Drug Dosage Form Design

Dosage Form ROUTES OF ADMINISTRATION

 Dosage forms are meant by which drug 1. Oral
molecules or delivered to sites of action  Tablets
within the body to produce desired  Immediate-release (IR)
therapeutic effects and minimum adverse  Enteric -Coated (EC)
effects  Sprinkles & Granules
 It is the combination of API and Excipients.  Effervescent tablets
 API is the chemical compound intended for  Orally- Disintegrating (ODTs)
used in treatment and prevention of  Controlled or Sustained Release
disease.  Sublingual
 Excipients are inactive pharmaceutical  Capsules
ingredients technological,  Hard Gelatin
biopharmaceutical/ or stability reasons.  Soft Gelatin
2. Topical / Transdermal
Why Dosage Forms?  Transdermal Patch
 Safe and convenient delivery of accurate  Creams
dosage  Ointments
 Protection from the atmosphere  Gels
 Protection from the gastric acid (EC tablet)
 Masking bitter, salty, or offensive taste or 3. Parenteral
odor  Intravenous
 Liquid formulation for insoluble and  Subcutaneous
unstable drugs  Intradermal Injections
 Rate- controlled drug Action  Intramuscular Injections
 Topical drug action  Intraspinal Injections
 Drug insertion into body cavity  Intrathecal
 Drug placement into bloodstream  Epidural
 For inhalation Therapy 4. Rectal
 Suppositories
 Rectal ointment & creams
CLASSIFICATION OF DOSAGE FORMS  Enemas
 Rectal Foams
Immediate 5. Vaginal
Release Release  Tablets
rate  Suppositories
Modified or Timed-Release  Creams
 Ointments
6. Ophthalmic / Ocular
 Solutions
 Ointments
Extended Release Delayed Release  Suspensions
 Examples
7. Pulmonary
8. Nasal

Controlled Release Sustained Release Targeted

release
State of Dosage form WORK FLOW Of Pre-formulation Studies
1. Solid
 Tablets
 Capsules
 Powders
2. Semi-solids
 Creams
 Ointments
 Gels
3. Liquids
 Monophasic
 Syrups
 Biphasic
 Suspension
 Emulsions
4. Gas
 Nebulized solutions
 Aerosols
Packaging
1. Unit Dosage Forms
 Tablets
2. Bulk Dosage Forms
 Powders
Pre-formulation Consideration
 Physical Consideration
WHAT IS NEEDED TO DESIGN A DOSAGE FORM?  Microscopic observation
1. Pre- formulation Studies  Macroscopic observation
2. Stability Studies  Particle size and shape
PRE- FORMULATION STUDIES  Solubility
 It is defined as the phase of research and  Polymorphism
development in which physical and  Physical form (crystal/ Amorphous)
chemical properties of drug molecule in  Flow properties
order to develop safe, effective and stable  Chemical Consideration
dosage form.  Hydrolysis
 It is the first step in rational dosage form  Oxidation
development substances  Reduction
 It is performed based on dosage forms to  Racemization
be developed.  Polymerization
OBJECTIVE OF PRE-FORMULATION STUDIES  Isomerisation
 To establish the physico-chemical  Photo stability
parameters of a new drug entity
 To determine its kinetic and stability
 To establish its compatibility with
common excipients
 It provides insights into how drug
products should be processed and
stored to ensure their quality
The purity of the chemical substances is Melting Point depression
essential for its identification as well as for the  A characteristic of a pure substance is
evaluation of its chemical, physical, and defined melting point or melting range.
biological properties. If not pure, the substance will exhibit a
depressed melting point.
 This phenomenon is commonly used to
Chemical Structures, form and
determine the purity of a drug
Properties reactivity
substances before inclusion in the same
dosage form.
Physical Physical description, Melting point or Freezing point
Properties Particle size, Crystalline  Defined as the temperature where the
structure, Melting point, pure liquid and solid exist in
Solubility. equilibrium.
 The melting point / range of a drug can be used
Biologic Ability to get a site of as an indicator of purity of chemical substances
properties action, Elicit a biologic (a pure substances would ordinarily be
response characterized by a very sharp melting peak.)
 An altered peak or a peak at a different
temperature may be indicative of an
Physical Form adulterated or impure drug.
Before the formulation of a drug substances into a
dosage form, it is essential that it will be chemically and Particle Size
physically characterized.  Certain physical and chemical
properties of drug substances are
affected by the particle size distribution,
including drug dissolution rate,
bioavailability, content uniformity,
taste, color and stability.
 In addition, properties such as flow
characteristics and sedimentation rates,
among others, are also important
factors related to particle size.
Polymorphism
 An important factor on formulation is
the crystal or amorphous form of the
drug substance. Polymorphic forms
usually exhibit different physio-
chemical properties including melting
point and solubility.
Microscopic examination  The changes in crystal characteristic can
 Microscopic examination of the raw influence bioavailability, chemical and
drug substance is an important step in physical stability, and have important
pre-formulation work. implications in dosage form process
 It gives an indication of particle size and functions.
particle size range of the raw materials
as well as the crystal structure.
Solubility Solubility and pH
 A drug must possess some aqueous  pH is one of the most important
solubility for therapeutic efficacy. factors involved in the
 For a drug to enter the systemic formulation process. Two areas
circulation to exert a therapeutic effect, of critical importance are the
it must first be in solution. effects of pH on solubility and
 Relativity insoluble compounds often stability.
exhibit incomplete or erratic  The effect of pH on solubility is
absorption. critical in the formulation of
 If the solubility of the drug substance is liquid dosage forms, from oral
less than desirable, consideration must and topical solutions to
be given to improve its solubility. intravenous solutions and
Solubility and particle size admixtures.
 Although solubility is normally Dissolution
considered a physiochemical  Dissolution rate can affect the
constant, small increases in solubility onset, intensity, and duration of
can be accomplished by particle size response, and control the overall
reduction. bioavailability of the drug from
the dosage form.
 The dissolution rate of drugs
may be increased by decreasing
the drug’s particle size.
 It may also be increased by
increasing its solubility in the
diffusion layer. The most
effective means of obtaining
higher dissolution rates is to use
a highly water soluble salt of the
parent substance.
Membrane permeability
 To produce a biological
response, the drug molecule
must first cross a biological
membrane.
 The biological membrane acts as
a lipid barrier to most drugs and
permits the absorption of lipid
Solubility and pH soluble substances by passive
 pH is one of the most important diffusion while lipid insoluble
factors involved in the formulation substances can diffuse across the
process. barrier only with considerable
 The effect pf pH on solubility is difficulty
critical in formulation of liquid
dosage forms, from oral and topical
solutions to intravenous solutions
and admixtures.
Partition coefficient
 In formulation development, the Stability Studies
octanol-water partition  Stability studies conducted in the
coefficient is commonly used it is pre- formulation phase based on
the indication of drug solubility Chemical Consideration.
profile in water and octanol

