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Transcript
INTRODUCTION
Preformulation study is the foundation of
developing robust formulation.
 It can be defined as a phase of research &
development process for an investigation of
physical and chemical properties of new drug
substance alone or in combination with other
excepients in order to development of safe and
effective dosage form.

OBJECTIVE
•
The overall objective of preformulation testing is to
generate information useful to the formulator:
•
To formulate stable and effective dosage form
To increased drug stability
To improve drug bioavailability
Reduce drug excipient incompatibility
•
•
•
APPLICATIONS…
Preformulation studies begins or shall be updated
 immediately after the synthesis and initial toxicity
screening of a new drug.
 when a newly synthesized drug shows
pharmacological evidence that requires further
evaluation in man
 when formulation and dosage form changes are
required
 when solid form changes of DS are required
Protocol for preformulation studies
OUTLINE OF PRINCIPAL AREAS OF
PREFORMULATION RESEARCH
Principal areas
Physico-chemical
properties
Organoleptic
properties
Particle size
and shape
Purity
Surface
area
Stability analysis
Bulk
characterisation
Crystallinity and
polimorphism
Hygroscopicity
Particle size
characterization
Bulk density
Solubility analysis
Ionization constant pka
PH solubility profile
Common ion
effect ksp
Thermal effects
Partition co-efficient
solubilization
Powder flow
properties
Solution stability
Dissolution
Solid state
stability
Bulk stability
Compatibilty
PREFORMULATION PARAMETERS
PREFORMULATION PARAMETERS
METHOD USED
Organoleptic Properties
Colour and Odour Determination
Crystallinity & Polymorphyism
X-ray Diffraction Studies (Lachman, 1991)
Fine Particle Characterization
Microscopic Method (Lachman, 1991)
Solubility Profile
Equilibrium Solubility Method (I.P. 2007)
Solubilization
(Lachman, 1991)
Analytical Method Development
UV Spectroscopic Method, HPLC Method
Ionization Constant, pKa
Determination of Spectral Shifts by UV Spectroscopy
(Lachman, 1991)
Partition Coefficient
Using octanol / water,(Lachman, 1991)
Bulk Density
Tapping Method (Lachman, 1991)
Powder Flow Properties
% Compressibility Determination, Angle of Repose (Lachman, 1991)
Compatibility With Excipients
DSC (Stulzer and Rodriques et al., 2008)
Stability
Solution and Solid State Stability (PCT/US03/35012)
Stability Indicating Method Development
Forced Degradation Studies (Rao et al., 2009)
7
ORGANOLEPTIC PROPRTIES
Colour:-Stability problems, improve appearance
by including dye in body or coating
 Taste:-palatability, flavours, and excepient may
be added.
 Odour:-degradation products, eg. Aspirin stable
form of drug to be used , flavours and
excepients may be used.

SUGGESTED TERMINOLOGY TO DESCRIBE
ORGANOLEPTIC PROPERTIES OF
PHARMACEUTICAL POWDERS
 Colour
Odour
Taste
Off-white
 Cream yellow
 Tan
 Shiny



Pungent
sulfurous
fruity
Aromatic
odourless
acidic
bitter
bland
intense
sweet
Tasteless
PURITY
Purity studies are essential for further studies
to be carried out safely.
 Impurities may make a compound toxic or
render it unstable.
 TLC,HPLC,GC and Paper chromatography used.
 HPLC-Impurity Index(II), Homogeneity index(HI).
 DTA, gravimetric analysis and melting point by
hot stage microscopy are other techniques.











Impurity index(II):defined as the ratio of all responses (peak
areas) due to components other than the main one to the
total area response.
Homogeneity index(HI): defined as the ratio of
response(peak area) due to main component to the total
response.
Eg.: main component –retention time: 4.39min
-area response: 4620
Impurities – 7 minor peaks ;area response: 251
- total area response : 251+4620
Impurity index : = 251/(4620+ 251)
= .0515
Homogeneity index : = 1 - .0515
= .9485
OTHER TOOLS IN ASSESMENT OF IMPURITY
Differential thermal analysis(DTA)
 Thermogravimetric analysis(TGA)
 Differential scanning calorimetry(DSC)
 Powder X-Ray Diffraction(PXRD)

PARTICLE SIZE AND SHAPE
Various chemical and physical properties of drug
substances are affected by their particle size
distribution and shapes.
 The effect is not only on physical properties as well
as biopharmaceutical behavior.
 It also influence the flow and the mixing efficacy
of powders and granules.
 Fine materials are relatively more open to attack
from atmospheric oxygen, humidity, than that of
coarse material.

