INDUSTRIAL PHARMACY:

PHARMACEUTICAL DOSAGE FORM DESIGN

GRADUATE COURSE IN PHARMACEUTICS

CREDIT: 3 Hours

PHARMACEUTICAL DOSAGE FORM DESIGN.................................................. 3

1.1

INTRODUCTION........................................................................................... 3

1.2

AIMS AND OBJECTIVES OF THE COURSE ............................................... 3

1.3

OBJECTIVES OF INDIVIDUAL STUDY UNITS ............................................ 4

1.3.1

Review and study of the different phases of product development ........ 4

1.3.2

Principles and factors of importance during development, production

and quality assurance of conventional dosage forms........................................... 6

1.3.3

Oral dosage forms ................................................................................. 7

1.3.4

Parenteral dosage forms...................................................................... 10

1.3.5

Design of dosage forms for topical and local drug delivery systems.... 13

1.3.6

Pharmaceutical aerosol products......................................................... 14

1.3.7

Rectal and vaginal suppositories ......................................................... 15

1.3.8

Novel dosage forms and biotechnology ............................................... 16

1.4

ASSIGNMENTS .......................................................................................... 17

1.5

REFERENCES............................................................................................ 18

1.6

Study Guide compiled by: ........................................................................... 19

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1 PHARMACEUTICAL DOSAGE FORM DESIGN

1.1

INTRODUCTION

To manufacture a pharmaceutical dosage form, it is necessary to combine the unique

properties of the drug with the unique properties of the specific dosage form as well
as quality control requirements. The whole process starts with the development and
clinical evaluation of the substance, proceeds via a preformulation phase for the drug
and ends with the dosage form, which may be produced industrially after the
necessary scale up procedures.
In this study guide the material that a student will have to manage to successfully
complete the course Pharmaceutical Dosage Form Design as part of the Ph.D. in
Pharmaceutics is outlined. It describes the aims and objectives of the course and
gives information about the study material that the student will have to use.

1.2

AIMS AND OBJECTIVES OF THE COURSE

The aim of this course is to enable the successful student to recognise and
understand the development process for pharmaceutical delivery systems that are
therapeutically effective, bioavailable, safe and elegant. The objective is to study the
different phases in the development of a dosage form.

The different phases for

conventional dosage forms include the stages in which the substance drug is clinically
tested, formulated, manufactured and the quality control procedures related to each
stage. Dosage form development using biotechnology and targeted dosage forms will
also be studied.
On successful completion of the course, the student should have acquired the
necessary background and understanding of the development process for
pharmaceutical products so that he/she could, through innovative thoughts and
scientific reasoning, design and evaluate new innovative pharmaceutical products.
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1.3

OBJECTIVES OF INDIVIDUAL STUDY UNITS

The course is divided into the following three study units each with its own study
objectives and assignments, i.e.:
1.

Review and study of the different phases of product development,

2.

General formulation factors and procedures, principles and factors of

importance during development, production and quality assurance of
conventional dosage forms, and

3.

Alternative and/or targeted dosage forms and biotechnological products.

1.3.1 Review and study of the different phases of product development

The first step in the research process of drugs is the scientific investigation and study
of the specific illness in order to form research teams whose work will lead to the
invention and development of new chemical entities with efficient actions.
Research teams in industry are multi-disciplinary and are composed of experts from
different scientific fields like chemistry, biochemistry, physics, statistics, medicine,
pharmacology, pharmaceutics, physiology, microbiology, etc. The main objective of
research is to produce safe drugs that may be preventative, curative or alleviate.
Subordinate objectives are:
1.

to understand the molecular basis of biological mechanisms for sick and healthy
persons;

2.

to develop new biological test methods;

3.

to develop a quantitative understanding of the physical, chemical and

physiological interactions of drugs with biological systems which may lead to
new drug design;

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4.

to understand absorption, transfer and action of a drug;

5.

to develop drugs with low toxicity, reproducible action and high specificity for a
given pathological condition, and

6.

to develop cost-effective drugs.

The processes of research follows a certain flow pattern for which planning is the
starting point; this is followed by laboratory scale synthesis, pharmacological and
toxicological selection, patent protection, phases I and II pre-clinical development and
testing and the three phases of clinical testing and registration.
The estimated cost for the development of a new drug is approximately $500 million
and takes on average between 8 and 15 years. The chance for success is 1 : 8 000 10 000 and marketing success approximately 25 %.

