NTA Level 6 • Semester 1 • PST06103

Formulation of Capsule Content

Pharmaceutical Production • Source Session/Topic 12

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Session 12: Formulation of Capsule Content

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Define formulation

• Outline preparation of fill materials for encapsulation

• Selection of capsule size

• Explain the determination of capsule fill weight and volume

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: Formulation (15 minutes)

|Activity: Brainstorming (5 minutes) |

| |

|ASK students to brainstorm on the following question: |

| |

|What is formulation? |

| |

|ALLOW few students to respond? |

| |

|WRITE their responses on the flip chart/ board |

| |

|CLARIFY and SUMMARISE by using the content below |

• Formulation is the process of determining types and quantities of

excipients to be mixed with the active ingredient (the drug) to produce a

final medicinal product

• The word formulation is also used to mean a dosage form

• In large scale or small scale preparation of filled hard gelatin capsules

is divided into the following general steps;

➢ Developing and preparing formulation

➢ Selection of size of capsules

➢ Filling the capsule shell

➢ Capsule sealing

➢ Cleaning and polishing the filled capsules

• Developing and preparing formulation involves determination of processes,

types and quantities of ingredients that will be used in forming a

mixture (fill material) to be filled into the capsule shells (in the hard

or soft gelatin capsules)

• Formulation of capsule fill materials employs two major groups of

ingredients, the active ingredients and the excipients

o The active pharmaceutical ingredients (API)

▪ The amount and type of active ingredients influence capsule size

and nature and amount of excipients to used in the formulation

▪ Active ingredients tend to make up to the high percentage of the

contents of a capsule compared to tablets

o The excipients

▪ Type and amount of excipient mixed with API depends on the type

of capsules to be produced (i.e. hard gelatin capsules or soft

gelatin capsules) and the nature of the fill materials i.e. solids

(powders, granules, pellets, tablets, small capsules), semi solids

and liquids (neat liquids, solutions and suspension)

• Pharmaceutical processes involved during formulation of capsule fill

material may include milling/comminution, blending/mixing, granulation,

pelletization and micronization

• Size of the capsule to be produced must be considered during formulation

of the fill material

STEP 3: Preparation of Fill Materials for Encapsulation (45 minutes)

Preparation of Dry Powders

• Dry powders are filled into hard gelatin capsules. Formulation and

preparation of these powders include processes and different substances

which promote the release of drug constituents from the hard gelatin

capsules

o Milling

▪ In order to achieve uniform drug distribution throughout a powder

mix, it is advantageous that the density and particle size of the

drug and non-drug components are similar. This is achieved by

particle size reduction (milling)

o Diluents

▪ Generally, hard gelatin capsules are used to encapsulate between

65 mg and 1 gram of powdered materials (drug and diluents required)

