Preformulation 2024

Design of dosage form
INDUSTRIAL PHARMACY (P.367)

Content
 Introduction
 Pre-formulation studies
 Physicochemical characterizations
 Analytical measures
 References
Dr.Ahlam Zaid Alkilani
Objectives
 Discuss the importance of preformulation and biopharmaceutics;
 Compare and contrast an Investigational New Drug (IND)
Application from a New Drug Application (NDA)
 List factors that limits oral bioavailability
 Discuss physicochemical properties assessment and impact of
knowledge generated on drug product development
 Describe how biopharmaceutical properties are assessed and
their application.

NEW DRUG DEVELOPMENT AND
APPROVAL PROCESS
PAGE 27: ANSEL’S

DRUG DEVELOPMENT
 The federal Food, Drug, and Cosmetic

Act, as regulated through Title of the U.S.
Code of Federal Regulations, requires a
new drug to be approved by the Food
and Drug Administration (FDA) before it
may be legally introduced in the market
DRUG DEVELOPMENT
 To gain approval for marketing, a drug’s

sponsor (e.g., a pharmaceutical company)
must demonstrate, through supporting
scientific evidence,
 thatthe new drug or drug product is safe and

effective for its proposed use.
DRUG DEVELOPMENT
 The
process and time course from drug discovery to
approval for marketing can be lengthy and tedious
but are well defined and understood in the
pharmaceutical industry.
DRUG DEVELOPMENT
 Only when the preclinical studies demonstrate adequate

safety and the new agent shows promise as a useful drug will
the drug’s sponsor file an Investigational New Drug
Application (IND ) with the FDA for initial testing in humans.
 If the drug demonstrates adequate safety in these initial

human studies, termed Phase 1,
 progressive human trials through Phases 2 and 3 are

undertaken to assess safety and efficacy.
SOURCES OF NEW DRUGS
 New drugs may be discovered from

a variety of natural sources or
synthesized in the laboratory.
IND FOR AN ORPHAN DRUG
 Under the Orphan Drug Act of 1983 as amended, an orphan

disease is defined as a rare disease or condition that affects fewer
than 200,000 people in the United States and for which there is no
reasonable expectation that costs of research and development
for the indication can be recovered by sales of the product in the
United States.
 Examples of such illnesses are cystic fibrosis, and conditions

related to AIDS.
THE NEW DRUG APPLICATION (NDA)
 If the three phases of clinical testing during the IND period

demonstrate sufficient drug safety and therapeutic effectiveness,
the sponsor may file an NDA with the FDA.
 The purpose of the NDA is to gain permission to market the drug

product.
 An NDA contains a complete presentation of all of the
preclinical and clinical results
Prefomulation studies
Introduction
 Pre-formulation testing is the first step in the rational
development of dosage forms.
 Drugs are rarely administered as pure chemical substances

alone and are almost always given as formulated
preparations or medicines

Pharmaceutics
Pharmaceutics converts a drug into a medicine.

Types of dosage forms
 They are classified according to:

Route of administration Physical form
Oral Solid
Topical Semisolid
Rectal Liquid
Parenteral
Vaginal
Inhaled
Ophthalmic
Otic

Objective
 The overall objective of pre-formulation
testing is to generate information useful to the
formulator in developing
1. stable
2. bioavailable dosage forms

Pre-formulation studies
 It is a group of studies that focus on the

physicochemical properties of a new drug
candidate that could affect the drug performance
and the development of a dosage form.

Formulation
 Formulation is the process of developing a

drug candidate into a drug product.
 Initially, there may be a number of potential drug
candidate molecules, each with a unique set of
physicochemical properties and each showing
activity towards a particular biological target.
Assay development
 No relevant physicochemical property can be

measured without an assay and so
development of a suitable assay is the first step
of preformulation.
Assay development
 The first assay procedures should require minimal amounts

of sample
 Ideally, experiments should allow determination of multiple

parameters. For instance, a saturated solution prepared to
determine aqueous solubility may subsequently be re-used
to determine a partition coefficient.
Assay development
 These properties are a function of molecular structure.