Following the illustration provided above, it is defined

as
Solid-state of the drug
alone

Solution Phase

with the expected excipients

[P is dependent on the drug concentration only if the

Drug and Drug Product Stability
drug molecules have a tendency to associate in
solution. Higher P value higher permeability and higher
bioavailability]
Physical and chemical stability of
pKa/ Dissociation constants Evaluation pure drug substances important
 Extent of ionization has an for pre-formulation.
important effect on the
formulation and
pharmacokinetic parameter of Drug Mechanism of
the drug.
Stability Degradation
 The extent of dissociation/
ionization is, in many cases,
highly dependent on the pH of
the medium containing the drug. Hydrolysis
 In the pharmacokinetic area, the
extent of ionization of a drug is
an important factor of its extent
of absorption, distribution, and Hydrolysis (solvolysis
process)
elimination.
 Dissolution constant or pka is
usually determined by
potentiometric titration.

Susceptible to he
(drug) molecules
hydrolytic process :
interact with water
esters, substituted
molecule to yield
amides, lactones, and
breakdown product.
lactams.
Oxidation Decarboxylation
 Is a chemical reaction that
removes a carboxyl group and
release carbon dioxide (CO2).
Loss of electrons from Usually, decomposition of
an atom or molecule.
RCOOH

aldehyde, alcohols,
phenols, sugars,
Free radicals
alkaloids &
unsaturated fat & oils.

Racemization
 Racemization refers to partial
conversion of one enantiomer Deamination
into another resulting in loss of  Removal of nitrogen containing
biological activity. amino group from organic
 Conversion of optically active amine.
compound into inactive
compound.
 It affects solubility, dissolution,
absorption and bioavailability of
drug.
 L- epinephrine is 15-20 times
more active than D-form while
racemic mixture has half of
inactivity than L-form.
Polymerization
 Any process in which relatively
small molecules, called
monomers, combine chemically
to produce a very large chain like
or net work molecule, called a
polymer. The monomers
molecules may be all alike, or
they may represent two, three, Drug Instability Detected by
or more different compounds.  Physical Appearance
 Color
 Odor
 Taste
 Texture of the
formulation

Fig. Paraformaldehyde
Oxidizable drugs Stabilized in Stability Testing
Formulation
1.) Accelerated 2.) Short term 3.) Long term
Exclusion Inclusion Stability accelerated stability studies
 Oxygen  Maintain a testing/Stress studies
favorable pH Testing
 Oxidizing agents  Antioxidants
 Trace metals  Chelating agents When real time Determines most Product is
 Light  Buffering agents data is stable of the subjected to
unavailable it is proposed different
 Heat
performed for formulations for climatic zones
 Other chemical shelf life a drug product
catalysis (temp. &
determination. lesser temp and
Accelerated humidity. humidity)
stability study is nationally &
Hydrolysable Drugs Stabilized in subjecting the internationally
Formulation. product to an predicted from
Reduction For
elevated level of the data
For certain
and the unstable antibiotic hydrolysable stress like generated from
elimination In Liquid In certain drugs the pH
of water for preparations injectable drugs, when an
of optimum
controlled continuing
aqueous
solid products
preparation is
stability. changes in stability studies
preparation
desired temperature or 12 months
humidity and
minimum.
By applying Water Anhydrous Use Dry form Between light.
a water replaced or vegetable
proof reduced in oils may be for pH 5 and
protective the used as the reconstitution 6, Use of
coating. formulation. drug's buffering Study Storage Minimum time
solvent agents.
condition period covered
By Use of
by data at
Powder
enclosing substitute for submission
and liquid-
maintaining injection Long term 25°C ± 2°C / 12 months
glycerin,
the drug in
propylene 60% ± 5% r.h. or
tightly
closed glycol, and 30°C ± 2°C /
containers. alcohol.
65% ± 5% r.h.
Intermediate 30°C ± 2°C / 6 months
65% ± 5% r.h.
 Trace metals in drug stabilized by completing or Accelerated 40°C ± 2°C / 6 months
binding metal by using specialized agents 75% ± 5% r.h.
(chelating agents- Cadisod edetate & EDTA)
 Container and solvent are source of difficulty in
preparing stable solutions of oxidizable drugs
which is eliminated by purification of source of
contaminant
 Light catalyst to oxidation reactions
preparations packed in light resistant or opaque
containers can enhance stability.