Description
PREFORMULATION STUDIES
By
Nitin Nama
Assistant Professor
Career Point School of Pharmacy
Career Point University, Kota
CONTENTS
Introduction
Major area of preformulation research
Organoleptic characters
Bulk characterization
Solubility characters
Stability characters
Conclusion
PREFORMULATION
It is defined as the phase of research and development in
which preformulation studies characterize physical and
chemical properties of a drug molecule in order to develop safe,
effective and stable dosage form.
OBJECTIVES
To establish the physico-chemical parameters of a new
drug entity.
To determine its kinetics and stability.
To establish its compatibility with common excipients.
It provides insights into how drug products should be
processed and stored to ensure their quality.
Major Area of Preformulation
Research
ORGANOLEPTIC CHARACTERS
BULK CHARACTERS
Crystallinity and polymorphism
Hygroscopicity
Fine particle characterization
Powder flow properties
SOLUBILITY ANALYSIS
ionization constant-PKa
pH solubility profile
Common ion effect-Ksp
Thermal effects
Solubilization
Partition co-efficient
Dissolution
STABILITY ANALYSIS
Stability in toxicology formulations
Solution stability
pH rate profile
Solid state stability
Bulk stability
Compatibility
ORGANOLEPTIC CHARACTERS
Colour,odour, taste of the new drug must be recorded
COLOUR ODOUR TASTE
Off-white pungent Acidic
Cream yellow sulphurous Bitter
tan Fruity Bland
shiny Aromatic Intense
Odourless Sweet
Tasteless
BULK CHARACTERIZATION
Crystallinity
Crystal habit & internal structure of drug can affect bulk&
physicochemical property of molecule.
Crystal habit is description of outer appearance of crystal.
Internal structure is molecular arrangement within the solid.
Change with internal structure usually alters crystal habit.
•Eg. Conversion of sodium salt to its free acid form produce both
change in internal structure & crystal habit.
Different shapes of crystals
Different shapes of crystals
Depending on internal structure compounds is classified as
Crystalline
Amorphous
Crystalline compounds are characterized by repetitious spacing of constituent
atom or molecule in three dimensional array.
In amorphous form atom or molecule are randomly placed.
Solubility & dissolution rate are greater for amorphous form than crystalline, as
amorphous form has higher thermodynamic energy.
Eg. Amorphous form of Novobiocin is well absorbed whereas
crystalline form results in poor absorption.
Polymorphism
It is the ability of the compound to crystallize as more than one
distinct crystalline species with different internal lattice.
Different crystalline forms are called polymorphs.
Polymorphs are of 2 types
• Enatiotropic
• Monotropic
The polymorph which can be changed from one form into another
by varying temp or pressure is called as Enantiotropic polymorph.
Eg. Sulphur.
Polymorphism
One polymorph which is unstable at all temp. & pressure is called as
Monotropic polymorph. Eg. Glyceryl stearate.
Polymorphs differ from each other with respect to their physical
property such as
• Solubility
• Melting point
• Density
• Hardness
• Compression characteristic
Eg. Chloromphenicol exist in A,B & C forms, of these B form is more
stable & most preferable.
ANALYTICAL METHODS FOR THE
CHARACTERIZATION OF SOLID FORMS
Microscopy
Hot stage microscopy
Thermal analysis
X-ray diffraction
Infrared (IR) spectroscopy
Proton magnetic resonance (PMR)
Nuclear magnetic resonance (NMR)
Scanning electron microscopy (SEM)
Microscopy
Material with more than one refractive index are anisotropic &
appear bright with brilliant colors against black polarized
background.
The color intensity depends upon crystal thickness.
Isotropic material have single refractive index and this substance
do not transmit light with crossed polarizing filter and appears
black.
Microscopy
Advantage :
By this method, we can study crystal morphology & difference
between polymorphic form.
Disadvantage :
This require a well trained optical crystallographer, as there are
many possible crystal habit & their appearance at different
orientation.
Hot stage microscopy
The polarizing microscope fitted with hot stage is useful for
investigating polymorphism, melting point & transition temp.