It is therefore of cardinal

importance that high productivity and high effectiveness be the criterion of research
because of the high costs involved.

Expertise is therefore a prerequisite to be

successful in the field of pharmaceutical research.

1.3.1.1 Objectives and outcomes for this study unit
The student must have a broad base of knowledge of the different phases of drug
design, testing and product development in order to contribute in a development team
and to evaluate the different facets of the process. In the context of this course it is
not expected of the student to become an expert on any specific aspect but he/she
must rather acquire a broad general working knowledge.
The student must be able to:
1.

Understand the essential aspects of a development plan for a new product.

2.

Understand the different phases in the development process of a new drug

and be able to describe its essential facets.

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3.

Understand all the considerations and phases of a multidisciplinary approach

to formulation and dosage form development.

1.3.2 Principles and factors of importance during development, production and

quality assurance of conventional dosage forms
The student must be able to recognise the distinctive properties to be taken into
account for the development of a conventional dosage form:
a.

a motivation of the choice of dosage form;

b.

a general formula;

c.

the specific manufacturing steps and processes;

d.

precautionary measures and tests to ensure the quality of the product, and

e.

test to control the quality.

The following are meant with conventional dosage forms:

1.

Oral dosage forms

1.1 Tablets and hard capsules, solutions, emulsions, suspensions, oral
sustained release products.

2.

Parenteral dosage forms

2.1 Injections, large volume parenterals, suspensions for injection.

3.

Dosage forms for local application

3.1 Ointments, creams and gels.

4.

Vaginal dosage forms

5.

Suppositories

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6.

Aerosol products

1.3.3 Oral dosage forms

In this division of pharmaceutical dosage forms, it is presumed that the choice of
route of application had already been made and that the oral route had been chosen
(not the other routes such as transdermal, rectal, parenteral, etc.). This choice would
have been made taking many factors into account, such as: physical and chemical
properties of the drug, type of effect desired, type of illness to be treated, speed of
action, duration of action, pharmacokinetic parameters, etc.
Oral dosage forms focus is on all dosage forms taken orally for a local effect in the
mouth, throat or gastrointestinal tract or for a systemic effect in the body after
absorption from the mouth or gastrointestinal tract.
Oral dosage forms can be divided into two main groups on the grounds of the
physical state of the dosage form during consumption, i.e. solid oral dosage forms
(tablets, capsules or powders) and liquid oral dosage forms (solutions, syrups,
emulsions and powders for suspensions).
Three steps are distinguished during the development of oral dosage forms, i.e.:
1.

the choice of the type of dosage form;

2.

the formulation and manufacture thereof, and

3.

the evaluation and control of the quality of the product.

In order to develop oral products it is necessary to know specific properties and

characteristics of this type of dosage form.

This guide will help student get this

knowledge or to refresh their memories.

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1.3.3.1 Outcomes: Choice of the type of oral dosage form

Students must be able to give an opinion (with the necessary motivations) on the
choice of the type of dosage form for a specific drug taking into account
preformulation data at their disposal.
The choice of the type of dosage form rests on the one hand on the type of effect
required (i.e. speed of action, duration of action, blood concentrations and
pharmacokinetic parameters) and on the other hand on physicochemical properties
and required dosage of the drug. Physicochemical properties of importance include:
physical form of the drug (liquid or solid), solubility in the presence of moisture and
heat, taste, flow and compressibility properties, etc.
1.3.3.2 Outcomes: Formulation and manufacture of oral dosage forms
In the case of oral solid dosage forms (especially tablets), the choice of the method of
manufacture has a specific influence on the composition of the formula. The primary
aim during preparation of mixtures for tabletting is to ensure good flow and
compressibility properties whereas mixtures for encapsulation must mainly possess
good flow properties.
Drug-related properties that may influence the choice of method of manufacture of
solid oral dosage forms include: Flow and compressibility, dose size and chemical
stability. In the case of liquid oral dosage forms the solubility, dose size and drug
stability play a major role.
The combination of drug(s) and excipients plays an important role in the physical and
chemical properties of the final product and determines to a great extent the final
quality and effectiveness of the product.
1.

In the case of liquid oral dosage forms the choice of excipients rests mainly on
two requirements, i.e. (1) ensuring maximum physical and chemical product
stability and (2) ensuring acceptable organoleptic product properties (i.e. taste,
colour, consistency, etc.)

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2.

In the case of solid dosage forms the choice of excipients is determined by

factors such as: the type of product and effect required. The chosen method of
manufacture, and the influence of excipients on the flow and compressibility
properties of the mixture/granulate.

