PREFORMULATION

Budipratiwi W.

Developing Target Product Profile

Intended Therapeutic Indication

Preferred Dosage Form
Anticipated Product Strength
Desired Release Profile and Skin
Penetration Goals
Cosmetic/Aesthetic Properties
Target Shelf Life

Drug Formulation
Disease characteristics
Local or systemic therapy
Patient conditions
Active Compound Candidate

Drug Delivery System

Formulation and Evaluation

Drug Candidate Selection

To select lead compounds for
pharmaceutical product
development:
a. Therapeutic rationale
b. Safety
c. Efficacy

Therapeutic Efficacy
1. The ability of to cross biological barriers
2. The ability of to travel to the target site
3. The ability of to interact with specific
receptors
But it is often more appropriate in
dermatological therapy to select compounds
based on their inability to breach relevant
biological barriers

Successfull Topical Dermatological

Formulation
Physically and chemically stable (adequate shelf life)
Releases API from the formulation and delivers it
Cosmetically elegant and acceptable to patients,
Contains only excipients that are necessary, FDAapproved or acceptable from a regulatory
perspective, and acceptable for the disease state
Easy to apply and compatible with the desired
packaging
Can be manufactured with a process that is scalable
to commercial levels

PREFORMULATION
A phase of research and development
process where the preformulation
scientists characterizes the physical,
chemical, and mechanical properties of
a new drug substance in order to
develop stable, safe and effective dosage
forms

OBJECTIVE
To establish the necessary physicochemical
properties
To choose the correct form of the drug substance
To formulate stable and effective dosage form
To increased drug stability
To improve drug bioavailability
To select compatible excipients
To generate information useful to the formulator
in developing optimal drug delivery system which
can be mass-produced.

WHY PREFORMULATION IS
IMPORTANT ?
a. Thorough preformulation work is
the foundation of developing
robust formulation.
b. Good preformulation will inevitably
lead to simple and elegant
formulations and successful
commercial products.

), it is often more appropriate in

dermatological therapy to select compounds based on their inability to breach relevant
biological barriers

PREFORMULATION STUDIES
Preformulation studies for Drug substance are:
1. Physico-chemical properties
2. Stability
3. Physico-mechanical properties
4. Solid State Compatibility
5. In Vitro Availability Properties
6. Other studies

1. Physico-chemical Properties
Organoleptic properties, includes the color, odor,
and taste of the drug
Molecular structure and weight
Particle properties, includes the size, shape, crystal
properties, and polymorphism potential
Solubility & permeability Melting point
Thermal analysis profile Hygroscopicity
Effect of pH on UV spectra Absorbance spectra
Ionization constant
Volatility
Solvate formation
Optical activity

Solubility
Parameters:
pH-Solubility profile (water or other solvents)
Temperature dependence
Solubilisation mechanisms
Salts forms
Co-solvency
Complexation
Prodrug
Analytical methods used to determine are
HPLC,UV spectroscopy, GC, fluorescence
spectroscopy.

Solubility > 1 % w/v

no dissolution-related absorption problem
Highly insoluble drug administered in small
doses may exhibit good absorption
The solubility of every new drug must be
determined as a function of pH over the
physiological pH range of 1 - 8

Biopharmaceutics
Classification System
Class

Solubility

Permeabitity

High

Good

Low

Good

High

Poor

Low

Poor

The Rule of 5
Poor permeations are more likely when:
1. There are more than 5 H-bond donors
(expressed as the sum of OHs and NHs)
2. There are more than 10 H-bond acceptors
(expressed as the sum of Ns and Os)
3. The MW is over 500
4. The log partition coefficient is over 5
5. Compound classes that are substrates for
biological transporters are exceptions
to the rule.

Ionization Constant
Henderson Hasselbalch equation
Determined by
1.UV or Visible spectroscopy
2. Potentiometric titration
pKa = pH at which acidic or basic
groups attached to molecules exist as
50% ionized and 50% nonionized in
aqueous solution

Particle Size and Shape

Effects of particle size distribution and
shape on:
a. Chemical and physical properties of
drug substances
b. Bioavailability of drug substances
c. Stability

POLYMORPHISM
Crystalline structures in more than one form with different
internal structures
Polymorphic forms Different physical-chemical
properties (including melting point and solubility)
Their existence can be determined by
- optical crystallography
- x-ray diffraction
- DSC (Differential Scanning Calorimetry)
- Thermal analysis
Evaluation of:
- crystal structure (microscopy, IR spectroscopy, thermal
analysis, x-ray diffraction)
- polymorphism and presence of a solvate form.

Polymorph Screening
Optimal crystal form and the
corresponding behavior in different
humidity conditions drugs stability
and solubility packaged, handled, and
stored
Crystal identify its shape or other
shape

2. Stability
Solid State

Solution

a. Temperature
a. Solvent
b. Light
b. pH
c. Humidity
c. Light
Extent a product retains within specified limits
and through its period of storage and use
Stability studies conducted in the preformulation
phase: Solid-state of the drug alone, Solution
phase, With the expected excipients

Other Studies
a. Purity: The purity of a compound must be determined.
occasionally an impurity can affect stability.
Example: Metal contamination at certain level of ppm may
cause deleterious effects on drug.
Techniques used to determine the purity are
(a) Thin-Layer Chromatography (TLC)
(b) High Pressure Liquid Chromatography (HPLC)
(c) Differential Thermal analysis
(d) Gravimetric thermal analysis
Provide the quantitative picture of homogeneity and also
direct evidence of presence of solvates.

b. Dissolution Rate
Time for the drug to dissolve in the fluids
at the absorption site (rate-limiting step
in absorption).
Dissolution rate of drugs is increased by
decrease in the particle size.
For higher dissolution rate highly
water soluble salt of the parent
substance is used.

Two methods in determining dissolution rates

of chemical compounds
1.Constant surface method - Intrinsic dissolution
rate of the agent - Characteristic of compound
and solvent under fixed experimental
conditions - mg dissolved/min/cm square
2.Particulate dissolution - Weighed amount of
powdered sample + dissolution medium in
constant agitation system - To study the
influence of particle size, surface area, and
excipients upon the active agent

c. Drug Excipient
Compatibility Drug
Component of the formulation which is
Pharmacologically Active.
Excipient : Components of a finished drug
product other than API which are added
during formulation for a specific purpose.
Example: Semisolid bases, pearlescence
agents, humectants, preservatives,
perfumes

 Importance of Drug Excipient Compatibility

Drug Excipient interactions may cause :
Substantial loss of potency
Undesirable change in performance i.e.,
Dissolution / Bioavailability
Change in Physical Appearance of dosage form
Degradation products may lead to toxicity

 Purpose of Drug Excipient Compatibility

Studies:
Identification of compatible excipients for a
formulation
Identification of stable storage conditions for
a drug in solid or liquid state
Techniques to detect Drug Excipient
Compatibilty
Differential scanning calorimetry (DSC)
Thin layer chromatography (TLC)
Accelerated stability studies

CONCLUSION
Preformulation studies of semisolid
preparations is an important tool to
know the drug-excipient
compatibility of drug with the
excipients and is useful tool to
determine various parameters, hence
preformulation studies are carried out
to obtain a stable, safe and effective
dosage form.