 Once known, further macroscopic (or bulk) properties
of the drug candidate can be measured,
 Table 23.2. These properties result from intermolecular
interactions
Assay
 Table 23.1 lists a range

o properties to be
measured during pre
formulation
ICH Guideline
Formulation
 Before a drug substance can be successfully formulated into a dosage form,
many factors must be considered.
1. Drug factors, such as the physical and chemical properties of the drug
substance
2. Therapeutic considerations, including consideration of the clinical indication to

be treated and patient factors (age, duration of action …. etc).
3. Biopharmaceutical considerations, including factors affecting the absorption of

the drug substance from different administration routes

THERAPEUTIC CONSIDERATIONS
Factors such as the need for

 Systemic or Local therapy,
 the Duration of action required and whether the
drug will be used in Emergency situations, need to
be considered.
 E.g. Patients requiring urgent relief from angina

pectoris tablets of nitroglycerin sublingually
 The age of the patient also plays a role in defining the types of dosage
forms made available.
 Infants liquid dosage forms
 Children Oral preparations , difficulty in swallowing solid dosage forms
 Adults solid dosage forms

 However, alternative liquid preparations are usually available for those unable to take
tablets and capsules.
Assignment 1
 Group 1: Pediatric Drug Development - Formulation Considerations

 Group 2: Oral Drug Development - Formulation Considerations
 Group 3: Liquid Drug Development - Formulation Considerations
 Group 4: Semisolid Considerations during Drug Development
Biopharmaceutical aspect of dosage forms
design
 Biopharmaceutics can be regarded as the study of the relationship

between the physical, chemical and biological sciences applied
to drugs, dosage forms and drug action.
 In general, a drug substance must be in solution before it can be

absorbed via absorbing membranes and epithelia of the skin,
gastrointestinal tract and lungs into body fluids.
 Drugs are absorbed in two general ways: by passive diffusion and

by
Dr.Ahlam carrier mediated transport mechanisms.
Zaid Alkilani
 When the dosage form is designed to deliver drugs
via the buccal, respiratory, rectal, intramuscular or
subcutaneous routes, the drug passes directly into
the circulation blood from absorbing tissues,
 whilst the intravenous route provides the most direct

route of all.

https://www.youtube.com/watch?v=mH81Q9Dtodc

The physicochemical properties of drug
substances
 Physicochemical characterization is essential for

a fundamental understanding of your API
(ACTIVE PHARMACEUTICAL INGREDIENT) and
critical to the drug development process.

PHYSICAL CHARACTERISTICS
 Particle Size & Surface Area.

 Polymorphism.
 Crystallinity.
 Hygroscopicity.
 Flow properties & Bulk density.
 Compressibility.
 Drug-Excipient Compatibility.
 Electrostatic charge.
 Osmolarity.
 Rheology.
 Wettability.
CHEMICAL CHARACTERISTIC
1) Hydrolysis.
2) Oxidation
3) Photolysis.
4) Polymerization.
5) Isomerization.
6) Decarboxylation.
7) Enzyme Decomposition.

The most important Drug factors in dosage
form design
 Particle size and surface area

 Solubility
 Dissolution
 Partition coefficcient and pKa
 Crystal properties : polymorphism
 Stability
 Organoleptic properties

Solubility
 Aqueous solubility is a critical attribute.

 No drug will reach its ultimate therapeutic target without first being in
solution.
 Consequently, it is the first physicochemical parameter to be
determined.
 It has been estimated that, historically, up to 40% o drug candidates
have been abandoned because of poor aqueous solubility, and
between 35–40% of compounds currently in development have an
aqueous solubility below 5 mg.mL−1 at pH 7.
Solubility
 What does solubility mean ?
 In what units is solubility measured?