PARTICLE SIZE DETERMINATION
Microscopy. Eg. Light microscope, electron
microscope.
 Anderson Pipette
 Sieving method
 Instruments based on light blockage(HIAC) and
blockage of electrical conductivity path(coulter
counter are available).

COMMON TECHNIQUES FOR MEASURING FINE
PARTICLES OF VARIOUS SIZES
Technique
Microscopic
Sieve
Sedimentation
Elutriation
Centrifugal
Permeability
Light scattering
Particle size (mm)
1 - 100
> 50
>1
1 - 50
< 50
>1
0.5 - 50
SHAPE DETERMINATION…..

Microscopy should be caarried out to determine the ratio of longest to
shortest dimension. It is a shape factor.
SHAPE FACTOR

Commonly used shape factor converts volume of particle ‘v’to its
volumetric mean diameter ‘av’
V=αv.av³

Shape factor may be defined which converts the surface area ‘s’of
a particle to its surface mean diameter ‘as’
S=αs.as²
Fractal Dimensions are carried out by imaging techniques.

In(N)=-nIn(g)+q
where:N=no.of squares.
g=length of grid size.
n&q are constants.
SURFACE AREA DETERMINATION
It is determined based on Brunaver Emitter
Teller (BET)theory of adsorption.
 Most substances adsorb mono molecular layer
of gas (Nitrogen) and temperature.
 Air adsorption and permeability methods.

CRYSTALLINITY AND POLYMORPHISM
Crystal habit and internal structure of a drug can affect bulk and physiochemical
properties

HABBIT: Outer appearance
of crystal.

Internal structure
Crystalline
Amorphous
CHARACTERIZATION OF SOLID FORMS
Solid forms
Crystalline
Amorphous

Repeated spacing of atoms
in three dimentional structure
Randomly placed atoms
or molecules

Have less energy
Need less energy to break
crystalline form
So solubility is less
Have high energy
Need less energy to break


solubility is high
ANALYTICAL METHODS FOR CHARACTERISATION
OF SOLID FORMS
Method
Microscopy
 Fusion methods
(hot stage microscopy)
 Infrared spectroscopy
 X-ray powder diffraction
 Scanning electron microscopy
 Thermogravimetric analysis
 Dissolution/Solubility analysis

Material reqired
per sample
1mg
1mg
2-20mg
500mg
2mg
10mg
mg to gm
MICROSCOPY




All substances are transparent examined under microscope –
are either isotropic or anisotropic
Isotropic substances do not transmit the light – appears black
– and have single refractive index. E.g. Sodium Chloride
Anisotropic substances – more than one refractive index –
appear bright and brilliant color – uniaxial and biaxial
Color depends upon – thickness of crystal and diff. in refractive
indices.
THERMAL ANALYSIS





Differential Scanning Colorimetry (DSC) and Differential
Thermal Analysis (DTH) measures the heat loss or heat gain resulting from physical or chemical changes.
Two types of processes
1) Endothermic : like fusion, boiling, sublimation, vaporization,
desolvation
Exothermic : like crystallization ,degradation
Quantitative measurement of these process have many
application in preformulation study including Purity,
Polymorphism, solvation, degradation
X-RAY DIFFRACTION

Crystalline materials gives characteristics pattern – by peaks in
certain position & varying intensities

different Polymorphs – different x-ray diffraction pattern due to
crystal lattice.

Single crystal x-ray analysis provides precise identification &
description of a crystalline substances.
POLYMORPHISM
- substances can exist in more than one crystalline form
 Polymorphic forms – diff. physical-chemical
properties (incl. melting pt. & solubility)
Enatiotropic
 Polymorphs:
Monotropic
 Determination method:
Thermodyanamically-van,t Hoff plot(solubility vs
temperature)
Directly – by microscopic determination
HYGROSCOPICITY
Many substances,particularly water soluble
salt form have a tendency to absorb
atmospheric pressure.
 Change in moisture level can influence
chemical stability , flowability, and
compactibility.
 It can be monitored by Karl Fischer
titration,TGA

