- 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.

30. 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.

32. Finishing of HGC
• Salt polishing.
• Cloth dedusting.
• Brushing.
Sorting
• Unfilled capsules.
• Filled unfitted capsule.
• Loose caps
Sealing or locking
- Application of moisture and slipping.
- Coloured band of gelatin.
- Interlocking rings
- Heat spot welding by a heated needle.

33. Soft Gelatin Capsules softgels
• Soft 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.

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

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

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

38. Plasticizer in Softgels
• Incorporated 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.

39. Water in Softgel
• Water 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.

40. Other additives in gel formulation
• Insoluble 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.

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

42. Types of softgel matrices
• Lipophilic 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.

43. Effect of pH of the fill
• The 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.

44. Manufacture of Soft Gelatin Capsules
• Plate process
• Rotary die process.
• Accogel
• Bubble method .
The most common used is the rotary die process.

45. 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.

46. Filling theory

49. Quality Control Tests for Capsules
• Visual inspection
- Appearance : shape, colour, size , thickness of the shell,
leakage test for softgels.
• Weight variation
• Disintegration test.
• Dissolution test.
• Content uniformitytest
Microbiological
Testing

50. Vegetarian Capsules

51. End of capsules
goodluck