Solubility
 For the final product, assuming oral delivery in a solid

form, solubility of the molecule above 10 mg mL−1 is
preferable.
 if the solubility of the drug candidate is less than 1 mg

mL−1 then salt formation, if possible, is indicated.
 Where solubility cannot be manipulated through salt
formation, then a novel dosage form will be required.
SOLUBILIZATION
Many different approaches have been developed to improve drug

solubility
1. Micronization:-
Eg. Griseofulvin shows increased solubility by reducing
particle size.
2. Change in pH:-
Eg. Solubility of Nimesulide increases as pH is increased.

3. Cosolvency:-
Addition of a water miscible solvent can often improve the solubility of a weak
electrolyte or non-polar compound in water by altering the polarity of the solvent.
4. Solubilization by surfactant:-
a surface active excipient can solubilize poorly soluble drug.

5. Complexation
Formation of Inclusion Compound:-
Enhanced solubility of drugs through inclusion of β cyclodextrin

and its dervivatives.

6 . salt formation
 A major improvement in solubility can be achieved by forming a

salt. Acceptable pharmaceutical salt counter-ions are shown in
Table 8.4.
 The solubility of slightly soluble acid is increased as the pH is

increased by addition of alkali, due to the formation of salt

Dissolution
 for Any drug to be absorbed, it must first be dissolved in the fluid

at the site of absorption.
 For example, an orally administered drug in tablet form is not

absorbed until drug particles are dissolved or solubilized by the
fluids at some point along the gastrointestinal tract, depending
on the pH-solubility profile of the drug substance.
 Dissolution describes the process by which the drug particles

dissolve.
Solubility
 Dissolution is a phase transition and in order to progress,

solid-solid bonds must be broken (e effectively, the solid
melts), while solvent-solvent bonds must be broken and
replaced by solute-solvent bonds (the drug molecules
become solvated)
Solubility
 With excess solid present, a position of equilibrium will be

established between the solid and dissolved drug.
 The concentration of drug dissolved at this point is known as

the equilibrium solubility (usually referred to simply as
solubility) and the solution is saturated.
 If the drug has an ionizable group then the equilibrium solubility
of the unionized form is called the intrinsic solubility (So).
 Intrinsic solubility is the equilibrium solubility of the free acid or
base of an ionizable compound at a pH where it is fully
unionized.
 This is important, because ionizable drugs will dissociate to a
greater or lesser extent, influenced by solution pH, and this will
affect the observed solubility.
Equilibrium solubility method (shake-
flask)
 Solubility studies of antiretroviral drugs were determined by

equilibrating excess amount of each drug in buffer solutions of
pH 1.2, 4.5, 6.8, 7.5 and purified water.
 In each flask were added 10 mL of media and the amount of
drug separately.
 Assays were performed in flasks.
 Incubator shaker was used to keep samples at 37 °C during
the test with agitation of 150 rpm for 72 hours (until achieve the
equilibrium condition)
Measurement of intrinsic solubility
 Ultraviolet (UV) spectroscopy is the first choice assay, for

reasons of
 familiarity,
 cost,
 the small volume of solution needed and
 the act that the majority of drugs contain at least one
functional group that absorbs in the UV region (190–390
nm).
 IF the aim of the preformulation screen is to understand solubility in

vivo, then solubility in biorelevant media should be determined.
 Assuming oral delivery, typical media would include simulated

gastric fluid (SGF), fed simulated intestinal fluid (FeSSIF) and/or fasted
simulated intestinal fluid (FaSSIF).
 Bio-relevant media tend to have higher ionic strengths and hence

the risk of salting out via the common ion effect is greater.
Salting out
 Salting out is a purification

technique that utilizes the
reduced solubility of certain
molecules in a solution of very
high ionic strength.
 The salting-out extraction technique
can be used for the extraction of drugs
from biological fluids.
Effect of impurities on intrinsic solubility
 Another issue or consideration at this stage is the chemical purity of

the sample.
 If the drug is pure, then its phase-solubility diagram should appear