POWDER
FLOW
 The pharmaceutical powders are classified as --FREE FLOWING
COHESIVE OR NON FREE FLOWING
 The powder flow are affected by the changes in –
Density
Particle Size
Shape
Free flowing drug may become cohesive and
Electrostatic Charge
necessitates an entirely new formulation strategy
Adsorbed Moisture
Several rates of flow (g/sec) determinations at each of variety of orifice
sizes (1/8 to ½ inches) should be made.
Greater the standard deviation between multiple flow rate measurements
greater is the weight variation in products produced from the powder.
It was found that the dependence of flow rate (w) on the true particle
density(ρ),gravity(g), orifice diameter(D) by
D= A (4w/60πρ√g)^1/n
A and n are constants dependent upon material and particle size
Other measures of free flowing powders is COMPRESSIBILITY.
%compressibility=(ρ1-ρ0)/ρ1
Angle of repose is not much useful as lack of precision
Cohesive Powders are characterized by TENSILE TESTING and
evaluated in a SHEAR CELL
SOLUBILITY




Solubility > 1 % w/v
=> no dissolution-related absorption problem
Highly insoluble drug administered in small doses
may exhibit good absorption
Unstable drug in highly acidic environment of
stomach, high solubility and consequent rapid
dissolution could result in a decreased
bioavailability
The solubility of every new drug must be
determined as a function of pH over the
physiological pH range of 1 - 8
DETERMINATION OF SOLUBILITY
Semiquantitative determination:
Solvent
(fixed volume)
Examine
visually
Vigorously
shaking
Adding solute in small
incremental amounts
Undissolved
solute particles ?
No
Yes
“LAW OF MASS ACTION”
Estimated solubility
Total amount
added up
Accurately Quantitative determination:
Excess drug powder
150 mg/ml (15 %)
+ solvent
Ampul/vial
(2-5 ml)
Shaking at constant
temperature
(25 or 37 oC)
2 - 8 oC ?
The first few ml’s of the filtrates should be
discarded due to possible filter adsorption
Same
concentration ?
48 hr
Determine the drug
concentration in the
filtrate
Membrane filter
0.45 mm
Determine the drug
concentration in the
filtrate
Membrane filter
0.45 mm
72 hr
? hr
Solubility
Determine the drug
concentration in the
filtrate
Membrane filter
0.45 mm
 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
UNIQUE PROBLEMS IN SOLUBILITY DETERMINATION
OF POORLY SOLUBLE COMPOUNDS
Solubility could be over estimated due to the
presence of soluble impurities
 Saturation solubility is not reached in a reasonable
length of time unless the amount of solid used is
greatly in excess of that needed to saturation
 Many compounds in solution degrade, thus
making an accurate determination of solubility
difficult
 Difficulty is also encountered in the determination
of solubility of metastable forms that transform to
more stable forms when exposed to solvents

pH-Solubility Profile
Stir in beaker
with distilled
water
Excess drug
powder
Determine the
concentration
of drug in
the filtrate
SOLUBILITY
Filter
Measure
pH of
suspension
pH
Continuous
stirring of
suspension
Stirring
Add
acid/base

Poorly-soluble weakly-acidic drugs:
pH

=
pKa + log [(St - So)/So]
(2)
Poorly-soluble weakly-basic drugs:
pH
=
pKa + log [So/(St - So)]
(3)
where
So = solubility of unionized free acid or base
St = total solubility (unionized + ionized)
 The process of solubilization involves the breaking of
inter-ionic or intermolecular bonds in the solute, the
separation of the molecules of the solvent to provide
space in the solvent for the solute, interaction between
the solvent and the solute molecule or ion.
Step 1: Holes opens in the solvent
Step2: Molecules of the solid breaks away from the
bulk
Step 3: The free solid molecule is intergraded into
the hole in the solvent
37
SOLUBILIZATION CAN BE ENHANCED BY:
Use more soluble metastable polymorph
Use of complexation (eg.Ribloflavin-xanthinescomplex)
 Use of high-energy co-precipitates that are mixtures of
solid solutions and solid dispersions (eg. Griseofulvin
in PEG 4000, 6000, and 20,000)
in PEG 4000 and 20,000 -> supersaturated solutions
in PEG 6000 -> bioavailability in human twice >
micronized drug
 Use of suitable surfactant

