PILOT PLANT SCALE-UP

TECHNIQUES FOR CAPSULES

AND LIQUID ORALS

By: Praful Joshi

Production considerations for

Capsules:
Materials
Method of production
Filling equipment

Materials:
Gelatin
Plasticizers

Colorants
Opacifying agents
Preservative
Water

Plasticizer:
-

Plasticizer used glycerin or sorbitol

5-10% is used in hard gelatin shell

10-15% is used in soft gelatin shell

Colorants:
-

Soluble dyes

Insoluble dyes

Opacifying Agents:

Titanium Dioxide (0.5%)

Water:

Hot de-mineralized water is used in the preparation of dipping

solution.

Method of production of
Gelatin:
Type A:
By acid hydrolysis: exhibits isoelectric
point at pH 9.0 Firmness
Type B:
By
alkaline hydrolysis: exhibits
isoelectric point at pH 4.7 Plasticity

Method of production of
Gelatin:
Mixture of both the types of gelatin is used for

capsule manufacturing process reason being

availability and cost considerations
Iron content in gelatin should not be more
than 15ppm if greater than 15ppm then it
reacts with color, shell and product
Gelatin viscosity should be 38 +/- 2 mps

Type A Acid Hydrolysis:

Pork skin
Washed
1%-5% HCl
10-30 hours
Acid removed
hot water extraction
Filter and vacuum
concentrated

Cooled to solidify
Air dry
Mill to size

Type B Alkaline Hydrolysis:

Method-1:
Dry bone or bone meal
Dicalcium phosphate and 5% HCl
10-15 days

10% Lime
4-8 weeks
Lime removal
pH adjustment
Hot water extraction
Filter
Vacuum concentration

Cooled to solidify
Air dry
Mill to size

Type B Alkaline Hydrolysis:

Method-2:
Calf skin
Wash
10% Lime
6-12 weeks
Water wash
10-30 hours

Hot water extraction

Filter
Vacuum
concentration

Cooled to solidify
Air dry
Mill to size

Manufacture of Hard Gelatin Capsules:

FFS Technology (Form Fill Seal)

Dipping
Spinning
Drying

Stripping
Trimming
Joining

Manufacturing of Hard Gelatin Capsules:

Gelatin gel of
Controlled viscosity is taken
Pins dipped for a particular
period of time

Gel sticks to the pin

Pins are spun for uniform

distribution of gel
Pins passed through
Drying chamber
Gel solidifies and is stripped
(removed)
Gel trimmed to particular length
(Body and Cap)

Joining of cap to body

Encapsulation of Hard gelatin

capsules:
To produce capsules on high speed equipment, the

processed powder blend must have the proper particle

size distribution and bulk density required to promote
good flow characteristics and to result in the formation of
compacts of the right size and sufficient cohesiveness to
be filled in the capsules
Physical properties - Bulk density, powder flow
characteristics
Chemical Properties - prolonged trials of many hours
using multiple batches are required for a process can be
judged as acceptable for routine production
The size and types of equipment may affect
the
granulation properties

Manufacture of Soft Gelatin Capsules:

Gelatin gel gelatin + plasticizer + water

Maintained at a particular temperature to remain as gel.
2 hoppers fill contents and gelatin (high temperature (930C)

molten state flows easily)

Manufacture of Soft Gelatin Capsules:

Gel passed between two compression roles (having depressions)

at cold temperature for solidification of gelatin

After gelatin is solidified gelatin ribbons are formed with
depressions and contents are filled into these depressions

Manufacture of Soft Gelatin Capsules:

After the contents are filled sealing of the shells is done between

370C and 400C

Liquids should be filled at gravity at 350C
Oils, suspensions and semisolids can be encapsulated

Size of Capsules:
20 minim oblong
16 minim oval

9 minim round

Filling equipments:
Eli Lilly, Indianapolis, Indiana
Parke-Davis, Detroit, Michigan
Hofliger and Karg, Waiblingen, Stuttgart, Germany
mG2 Macchine Automatiche, Pianoro, Italy
Fratelli Zanasi, Bologna, Italy
Cap-Fill Products, Ardmore, Pennsylvania
Dott Bonapace, Milano, Italy
Abbott Laboratories, North Chicago, Illinois
Hoffmann-La Roche, Nutley, New Jersey

Filling operations:
Empty capsules
Formulation
Finishing

Special Techniques Imprinting, Sealing,

Capsule locking

Processing conditions:
Humidity

and temperature should be

controlled during manufacturing and storage
High Humidity swelling of capsule shells,
dimension increases
Low Humidity shrinking of capsule shells,
brittle and dimension decreases
High temperature degradation of capsule
shells

Evaluation of Capsules:
Following are the tests that should be carried out
for evaluation of the capsules

Uniformity of weight
Content of the active ingredients in the

capsules
Disintegration Test
Dissolution

Test

Production considerations in
Liquid Orals:
Tank Selection
Mixing and Dispersion
Filtration and Clarification
Transfer and Filling

Preservative Evaluation

Tank Selection:
Depends on size, shape, working capacity
and construction
Material used for tank construction should
not affect physical or chemical stability
Glass-lined tanks are not used possibility of
breakage and thus contaminating the
product
Magnetic SS interiors are used since particles
resulting from abrasion can be extracted
from the bulk liquid by in-line magnets

Tank Selection:

Adequate clean-up procedures developed

Valve assembly to be examined for complete drainage
For viscous liquids and suspensions flush bottom valves are

used to avoid dead spots

Mixing and Dispersion:

Mixing of wide variety of vehicles, suspending

agents, emulsifying agents, thickening agents

and flavoring agents employed in liquid
products makes the evaluation of mixing
equipment an important parameter in pilot
operation
Insertion of tank baffles or reduction in
agitation speed are used in case of air
entrapment during mixing of viscous liquids

Filtration and Clarification:

Filtration an important parameter for ensuring the clarity in

the scale-up products

Pressurized filtration depending upon the viscosity, volume
and rate requirements

Transfer and Filling:

Filling important parameter in the transfer of liquids from

tank to tank and into containers

New batches should not be started until the previous batches
are completely emptied from the tanks.

Preservative Evaluation:

Preservative evaluation should be done in

addition to physical and chemical tests

Depending on the nature of the product and
degree of protection required carbon dioxide
or nitrogen can be overlaid during filling or
holding stages.
Bacteriological testing should be done, to know
if the concentration of preservative is to be
increased in the formulation

References:
The Theory and Practice of Industrial Pharmacy 2nd Edition
by Lieberman and Lachman
Pharmaceutical Sciences by Remington
Pharmaceutical Sciences by Cooper
Pharmaceutical Sciences by Tucker and Hayes
Pharmaceutical Sciences by Tucker and Rednick

Thank you
Seminar on Pilot Plant Scale-Up Techniques for Capsules and
Liquid Orals By Praful Joshi
Faculty: Dr. Bijaya Ghosh