as in Figure 23.5.
 Initially, all drug added to the solvent dissolves and the gradient of
the line should be unity.
 When saturation is achieved, addition of further drug does not result

in an increase in concentration and the gradient becomes zero.
 However, new drug

candidate material is
rarely pure.
 When a single impurity
is present, the phase-
solubility diagram will
appear as shown in
Figure 23.6.
 From the origin to point A both

components dissolve.
 At point A the first compound has
reached its solubility.
 The line AB represents the
continued dissolution of the
second compound.
 At point B the second compound
reaches its solubility and the
gradient of the line BC is zero.
 The solubility of the first compound (S1) can be

determined by extrapolation of line AB to the y-axis.
 The solubility of the second compound (S2) is the

difference between the solubility at BC (= S1+ S2) and the
y-intercept of the extrapolated line AB.
 The same principles apply if further impurities are present.

 An alternative experiment is to
prepare our solutions of the drug
candidate with different phase
ratios of drug to solvent (say 3, 6,
12 and 24 mg of drug in 3 mL),
 measure the solubility of each
and then extrapolate the data to
a theoretical phase-ratio of zero
(Fig. 23.7).
 If the drug is pure then solubility

should be independent of phase-
ratio.
 If the impurity acts to increase
solubility ( or instance, by self-
association, complexation or
solubilization), then the gradient of
the plotted line will be positive,
 whereas if the impurity acts to

suppress solubility (usually by the
common ion effect) then the
gradient of the line will be negative.
 The point at zero phase ratio in Figure

23.7 implies that the impurity
concentration is zero and thus the
true solubility can be estimated.
 The purity of a sample may also

be checked with DSC, since the
presence of an impurity (even
minor amounts) will lower and
broaden the melting point.
 Qualitatively, if the melting
endotherm recorded using DSC
is very broad, then the sample is
likely to be impure
Molecular dissociation
 The Henderson-Hasselbalch equations allow calculation of the

extent of ionization of a drug as a function of pH, if the pKa is
known.
 When the pH is significantly below the pKa (by at least 2 pH

units), a weakly acidic drug will be completely unionized
 and when the pH is significantly above the pKa (by at least 2
pH units) a weakly acidic drug will be fully ionized (and vice
versa or a basic drug).
 The degree of ionization will affect solubility because ionized

species are more freely soluble in water.
 Taking the acid-species Henderson- Hasselbalch.

 [A−] represents the saturated concentration of ionized drug (Si) and
 [HA] represents the saturated concentration of unionized drug (i.e.
the intrinsic solubility, So)
 then the equation may be re-written as:
 Drugs exist in two forms ionized (water soluble)
nonionized forms (lipid soluble) in equilibrium.
 Drug ionized form + nonionized form
 Only nonionized form (lipid soluble) is absorbable.
 The ratio between nonionized form / ionized form is
determined by pH of the medium and pKa of the drug.
 Equation 23.14 allows

calculation of the total
solubility of an acidic drug as
a unction of pH.
 Total solubility will be equal to

the intrinsic solubility at pH
values below pKa and
 will increase significantly at

pH values above pKa.
 pKa of the drug (Dissociation or ionization constant): is
defined as pH at which half of the substance is ionized &
half is unionized.
 The lower the pKa value of the acidic drug the stronger
the acid e.g aspirin (Pka= 3.0 ).
 The higher the pKa value of a basic drug, the stronger the
base e.g propranolol ( pKa= 9.4)
Partition coefficient (p) and pka
 The partition coefficient, logP, is a commonly used way of defining relative
hydrophobicity (also known as lipophilicity) of compounds.
 Lipophilicity is needed for the compounds to permeate through the various

biological membrane.
 Lipophilicity is typically measured as the compounds distribution between

non-aqueous (octanol) and aqueous (water) phase and the result is
expressed as logP.

