PREFORMULATION
STUDIES:
PHYSICOCHEMICAL
CHARACTERIZATION OF
NEW DRUG MOLECULES
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SOLUBILIZATION
Solubilization is defined as the spontaneous
passage of poorly water soluble solute
molecules into an aqueous solution of a soap
or detergent in which a thermodynamically
stable solution in formed
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It is the process by which apparent solubility of an otherwise
sparingly soluble substance is increased by the presence of surfactant
micelles .
MICELLES: -
The mechanism involves the property of surface active agents
to form colloidal aggregates known as micelles .
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When surfactants are added to the liquid at low concentration they
tend to orient at the air-liquid interface .
On further addition of surfactant the interface becomes completely
occupied and excess molecules are forced into the bulk of liquid.
At very high concentration surfactant molecules in the bulk of liquid
begin to form micelles and this concentration is know as CRITICAL
MICELLE CONCENTRATION (CMC)
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General Method of Increasing
the Solubility
Addition of co-solvent
pH change method
Reduction of particle size
Temperature change method
Addition of Surfactant
Dielectrical Constant
Complexation
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Partition Coefficient
A measurement of drug lipophilicity i,e the ability to cross the cell
membrane p
o/a
c o rg a n ic
c aque ous
Distribution coefficient ( pH pKa )
log D log P log (1 10 )
For acids: 10 10
10
pKa pH
For bases : log 10
D log P l o g (1 1 0
10
)
10
The octanol-water system is widely accepted to explain these phenomenon.
Buccal membrane : butanol-pentanol system
Blood-Brain barrier: chloroform-cyclohexane
Determined by SHAKE FLASK METHOD
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SHAKE FLASK METHOD
Drug is shaken between octanol and water.
Aliquot is taken and analyzed for drug content
RULE OF FIVE : for drug permeates through passive diffusion
1. Log P not greater than 5
2. Molecular weight >500
3. There are more than 5 hydrogen bond donors (number of NH + OH)
4. There are more than 10 hydrogen bond acceptors (number of hydrogen +
oxygen )
5. Molar refractivity should be between 40-130
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Rate Rate
constant of constant of
absorption
K
dissolution
d K
Solid drug in Drug in solution a Drug systemic
the G.I in the G.I fluid circulation
Fluid
When Kd << Ka ,dissolution is significantly slower and the absorption is
described as dissolution-rate limited.
The dissolution rate of drug substance in which surface area is constant
during dissolution is described by Noyes-Whitney equation.
dC/dt=dissolution rate
dC h=diffusion layer thickness
DA
dt hV (C S C ) C=solute concentration in bulk solution
V=volume of the dissolution medium
D=diffusion coefficient
A=surface area of the dissolving solid
Cs=solute concentration in the diffusion
layer
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Constant surface area is obtained by compressing powder into a disc of
known area with a die and punch apparatus.
Hydrodynamic conditions are maintained with Static-disc dissolution
apparatus and Rotating disc apparatus
fig : static dissolution apparatus and rotating disc apparatus
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STABILITY ANALYSIS
1. Solution stability
2. Solid state stability
SOLUTION STABILITY
The decomposition of drug occurs through hydrolysis,
oxidation,
photolysis.
Hydrolysis (anaesthetics, vitamins etc )
a) Ester hydrolysis
R’-COOR + H+ + OH- RCOOH + ROH
ester acid
b) Amide hydrolysis alcohol
RCONHR’ + H+ + OH- RCOOH + H2N-R’
amide acid
amine
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Oxidation
used to evaluate the stability of pharmaceutical preparations
Eg : steroids, vitamins, antibiotics, epinephrine
Autoxidation
Materials + molecular oxygen
homolytic fission
Free radicals are produced.
Oxygen sensitivity is measured
by bubbling air through the
compound or
adding hydrogen peroxide.
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Photolysis
pharmaceutical compounds
exposure to uv light
absorbs the radiant
energy
undergoes degradative reactions
SOLID-STATE STABILITY
1o objective: identification of stable storage conditions.
identification of compatible excipients.
Solid-state stability depends on the temperature , light, humidity,
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Solid-State Stability profile of a new
compound
Samples are placed in open vials and are exposed directly to a variety
of temperatures, humidities, and light intensities for up to 12 weeks.
Vials exposed to oxygen and nitrogen to study the surface oxidation and
chemical stability , polymorphic changes and discolouration.
Stability data obtained at various humidities may be linearized with
respect to moisture using the following apparent decay rate constant (KH )
k H
[gpl].k 0
gpl= concentration of water in atmosphere in units of grams of water per liter
of dry air .
ko = decay rate constant at zero relative humidity
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Mole fraction of the solid that has liquefied (Fm ) is
directly proportional to its decay rate.
H 1 1
ln k app ln F m
R
fus
[T T ]
m
H fus -molar heat of fusion
Tm - absolute
melting point T
-
absolute temperature R
- gas constant
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Drug- excipient compatibility
Compatibility test play a very important role in the preformulation
studies of oral dosage forms
An incompatibility in the dosage form can result in any of the following
changes:
Changes in organoleptic properties
Changes in dissolution performance
Physical form conversion
An decrease in potency
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METHOD
Drug + Excipients
(1:1)
Powder samples dispersed into glass ampoules
1 ampoule 1 ampoule (sample
+ water)
stored at a particular temperature (500 C) and analysed
In emulsions the studies include measuring the critical micelle
concentration of the formulations
For oral use preparations compatibility of the ingredients
(ethanol, glycerine, syrup, sucrose, buffers and preservatives)
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Stability Studies
During preformulation phase
• Solid-state of the drug alone
• Solution phase
• with the expected excipients
Drug and Drug Product Stability
Evaluation of:
• physical and chemical stability of pure drug substances -
important for preformulation.
Drug Stability : Mechanisms of Degradation
• Chemically drug substances with different
susceptibilities toward chemical instability
Destructive processess
• Hydrolysis
More susceptible to esters, amides, lactones.
• Oxidation
More susceptible to aldehydes, phenols, alcohols.
Drug and Drug Product Stability
Five types:
Chemical Stability
important for selecting:
*storage conditions (temp., light, humidity)
*proper container for dispensing
*anticipating interactions when mixing drugs & dosage
forms
* must know reaction order & rate
• Physical - original physical properties, appearance,
palatability, uniformity, dissolution and suspendability are
retained.
• Microbiologic –sterility/resistance to microbial growth
• Therapeutic –therapeutic effect remains unchanged
• Toxicologic - no significant increase in toxicity occurs.
BCS Classification
• Class I: High solubility, high permeability
(Metoprolol)
• Class II: Low solubility, High permeability
(Aceclofenac)
• Class III: High solubility, Low permeability
(Captopril)
• Class IV: Low solubility, low permeability
(Chlorothiazide)