▪ If the dose of the drug in a single dose is smaller than 65 mg to

produce the proper fill, lactose, microcrystalline cellulose, and

pre-gelatinized starch are common diluents used in capsule filling

▪ If the amount of drug is larger enough to fill a capsule

completely, a diluents may not be required

▪ Diluents are present in the greatest concentration of all

excipients

o Lubricants

▪ They are added to prevent adhesion and facilitate the flow of

powder in capsule filling machine e.g. Magnesium stearate and talc

o Glidants

▪ The powder mixture or granules must be free-flowing to allow

passage from the hopper by the addition of a glidant such as 1%

silicon dioxide

▪ Lubricants and glidant are used to improve the filling properties

o Wetting agents

▪ These are agents added to facilitate wetting (improve water

penetration) of the drug substance by gastrointestinal fluid to

enhance dissolution and overcome the problem associated with water

insoluble lubricants such as magnesium stearate which can delay

the dissolution of the drug and its absorption

▪ Sodium lauryl sulphate is a common wetting agent used in

capsules

o Disintegrants

▪ Produce disruption of the powder mass when the capsule is in

contact with body fluids e.g. crospovidone, sodium and starch

• Preparation of Granules and Pellets

o Granules and pellets are packed in capsules instead of powders to

produce modified release patterns

o Granules are produced by granulation process and are more irregular

than pellets which are spherical and produced by microencapsulation

technique

• Preparation of Tablets and Capsules

o Tablets and small capsules may be encapsulated in hard gelatin

capsules

o Tablets and capsules can be encapsulated in order to produce special

release forms or to separate incompatible ingredients

o Small tablets are made and placed inside capsules following addition

of small quantity of the powder and filling completed

o Additionally, for separation of one ingredient from another in the

formulation, a small capsule (e.g. number 5) is filled with powder of

one ingredient and placed into a larger capsule with the remaining of

ingredients in the formulation

• Preparation of Semisolids

o Can be used for both liquid and solid active ingredients

o Mixtures for filling need to be liquid only when filled and should

semisolid after being inside the capsules

o The materials to be filled must be either thermosoftening or

thixotropic in nature to be liquefied by heating or shearing forces

using heated hopper with a stirrer and revert to solid state within

the capsule shell

o This type is used when;

▪ Potent drugs are being encapsulated to improve uniformity of

filling

▪ Toxic drugs are being encapsulated to reduce contamination with

filling powders and improve safe handling

• Preparation of Liquids

o Liquids are generally filled into soft gelatin capsules and in some

instances into hard gelatin capsules

o Gelatin capsules are not suitable for encapsulation of aqueous liquids

(water softens the gelatin and produce distortion of the capsules)

o Non aqueous liquids such as fixed oils or volatile oils that do not

interfere with the stability of the gelatin shells may be filled in

gelatin capsules

o The liquids may be pure, or solution of solids in liquids, miscible

liquids or suspension of solid drugs in a carrier

o The suspension are prepared in the general techniques for preparation

of suspension with suitable suspending agents

o After filling the liquids into the capsules, the shells are sealed to

retain the liquids

STEP 4: Selection of Capsule Size (15 minutes)

• Capsules vary in shapes and sizes.

• Determination of capsule size is important during formulation of the fill

materials because the amount of excipients to be included is dependent

upon the size or capacity of the capsule to be selected

• For hard gelatin capsules range from 000 (the largest) to 5 (the

smallest)

o Factors considered when selecting capsule size are;

▪ Amount of fill material to be encapsulated

▪ Density and compressibility of the fill material

o The final determination may largely be the result of trial and error

• For soft gelatin capsules, size of the capsule depends on the amount of

fill material encapsulated and the filling methods e.g. size of the mould

• The fill materials (solids, liquids and semisolids) must be prepared

prior to filling into the capsules

STEP 5: Determination of Capsule Fill Weight and Volume (25 minutes)

• Because empty gelatin capsules are manufactured in various sizes, varying

in length, in diameter and capacity

o The fill contents must be formulated in such a way that one dose is

contained in the volume represented by a given capsule size

• Capsule fill weight is determined by the following relation;

o Capsule fill weight = Tapped bulk density of formulation x Capsule

volume

• Selection of capsule size is done when the product is being developed or

in extemporaneous compounding of prescription

STEP 5: Key Points (5 minutes)

• Developing and preparing formulation involves determination of processes,

types and quantities of ingredients that will be used in forming fill

material to be filled into the hard or soft gelatin capsules

• Formulation of capsule fill materials employs the active ingredients and

excipients

• During formulation, pharmaceutical processes to be used in mixing the

ingredients to obtain a fill mix are also identified

• Determination of capsule size is important during formulation of the fill

materials because the amount of excipients to be included is dependent

upon the size or capacity of the capsule to be selected

• The fill contents must be formulated in such a way that one dose is

contained in the volume represented by a given capsule size

STEP 6: Evaluation (5 minutes)

• What is capsule formulation?

• How are various fill materials for encapsulation formulated?

• How is capsule size determined?

References

Aulton M.E & Kevin M.G, (Eds): (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.)Churchill Livingstone

Hugo and Russell (2011), Pharmaceutical Microbiology (8th ed.) , Willey-

Blackwel publications

Gennaro, R. A, et al. (Eds) (1995) Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed.): Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B et al. (1988): Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W. Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics (12th ed.): The Pharmaceutical Press, London

Polderman, J. (1990) Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A, Editor: (1977) Bentley’s Textbook of Pharmaceutics, (8th ed.)

Baillie're Tindall. London Kamm, G. and Kohler, B. Editors: (1995)

Manual for Decentralized Infusion Production, Infusion Unit Project

Tanzania

Schmidt, O. (ed) (2000) Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al. (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone,

Edinburgh.

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