Partition coefficient (p) and pKa
 The dominating factors that influence the absorption of

weak acids and bases are the pH at the site of absorption
and the lipid solubility of the unionized species.
 These factors, together with the Henderson–Hasselbalch

equations for calculating the proportions of ionized and
unionized species at a particular pH, constitute the pH-
partition theory for drug absorption.

Permeation across biological membrane

 Cell membranes are more permeable to the un-ionized forms of drugs
than to their ionized forms, mainly because of
1. The greater lipid solubility of the un-ionized forms and

2. The highly charged nature of the cell membrane, which results in
binding or repelling of the ionized drug and thereby decreases cell
penetration.
3. Ions become hydrated through association with water molecules,
resulting in larger particles than the undissociated molecule and again
decreased penetrating capability.
Determination of log P
 Assuming that a UV assay is available

 Prior to measurement, the solvents to be used
should be mixed with each other and allowed to
reach equilibrium.
 n-octanol in water
 The drug is dissolved in the aqueous phase to a known

concentration.
 Equal volumes of aqueous drug solution and n-octanol are then

mixed in a separating funnel.
 The mixture is shaken vigorously or a period of time (usually 30

minutes, to maximize the surface area of the two solvents in
contact with each other) while the drug partitions.
 The phases are allowed to separate (5 minutes) and

then the concentration of drug remaining in the
aqueous phase is determined,
 Figure 23.9. By difference, the concentration of drug in

the n-octanol phase is known:
 The use of n-octanol tends to reflect absorption from the

gastrointestinal tract, which is why it is the default option;
but n-octanol may not be the best organic phase.
 Hexane or heptane can be used as alternatives,

although they will give different partition coefficient
values from n-octanol and are also considered to be less
representative of biological membranes because they
cannot form any hydrogen bonds with the solute.
Group discussion
 Which one of the following drugs

will be best absorbed in stomach
(pH=3)?
 Aspirin pka=3.0
 warfarin pka=5.0
Group discussion
 Arrange the following drugs in ascending order from least to

greatest in rate of absorption in small intestine (pH=7.8)?
 Propranolol pka= 9.4
 Aspirin pka=3.0
 warfarin pka=5.0
Answer
 Aspirin (the least absorption), warfarin,

propranolol (the greatest absorption).
Group discussion
 The substances used as drugs were

1. aspirin (a weak acid, also known as acetylsalicylic acid),
2. 3-aminophenol (a weak base),
3. paracetamol (a neutral substance, also known as acetaminophen).
 Where are drugs absorbed in the gastrointestinal

system?
Particle size and surface area
 Study of particle size gives an information about solubility,

dissolution rate, absorption, etc.
 Particle size and surface area of a solid drug are inversely

related to each other
 In many cases, for both drugs and additives, particle size

reduction is required to achieve the desired
physicochemical characteristics.
Particle size and surface area
 Poorly aqueous soluble drugs showing a dissolution rate-limiting

step in the absorption process
micrometre or nanometre size, with large specific surface,
dissolves at faster rates
lead to improved drug absorption by passive diffusion.

Examples on Dosage forms that
are affected by particle size,
including
Suspensions Inhalation
aerosols for
optimal
Topical
(for controlling penetration of (for
flow properties drug particles freedom
and particle to absorbing from
interactions) mucosa) grittiness)

Deposition of particles in the various
regions of the respiratory tract.

 Reduction in particle size improve
solubility but sometimes ………..
 Fine powders can also increase air adsorption or

static charge, leading to wetting or agglomeration
problems .
 Micronizing drug powders can lead to changes in

crystal STRUCTURE which cause reduced chemical
stability. Amorphous
Crystalline

Solid state properties:
 drug substances can be

1. Amorphous (i.e. without regular molecular lattice
arrangements),
2. Crystalline, anhydrous, at various degrees of hydration or
solvated with other entrapped solvent molecules, as well
as varying in crystal hardness, shape and size.
3. Polymorphism, many drug substances can exist in more
than one form with different molecular packing
arrangements in the crystal lattice.
 Polymorphic transitions can also occur during milling, granulating, drying
and compacting operations (e.g. transitions during milling for digoxin and
spironolactone).
 Reversion from metastable forms, if used, to the stable form may also occur
during the lifetime of the product.
 In suspensions, this may be accompanied by changes in the consistency of

