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Pre Formulation

Preformulation testing involves investigating a drug's physical and chemical properties alone and when combined with excipients. This helps formulators develop stable, bioavailable dosage forms. Key tests include determining solubility, dissolution behavior, partition coefficient, ionization constant, and solid state properties. Solubility and dissolution are especially important to ensure the drug is in solution and can be absorbed. These techniques provide critical information to guide formulation selection and development.

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52 views25 pages

Pre Formulation

Preformulation testing involves investigating a drug's physical and chemical properties alone and when combined with excipients. This helps formulators develop stable, bioavailable dosage forms. Key tests include determining solubility, dissolution behavior, partition coefficient, ionization constant, and solid state properties. Solubility and dissolution are especially important to ensure the drug is in solution and can be absorbed. These techniques provide critical information to guide formulation selection and development.

Uploaded by

Diana
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© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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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

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