Preformulation Techniques
and
Formulation Selection
Pharmaceutical sciences :
Stage I : screen compounds and select drug candidates
Stage II : select salts and solid forms
Stage III : evaluate drug properties
Critical physical chemical properties
1. Drug should be in SOLUTION
2. Must be BIOAVAILABLE
3. Must be MANUFACTURABLE
Preformulation is :
Preformulation testing is the first step in the rational
development of dosage forms of a drug substance
It can be defined as an investigation of physical and
chemical properties of a drug substance alone and when
combined with excipients.
The overall objective of preformulation testing is to
generate information useful to the formulator in
developing stable and bioavailable dosage forms which
can be mass-produced
Preformulation
is a case of LEARNING before DOING
Dissolution
Behavior
Partition
Solubility
coefficient
Material
Ionization
Stability
constant
Solid state
properties
SOLUBILITY
Importance of solubility
Drug should be in solution to be absorbed
Drug candidates are becoming lipophilic and poorly soluble
How soluble is soluble enough ?
Dependent on dose and permeability
Biopharmaceutical classification system
BCS of Drugs
How to determine solubility
Semiquantitative determination
Solvent Vigorously Examine
(fixed volume) shaking visually
Adding solute in small
incremental amounts
Undissolved
solute particles ?
No Yes
“LAW OF MASS ACTION”
Estimated solubility Total amount
added up
Quantitative determination
Shaking at constant
Excess drug powder Ampul/vial temperature
150 mg/ml (15 %) (2-5 ml) (25 or 37 oC)
+ solvent 2 - 8 oC ?
The first few ml’s of the filtrates should be
discarded due to possible filter adsorption 48 hr
Determine the drug Membrane filter
concentration in the 0.45 m
filtrate
72 hr
Same Determine the drug Membrane filter
concentration ? concentration in the 0.45 m
filtrate
? hr
Solubility
Determine the drug Membrane filter
concentration in the 0.45 m
filtrate
Solubility and Dissolution improvement
Salts
Cosolvent, oils, emulsions and microemulsion
Surfactants
Complexes (eg. cyclodextrin)
Solvates
More soluble polymorphs
Amorphous
Pro-drugs
Micronization
Nanosizing
Super critical fluid technologies
Log aqueous solubility (mol) 5
Indomethacin
4 (weak acid)
3 Chlorpromazine
(weak base)
2
1 Oxytetracycline
(amphoteric)
2 4 6 8 10 12 14
pH
Dissolution behavior
Dissolution rate for poorly soluble compounds may often
be the rate limiting step to absorption
Bio relevant dissolution media should be the most
important consideration
How to determine dissolution of actives ?
Nelson constant surface method
Dissolution
medium
Rotating
Paddle
Harden wax
or paraffin Tablet surface
Partition coefficient
Like biological membrane in general, the GI membranes
are largely lipoidal in character.
The rate and extent of absorption decreased with the
increasing polarity of molecules.
Partition coefficient (distribution coefficient): the ratio in
which a solute distributes itself between the two phases
of two immiscible liquids that are in contact with each
other (mostly n-octanol/water).
Partition coefficient can be modified via prodrug approach
Ionization Constant
The unionized species are more lipid-soluble and hence
more readily absorbed.
The GI absorption of weakly acidic or basic drugs is
related to the fraction of unionized drug in solution.
Factors affecting absorption:
- pH at the site of absorption
- Ionization constant
- Lipid solubility of unionized species
“pH-partition theory”
Henderson-Hasselbalch equation
For acids:
pH = pKa + log [ionized form]/[unionized form]
For bases:
pH = pKa + log [unionized form]/[ionized form]
Determination of Ionization Constant
1. Potentiometric pH-Titration
2. pH-Spectrophotometry Method
3. pH-Solubility Analysis
Solid state properties
Organoleptic (color, particle size, flow)
Particle shape and size specific surface area
Polymorphism
Melting point
Hygroscopicity
Compressibility
Density
Particle size & Surface area
Microscopy
Shieving
Particle size analyzer (light / laser / electrical conductivity)
Surface area based on BET theory of absorpsion
Polymorphism by XRD
Stability
Solid state stability
Solution state stability
Compatibility studies : stability in presence of excipients
Solid state Stability
In general solid state reaction more slower and more
difficult to interpret compared to solution.
Use stressed condition :
High temperature
Use 40, 50, 60oC. Use 5oC as control
Stable in 60oC for 30 days
High humidity
Use desiccator with various salts
Oxidative stability
Use chamber with Oxygen (usually 40% )
Photolytic stability
Use ICH guideline
Solution State Stability
Identification condition necessary to form stable solution
Consider :
Effect of pH
Effect of temperature
Effect of solvents
Effect of light
Effect of Oxygen
Use Arrhenius law
Compatibility Studies
Compatibility studies of new drug should consider two or
more excipients of the same class.
Mixture in specific ratio, use 5 % water if needed.
Three techniques commonly use :
TLC
DTA/DSC
Diffuse reflectance spectroscopy