 Partition Coefficient
 It is the ratio of unionized drug distributed
between organic and aqueous phase at equilibrium.
P o/w = ( C oil / C water )equilibrium
•It ratio of unionised drug in organic &
aq.Phase
•It measure lipophilicity
•Major role in drug transport
•Analytical separation
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
Dissolution
kd << ka => “dissolution rate-limited”
D
kd
Xg
Dissolution
ka
Absorption
Absorption site
(gi-tract)
C, Vc
Xc
ke
Central compartment
(blood circulation)
Diagram showing dissolution and absorption of
solid dosage form into blood circulation
PADDLE TYPE
BASKET TYPE
2 types of systems to maintain uniform hydrodynamic
conditions
1.STATIC DISC DISSOLUTION APPARATUS
2.ROTATING DISC APPARATUS
INTRINSIC DISSOLUTION
FILM THEORY
The dissolution of a solid in its own solution is
adequately described by Noyes-Nernst’s “Film Theory”
-dW =
DAK (Cs - C)
(9)
dt
h
where
dW/dt = dissolution rate
A = surface area of the dissolving solid
D = diffusion coefficient
K = partition coefficient
h = aqueous diffusion layer
Cs = solubility of solute
C = solute concentration in the bulk medium





Intrinsic dissolution rate (mg/cm2/min) is characteristics
of each solid compound in a given solvent under fixed
hydrodynamic conditions
Intrinsic dissolution rate helps in predicting if absorption
would be dissolution rate-limited
> 1 mg/cm2/min --> not likely to present dissolution ratelimited absorption problems
< 0.1 mg/cm2/min --> usually exhibit dissolution ratelimited absorption
0.1 - 1.0 mg/cm2/min --> more information is needed
before making any prediction
Amount Dissolved (mg in 500 ml)
Effect of particle size of phenacetin on dissolution
rate of the drug from granules
0.11 - 0.15 mm
0.15 - 0.21 mm
0.21 - 0.30 mm
0.50 - 0.71 mm
SOLID STATE STABILITY



for identification of stable storage condition
also for identification of compatibale excipient for a formulation
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
PHOTOLYTIC STABILITY
Many drugs fade or dropped on exposure light.
 Exposure of drug 400 and 900 foot-candles of
illumination for 4 and 2 week periods
respectively is adequate to provide some idea
of photosensitivity.
 Resulting data may be useful in determining if
an amber colored container is required for
formulation .

STABILITY TO OXIDATION



Drug’s sensitivity to oxidation can be examined by exposing it
to atmosphere of high oxygen tension. Usually a 40% oxygen
atmosphere allows for rapid evaluation
Samples are kept in desiccators equipped with three-way
stop cocks, which are alternatively evacuated and flooded
with desired atmosphere.
The process is repeated 3 or 4 times to ensure 100%
desired atmosphere. Results may be useful in predicting if
an antioxidant is required in the formulation or if the final
product should be packaged under inert atmospheric
conditions.
SOLUTION PHASE STABILITY
As compared with the dry form, the degradation is
much rapid in solution form. It is important
ascertain that the drug doesn’t degrade when
exposed to GI fluid.
 The pH based stability study, using different
stimulator GI condition can be designed.
 A poor solution stability of drug may urge the
formulator to choose a less soluble salt form,
provided the bioavailability is not compromised

COMPATIBILITY STUDIES



The knowledge of drug excipients interaction is useful for the
formulation to select appropriate excipients.
The described preformulation screening of drug excipients
interaction requires only 5mg of drug in a 50% mixture with
the excipients to maximize the likelihood of obscuring an
interaction .
Mixtures should be examined under nitrogen to ultimate
oxidation and paralytic effect at a standard heating rate on
DSC, over a temperature range, which will encompass any
thermal changes due to both the drug and appearance or
disappearance one or more peaks in themogrames of drug
excipient mixtures are considered of indication of interaction.
Flow diagram to identify excepient
compatibility with drug
No
interaction
Drug
DSC
50%Mixture of
Drug &
excepient
Excepient
recommend
ed
Interaction
Excepient
HPLC
Or TLC
Alternative excepient
suggested
Yes
Drug
breakdown
No
FORMULATION RECOMMENDATION
Upon completion of preformulation evaluation of
a new drug candidate, it recommended that a
comprehensive report be prepared highlighting
problems associated with this molecule
 These Reports re extremely important in
preparing regulatory documents

CONCLUSION





Preformulation studies have a significant part to play in
anticipating formulation problems and identifying logical path
in both liquid and solid dosage form technology.
By comparing the physicochemical properties of each drug
candidate with in a therapeutic group, the preformulation
scientist can assist:
the synthetic chemist to identify the optimum molecule,
provide the biologist with suitable vehicles to elicit
pharmacological response and
advise the bulk chemist about the selection and production of
the best salt with appropriate particle size and morphology for
subsequent processing.