Disadvantage :
In this technique, the molecules can degrade during the melting
process.
Thermal analysis
Differential scanning calorimetry (DSC) & Differential thermal analysis
are (DTA) are particularly useful in the investigation of polymorphism.
It measures the heat loss or gain resulting from physical or chemical
changes within a sample as a function of temp.
For characterizing crystal forms , the heat of fusion can be obtained from
the area under DSC- curve for melting endotherms.
Similarly, heat of transition from one polymorph to another may be
calculated.
A sharp symmetric melting endotherm can indicate relative purity of
molecule.
A broad asymmetric curve indicates presence of impurities.
X-ray diffraction
Working :
When beam of nonhomogenous X-ray is allow to pass through the crystal, X-ray
beam is diffracted & it is recorded by means of photographic plate.
Diffraction is due to crystal which acts as 3 dimensional diffraction grating toward
X-ray.
Random orientation of crystal lattice in the powder causes the X-ray
to scatter in a reproducible pattern of peak intensities.
The diffraction pattern is characteristic of a specific crystalline
lattice for a given compound.
An amorphous form does not produce a pattern mixture of different
crystalline forms.
Single – Crystal x-ray provide the most complete information
about the solid state.
HYGROSCOPICITY
Many drug substances, particularly water –soluble salt forms, have a
tendency to adsorb atmospheric moisture.
Adsorption and moisture content depend upon the atmospheric humidity,
temperature, surface area, exposure and the mechanism of moisture uptake.
The degree of Hygroscopicity is classified into four classes:
Slightly hygroscopic: increase in weight is ≥ 0.2% w/w and < 2% w/w
Hygroscopic : increase in weight is ≥ 0.2 % w/w and < 15 % w/w
Very hygroscopic : increase in weight is ≥ 15% w/w
Deliquescent : sufficient water is adsorbed to form a solution
Hygroscopicity is tested by:
Samples are exposed to the moisture
exposed to controlled relative humidity environments
moisture uptake is monitored at different time points
Analytical methods which is used are :
Gravimetry
Karl Fischer Titration
Gas chromatography
PARTICLE SIZE
Particle size is characterized using these terms :
Very coarse, Coarse, Moderately coarse, Fine,Very fine .
Particle size can influence variety of important factors :
– Dissolution rate
– Suspendability
– Uniform distribution
– Penetrability
– Lack of grittiness
Methods to Determine
Particle Size
Sieving (5µ-150µ)
Microscopy(0.2µ-100µ)
Sedimentation rate method(1µ-200µ)
Light energy diffraction(0.5µ-500µ)
Laser holography(1.4µ-100µ)
POWDER FLOW PROPERTIES
Powder flow properties can be affected by change in particle size,
shape & density.
The flow properties depends upon following-
Force of friction.
Cohesion between one particle to another.
Fine particle posses poor flow by filling void spaces between
larger particles causing packing & densification of particles.
By using glident we can alter the flow properties.
Eg. Talc
Determination of Powder Flow
Properties
By determining Angle of Repose. Angle of Type of Flow
Repose
A greater angle of repose indicate ( In degree)
poor flow.
<25 Excellent
It should be less than 30°. & can be
determined by following equation.
25-30 Good
tan θ = h/r.
where, θ = angle of repose. 30-40 Passable
h=height of pile.
>40 Very poor
r= radius.
Methods to determine angle
of repose
Static angle of
repose
§ Fixed-funnel
method
§ Fixed-cone method
Kinetic or dynamic
method
§ Rotating cylinder
method
§ Tilting box method
Determination of Powder Flow
Properties
Measurement of free flowing powder by compressibility.
Also known as Carr’s index.
CARR’S INDEX(%) =(TAPPED DENSITY – POURED DENSITY) 100
X
TAPPED DENSITY
Itis simple, fast & popular method of predicting
powder flow characteristics.