The acquirement of/and assurance of

good tabletting properties (exclusion of tabletting problems such as laminating,

capping, punch and the adhesion, etc. In general the inclusion of excipients
must contribute positively to the quality and effectiveness of the final product.
Students must be able to make knowledgeable contributions with regard to
composition of formulas for a chosen oral dosage form as well as the decision on the
method of manufacture considering the available preformulation data. They must
also be able to identify problems during tabletting and relate these to problems during
formulation and/or manufacture and be able to recommend remedial actions.
1.3.3.3 Outcomes: Evaluation of oral dosage forms
In-process evaluation as well as evaluation of the final product is necessary in order
to ensure that the product received by the patient complies with all requirements with
regard to quality (assay), effectiveness and safety. In-process evaluation is aimed at
discovering and solving formulation and manufacturing problems as soon as possible,
whereas the aim of final product evaluation is to ensure quality effectiveness and
safety of the product.
The tests mentioned must entail the determination of physical properties and assay of
the product and comparing these with official requirements or standards (including
shelf-life and expire date in the final package with the aid of accelerated and long
term stability trials).

From the formulator's viewpoint, it is important to keep the

following in mind: Quality is built into a product through good manufacturing and
laboratory practices; it cannot be tested into the product!
Students must be able to point to and motivate the in-process evaluation tests for the
chosen dosage form. To identify and motivate the times during which these tests
must be done, motivate the different evaluation tests on the final product, be able to
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evaluate the results of these tests and be able to make relevant conclusions from the
data.
1.3.4 Parenteral dosage forms
The therapeutic effectiveness, biological availability and safety valid for all
pharmaceutical dosage forms are also applicable to parenteral dosage forms. Seeing
that the highly effective first line of body defence, i.e. the skin and mucus membranes
is bypassed during application of parenteral dosage forms, a number of unique
demands and considerations are to be met, i.e.:
1.

Sterility.

2.

Product must be free of foreign particles.

3.

Absence of pyrogens.

4.

Choice of raw materials, solvents and excipients. The choice of raw materials,
solvents and excipients is limited. Toxicity and irritating properties of many raw
materials limit their choice in parenteral dosage forms. For the same reasons
pH and isotonicity are also of importance in the case of these products.

5.

Choice of packaging materials. Because of the inmate contact of parenteral

components with packaging material and because of the fact that these
products as water solutions are subjected to high temperatures during
sterilisation, the packaging material may have a large influence on the
physiological acceptability or stability of the product.

For these reasons

different pharmacopoeia specify specific requirements for packaging materials

for sterile products.
6.

The product must be non-toxic, non-irritating and not sensitising.

7.

Stability. Drugs and excipients are mostly in solution or in any case in contact
with water and the product is subjected to sterilisation processes such as

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heating, ionising, radiation, gas sterilisation, etc. which may enhance

breakdown reactions. These breakdown reactions may in turn lead to toxicity,
irritating properties and can in certain instances cause physical contamination.
8.

Physiological factors, i.e. absorption, irritation, etc.

All activities or actions, be they at the industrial, dispensing or application level, are
aimed at the incorporation and preservation of these properties in the product. These
properties must be built into the product during manufacturing processes and
maintained by formulation, packaging and storage. It is the duty of the Industrial
pharmacist, be it in his own capacity or in conjunction with other members of the
product development team, to ensure these properties.
In case of the industrial pharmacist, the duty entails the following:
*

Knowledge of the formulation and composition of different physical forms of

parenteral products.

Unique and differentiating properties of this dosage form and the quality control
measures applicable.

In order to satisfy the aims the student must renew his knowledge of the theoretical
principles emphasised below with the use of the given references in order to be able
to apply these in practice during the formulation or planning of parenteral dosage
forms.
1.3.4.1 Outcomes: The influence of pharmaceutical and biological factors in
parenteral formulation and application
The student must be able to integrate the different factors having an influence on
formulation and manufacture of parenteral dosage forms into the product
development process.
1.

The chemical and physical properties of drug and excipients.

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2.

The requirements for raw material and packaging material.

3.

The volume of the injection.

4.

The purpose of the preparation.

5.

The route of application and the biopharmaceutical parameters involved.

1.3.4.2 Outcomes: The composition and properties of/and requirements for the
different physical forms of parenteral dosage forms
The student must know the basic composition and properties as well as the methods
of manufacture and requirements of the different physical forms of injectables and
must be able to convert these into the whole product development process.
1.