the preparation which affects its shelf-life and stability.
 Such changes can often be prevented by additives, such as hydrocolloids

and surface-active agents.
 In general, drug substances decompose as a
result of the effects of heat, oxygen, light and
moisture.
 Drugs can be classified according to their sensitivity to

breakdown:
1. Stable in all conditions (e.g. kaolin)
2. Stable if handled correctly (e.g. aspirin)
3. only moderately stable even with special handling
(e.g. vitamins)
4. Very unstable (e.g. certain antibiotics in solution form).

Organoleptic properties
 Pharmaceutical dosage forms have to be acceptable to the

patient.
 Many drug substances require addition of flavor and / or colors
 Sucrose or sodium saccharin are available and used as sweetening

agents


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Design of dosage form

INDUSTRIAL PHARMACY (P.367)

Dr.Ahlam Zaid Alkilani

PAGE 27: ANSEL’S

 The federal Food, Drug, and Cosmetic

 To gain approval for marketing, a drug’s

 thatthe new drug or drug product is safe and

 Only when the preclinical studies demonstrate adequate

 If the drug demonstrates adequate safety in these initial

 progressive human trials through Phases 2 and 3 are

 New drugs may be discovered from

 Under the Orphan Drug Act of 1983 as amended, an orphan

 Examples of such illnesses are cystic fibrosis, and conditions

 If the three phases of clinical testing during the IND period

 The purpose of the NDA is to gain permission to market the drug

 Drugs are rarely administered as pure chemical substances

Dr.Ahlam Zaid Alkilani

Pharmaceutics converts a drug into a medicine.

Dr.Ahlam Zaid Alkilani

 They are classified according to:

Dr.Ahlam Zaid Alkilani

Dr.Ahlam Zaid Alkilani

 It is a group of studies that focus on the

Dr.Ahlam Zaid Alkilani

 Formulation is the process of developing a

 No relevant physicochemical property can be

 The first assay procedures should require minimal amounts

 Ideally, experiments should allow determination of multiple

 These properties are a function of molecular structure.

 Table 23.1 lists a range

2. Therapeutic considerations, including consideration of the clinical indication to

3. Biopharmaceutical considerations, including factors affecting the absorption of

Dr.Ahlam Zaid Alkilani

Factors such as the need for

 E.g. Patients requiring urgent relief from angina

 Infants liquid dosage forms

 Children Oral preparations , difficulty in swallowing solid dosage forms

 Adults solid dosage forms

 Group 1: Pediatric Drug Development - Formulation Considerations

 Biopharmaceutics can be regarded as the study of the relationship

 In general, a drug substance must be in solution before it can be

 Drugs are absorbed in two general ways: by passive diffusion and

 whilst the intravenous route provides the most direct

Dr.Ahlam Zaid Alkilani

Dr.Ahlam Zaid Alkilani

 Physicochemical characterization is essential for

Dr.Ahlam Zaid Alkilani

 Particle Size & Surface Area.

Dr.Ahlam Zaid Alkilani

 Particle size and surface area

Dr.Ahlam Zaid Alkilani

 Aqueous solubility is a critical attribute.

 What does solubility mean ?

 In what units is solubility measured?

 For the final product, assuming oral delivery in a solid

 if the solubility of the drug candidate is less than 1 mg

Many different approaches have been developed to improve drug

Dr.Ahlam Zaid Alkilani

a surface active excipient can solubilize poorly soluble drug.

Dr.Ahlam Zaid Alkilani

Formation of Inclusion Compound:-

Enhanced solubility of drugs through inclusion of β cyclodextrin

Dr.Ahlam Zaid Alkilani