Determination of Powder
Flow Properties
Carr’s Index Type of flow
5-15 Excellent
12-16 Good
18-21 Fair To Passable
23-35 Poor
33-38 Very Poor
>40 Extremely Poor
SOLUBILITY STUDIES
Solution phase equilibrium with solid phase at a stated
temperature and pressure .
Determines amount of drug dissolved, amount of drug
available for absorption.
Solubility reduction is carried out in certain conditions:
Enhancement of chemical stability.
taste masking products.
Production of sustained release products.
Descriptive Term Parts of solvent required
for 1 part of solute
Very Soluble Less than 1
Freely Soluble From 1 to 10
Soluble From 10 to 30
Sparingly Soluble From 30 to 100
Slightly Soluble From 100 to 1000
Very Slightly Soluble From 1000 to 10,000
Practically insoluble 10,000 and Over
The equilibrium solubility is based on the phase-solubility
technique proposed by Higuchi-Connors .
Method:
Drug dispersed in solvent in a closed container
agitated at a constant temperature using shakers
samples of the slurry are withdrawn as a function of time
clarified by centrifugation and assayed by HPLC, UV, GC etc
General Method of Increasing the Solubility:
Addition of co-solvent
pH change method
Reduction of particle size
Temperature change method
Hydotrophy
Addition of Surfactant
Dielectrical Constant
Complexation
pKa determination
pKa is the dissociation constant of a drug.
The un-ionized drug is lipid soluble thus permeates through lipid membrane.
The ionized substance is lipid insoluble therefore permeation is slow.
Degree of ionization depends on pH.
Henderson-Hasselbalch equation
For basic compounds: [ionized]
pH pKa
[un
ionized]
[un
pH pKa
For acidic compounds: ionized]
[ionized]
( pH pKa )
%ionized 10
( pH pKa )
1 10
Determined by uv spectroscopy, potentiometric titration, titrimetric method.
Partition Coefficient
A measurement of drug lipophilicity i,e the ability to cross the cell
membrane
p
c o/a
o rg a n ic
Distribution coefficient c aque ou
( pH pKa )
For acids: log D log P log 1 10
(s )
10 10 10
pKa pH
For bases : l o g 1 0 D l o g (1 1 0
log 10
P )
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
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 is 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
DISSOLUTION
Rate constant Rate constant
of of absorption
Kdissolution
d Drug in solution
K a
Drug systemic
Solid drug in
the G.I Fluid in the G.I fluid circulation
When Kd << Ka ,dissolution is significantly slower and the absorption is described
as dissolution-rate limited.
dC/dt=dissolution rate
The dissolution rate of drug
h=diffusion layer thickness
Substance in which surface area is C=solute concentration in bulk solution
Constant during dissolution is V=volume of the dissolution medium
described by Noyes-Whitney equation. D=diffusion coefficient
A=surface area of the dissolving solid
dC DA S Cs=solute conc. in the diffusion layer
dt
=
hV C =C
( )
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
STABILITY ANALYSIS
1. Solution stability
2. Solid state stability
SOLUTION STABILITY
The decomposition of drug occurs through hydrolysis, oxidation, photolysis.
Hydrolysis (anaesthetics, vitamins etc )
Ester hydrolysis
R’-COOR + H+ + OH- RCOOH + ROH
ester acid alcohol
Amide hydrolysis
RCONHR’ + H+ + OH- RCOOH + H2N-R’
amide acid amine
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.
Photolysis :
pharmaceutical compounds
exposure to uv light
absorbs the radiant energy
undergoes degradative reactions
SOLID-STATE STABILITY
Objective:
identification of stable storage conditions.
identification of compatible excipients.
Solid-state stability depends on the temperature, light,
humidity, polymorphic changes, oxidation.
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= Conc. of water in atmosphere in units of grams of water per liter of dry air .
ko = Decay rate constant at zero relative humidity
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
CONCLUSION
Preformulation studies on a new drug molecule provide useful
information for subsequent formulation of a physicochemically
stable and biopharmaceutically suitable dosage form.
Preformulation work is the foundation of developing efficacious
and economical formulations.
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