Parenteral solutions.

2.

Parenteral suspensions.

3.

Parenteral emulsions.

4.

Freeze-dried products.

5.

Large volume parenteral solutions.

The following factors are of special importance:

1.

Excipients and how this relates to the route of application.

2.

Toxicity and irritation potential.

3.

The role of pH.

4.

Stabilization.

5.

Sterilization methods.

6.

Particle or drop size where applicable.

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1.3.5 Design of dosage forms for topical and local drug delivery systems
Dosage forms for topical and local application cover a wide variety of dosage forms,
i.e. liquids (solutions, emulsions and suspensions), semi-solid preparations (ointments
and pastes) and powders.

The most important function of skin preparations is

protection against external influences, concentration of actives in the skin to effect

healing and absorption of the active ingredient through the skin to give a systemic
action.
The effectiveness of preparations for local application is influenced by the following
properties of the active ingredient: concentration, solubility, distribution coefficient,
dissolution rate as determined by the physical form of the drug (i.e. particle size,
surface, etc.) and permeability inside or through the skin. The second important
factor determining the effectiveness of preparations for local application is the
condition of the skin, i.e. water content, degree of injury of skin surface, place of
application, treated skin surface, pre-treatment of skin and age of patient.
The topical carrier material affects contact between skin and active ingredient. The
goal of the carrier material is to ensure the effectiveness of the active ingredient.
Important properties of dosage forms for local application are that it must be nonirritating or sensitising, cosmetically acceptable, stable and easy to apply.
The biological activity of a topically applied application is mainly dependent on the
rate of release from the carrier and penetration into the skin.

While formulating

preparations for local application, it must also be kept in mind that irritation or
sensitisation of the skin must be prevented. The release of the active ingredient form
the carrier and more specifically the rate of release as well as biological activity is
dependent on:
*

the chemical structure of the drug;

the physical state of the drug;

the type of dosage form;

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the presence/absence of penetration enhances, and

the pharmaceutical manufacturing procedure.

Changes in the physical properties of a preparation can enhance the diffusion of the
active from carrier into the skin. Factors enhancing release from the carrier include a
high active ingredient concentration in order to get a high carrier-skin concentration
gradient, a high activity coefficient in the carrier to enhance release and a favourable
distribution coefficient between carrier and the skin.
1.3.5.1 Objectives and outcomes for topical and local delivery systems
The student must know the basic composition and properties as well as the methods
of manufacture and requirements of the different physical forms of topical dosage
forms and must be able to convert these into the whole product development process.
1.3.6 Pharmaceutical aerosol products
Aerosol products are unique delivery systems since they contain a propellant(s) to
force the product out of the container in the required form and quantity that are
necessary.

The product contains the drug that may be formulated in a solution,

emulsion or suspension. The propellant either can be liquefied or compressed gases.

Aerosol products can be used to deliver drugs for local action (on skin, in the nose
and lungs) or systemic action where it is also applied via the nose and lungs. In the
case of aerosol products for local application it is supplied with valves enabling the
user to determine the amount marked off or released.

In the case of inhalation

aerosol products, a specific quantity is released each time the valve is activated.
The principles of formulation of solutions, emulsions or suspensions are applicable in
this case but the influence of the propellant on the stability of the product must be
taken into account.

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1.3.6.1 Objectives and outcomes for aerosol products

The following aspects are important for the student to know about the formulation of
aerosol products:
1.

Which propellants - compressed and liquefied gases;

2.

Different valve systems - continuous spray and soign;

3.

Different containers for products - glass, metal or synthetic material;

4.

What kind of action of aerosol products - foam, spray or solid stream products;

5.

Which factors influencing the particle size in case of inhalation aerosol

products;

6.

Typical formula for a suspension inhalation aerosol product and a local solution
aerosol product, and

7.

Method of manufacture - schematic diagram.

1.3.7 Rectal and vaginal suppositories

Two kinds of suppositories are most often formulated:
1.

Rectal suppositories: The formulation of rectal suppositories is basically the

same as that of suspensions, solutions and emulsions with a special carrier
medium (the base) which is solid at room temperature but which melts at body
temperature and/or dissolves in rectal fluids. The purpose is to deliver drugs
for either local or systemic action.

2.

Vaginal suppositories: Vaginal suppositories are formulated in the same way

as solution tablets or solution suppositories.

