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