The purpose is only for local

action.

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Apart from solid forms, liquid forms are also used for both rectal and vaginal
application, i.e. enemas and irrigation solutions ("douches"). In the case of semi-solid
dosage forms, the types of base used are important for effectiveness.
1.3.7.1 Objectives and outcomes for suppositories
Aspects of importance with regard to these dosage forms that the student must know
and understand are:
1.

Physiology and anatomy of the route used for application of the dosage forms.

2.

The properties of suppository based available,

3.

The differences in formulation of water soluble and water insoluble drugs in

suppositories,

4.

Quality assurance tests that must be carried out on rectal and vaginal
suppositories.

1.3.8 Novel dosage forms and biotechnology

New ways to deliver drugs and unique ways to target and/or localise it at target areas
in the patient's body are discovered almost weekly. It is mainly done to make dosage
easier, more effective and to get fewer side effects. Technological developments
make it possible to realise new and innovative delivery methods and systems.
1.3.8.1 Aims and objectives for novel drug delivery
The student must have the necessary knowledge of the principles by which drugs are
targeted, localised and automatically delivered and must know how the dosage forms
are formulated and manufactured. After studying this subject, the student must be
able to describe and give the methods of manufacture of these new drug delivery
systems. They should also be able recognise the potential use of new and innovative

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drugs such as proteins, peptides etc. and be able to propose suitable dosage forms
and delivery systems for these drugs.

1.4

ASSIGNMENTS

The following assignments must be completed:

1.

Give an overview of the essential aspects (different phases) of a development

plan for a new pharmaceutical product.

2.

Write in three pages a protocol for the development of an aspirin effervescent

tablet. The object being to produce a clear solution after effervescence.

3.

You must formulate a proposal for the formulation of a benzodiazepine

(diazepam) injection.

Reason and supply reasons for differences in

considerations and formulas when an intramuscular or an intravenous injection

must be prepared.
4.

You are instructed to formulate a Tetracaine HCl preparation for local

application.

Reason out and supply the reasons (with the necessary

references) for your considerations during formulation. Give the differences in

considerations and the formula when you were to prepare a gel, ointment or
cream.

Give the specification for raw materials, motivation for inclusion of

excipients and quality control measures that must be met during the product
development process for this product.
5.

You must formulate an inhalation aerosol product of salbutamol in either a

suspension or a solution system. You must use non-fluorinated propellants.
Give a motivation for your formulae and give the quality assurance tests that
you will do on the final product.

6.

You must formulate a suppository of cyclizine hydrochloride. Give a motivation

for your formula and supply the quality assurance tests that you will perform
during the development phase and on the final product.

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7.

Give the basic principles of the methods of delivery, the manufacturing

methods and the quality control procedures applicable for a new non-traditional
drug delivery system of your choice (approximately 3 pages typed).

Completed assignments must demonstrate that the student understands the course
material and is able to apply the knowledge in practice. During the evaluation of
assignments, focus will be placed on assessing the originality of answers, correct
interpretation of the problem, and applicability of the students approach.
When doing the assignments concentrate on getting the information from the
references listed at the end of this study guide.

1.5

REFERENCES

Prerequisite
The student must have a thorough knowledge of the different types of dosage forms,
the formulation thereof and the production processes unique to a specific dosage
form.
Prescribed work
1.

Lachman, L., Liebermann, H.A. & Konig, J.L. 1986. The theory and practice of
industrial pharmacy, 3rd ed., Chapter 5 to 21.

Other works that may be consulted

1.

AULTON, M.E. 1988. Pharmaceutics: the science of dosage form design.

Churchill Livingstone : Edinburg.

2.

BANKER, G.S. & RHODES, C.T.

1990.

Chapters 8 - 12 & 16.

Modern

Pharmaceutics. 2nd edition. Marcel Dekker : New York.

3.

BARTLING, D. & HADAMICK, H. 1990. Development of a drug - its long way

from laboratory to patient. Darmstadt, Germany.

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4.

OSBORNE, D.W. & AMANN, A.H. 1990. Topical drug delivery formulations.
New York : Marcel Dekker Inc. p. 1-12; 197-211.

1.6

STUDY GUIDE COMPILED BY:

Melgardt M. de Villiers, Ph.D., Department of Basic Pharmaceutical Sciences, College

of Pharmacy, University of Louisiana at Monroe, Monroe LA 71209, E-mail:
devilliers@ulm.edu.

Melgardt de Villiers, Ph.D.

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