Preliminary evaluation and molecular optimization, Bulk characterization , material crystalinity, polymorphism. Thermal properties, hygroscopicity. Particle characterization, bulk density, powder flow properties, solubility analysis, pKa determination, pH, solubility proficle, effect of temperature, solubilization, partition coefficient, dissolution, stability analysis, solution stability and solid state stability.

1. Md. Imran Nur Manik
Lecturer
Department of Pharmacy
Primeasia University

2. Introduction to Preformulation
Preformulation is the branch of Pharmaceutical science
that utilizes biopharmaceutical principles in the
determination of physicochemical properties of the drug
substance.
Prior to the development of any dosage form new drug ,
it is essential that certain fundamental physical &
chemical properties of drug powder are determined .
This information may dictate many of subsequent event
& approaches in formulation development.
This first learning phase is called as preformulation.

3. INTRODUCTION
DEFINITION:-
Investigation of physico-chemical properties of
the new drug compound that could affect drug
performance and development of an
efficacious dosage form”.
Requires to maintain Stability,Efficacy,
Quantity,Bioavailability and Standards of Drug.

4. Objective of the Preformulation
Considerationis
Objectives of the Preformulation Considerations are
To provide and understand
The degradation process,
Any adverse conditions relevant to the drug,
Bioavailability,
Pharmacokinetics and formulation of similar
compound and
Toxicity.

5. Usefulness of Preformulation
Considerationis
Preformulation influences aids in the
(a) Selection of the drug candidate itself,
(b) Selection of formulation components,
(c) API& drug product manufacturing processes,
(d) Determination of the most appropriate container
closure system,
(e) Development of analytical methods,
(f) Assignment of api retest periods
(g) The synthetic route of the api,
(h) Toxicological strategy.

6. Drug Discovery Literature Search
Preliminary Data
•Stability assay
•Key Stability Data
•Key solubility Data
Molecular Optimization
Salts & solvates
 Prodrugs
Evaluation & Selection of Drug
Formulation Request
Physical Characterization
•Bulk properties
•Solubility profile
•Stability profile
Formulation Development
•Compatibility & Stability
•Dissolution
•Bioavailability
Phase I Formulation
•IND Stability
•Bioavailability
•Scale-up
Investigational New Drug (IND) Application
Process Research
•Improve Yield
•Alternate route
•Produce bulk
Process Development
•Bulk scale-up
Analytical Research
•Assay development
Analytical Research
•Bulk clearance
•Toxicity potency
•Formulation assay
•IND formulation stability
Bioavailability
•In-vivo models
Toxicology
•Acute
•Chronic

7. Preliminary evaluation and
molecular optimization
a) Compound identity.
b) Formula and molecular weight.
c) Structure.
d) Therapeutic indications:
- Probable human dose.
- Desired dosage form(s)
- Bioavailability model
- Competitive products
Contd…

8. e) Potential hazards
f) Initial bulk lots:
- Lot number
- Crystallization solvent(s)
- Particle size range
- Melting point
- % volatiles
g) Analytical methods:
- HPLC assay
- TLC assay
- UV/ Visible spectroscopy
Contd…8
Preliminary Evaluation

9. ORGANOLEPTIC PROPERTIES
COLOR ODOUR TASTE
OFF-WHITE PUNGENT ACIDIC
CREAM-YELLOW SULFUROUS BITTER
SHINY FRUITY SWEET
AROMATIC TASTELESS
ODOURLESS TASTELESS
9

10. Factors determining the activity of
drugs
A large number of factors play their roles in
determining the activity of a drug. Thus successful
integration of these factors results in successful
drug therapy.
These factors include
1. Physico-chemical characteristics of the drug
2. Physicochemical Characteristics of dosage
form
3. Characteristics of the biological system
involved
4. Other factors

11. Physico-chemical characteristics
of the drug
These includes
a) Solubility of the drug and its dissolution rate,
b) Particle size and effective surface area,
c) Plymorphism, Amorphism,Pseudopolymorphism
d) Salt form of the drug,
e) Lipophilicity of the drug,
f) Drug pKa & pH,
g) Drug Stability.

12. Physicochemical Characteristics
of dosage form
It encompasses
a) Disintegration time,
b) Dissolution time,
c) Manufacturing variation,
d) Nature and Type of dosage form,
e) Product age and Storage condition
f) Pharmaceutical ingredients.

13. Characteristics of the biological
system involved
Generally four types of biological factors are involved.
They are as follow
I. Absorption Related Factors: Which includes
a) Route of drug administration,
b) Gastric Empting time,
c) Intestinal transit time,
d) Interaction of Drug with the components of GIT.
e) Protein binding

14. II. Dissolution Related Factors: This Include
a) Lipid Solubility
b) Membrane permeability
c) Enterohepatic cycling
III. Biotransformation related factors: This Includes
a) Biological half life
b) Pre-systemic Metabolism at luminal gut wall
c) Hepatic Tissue Protrusion
d) Genetic effect

15. IV. Excretion related factors: This Includes
a) Glomerular Filtration
b) Drug interaction
Other factors
There are some other types of factors which includes
I. Individual Factors: This Includes
a) Age
b) Sex
c) Body weight
d) Diet
e) Pregnancy

16. II. Pharmacologic Factors: This Includes
a) Log dose Response
b) Drug receptor
c) Drug interaction
d) Drug Concentration
e) Drug binding competition
f) Synergism
III. Clinical effect: This Includes
a) Placebo Effect
b) Concurrent disease
c) Precision in diagnosis

17. Characterization of an unidentified chemical with major
three parameters is called bulk characterization.
It is required to avoid misleading in the prediction of stability
or solubility which depends on particular crystal form.
It encompasses
Bulk Characterization
Crystallinity and polymorphism
Hygroscopicity
Fine particle characterization
Bulk density
Powder flow properties
Bulk characterization

18. Solubility analysis
a) Ionization constant- pKa
b) pH Solubility profile
c) Common ion effect
d) Thermal effectS
e) Solubilization
f) Partition co-efficient
g) Dissolution
Stability analysis
a) Stability in toxicology formulations
b) Solution state stability
 pH rate profile
c) Solid state Stability
 Bulk stability
 Compatibility

19. POWDER FLOW PROPERTIES
 Powder flow properties can be affected by change in
particle size, shape & density.
 The flow properties depends upon following-
1. Force of friction.
2. 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.
e.g. Starch, Talc.

20. Determination of Powder Flow Properties
 By determining Angle Of
Repose.
 It is a maximum angle
between the surface of a
pile of powder & horizontal
plane.
 A greater angle of repose
indicate poor flow.
 It should be less than 30°.
& can be determined by
following equation.
tan θ = h/r.
where, θ = angle of
repose.
h=height of pile.
r= radius.
Angle Of
Repose
( In degree)
Type Of Flow
<25 Excellent
25-30 Good
30-40 Passable
>40 Very poor

21. It is a maximum angle between the surface of a pile of powder & horizontal plane.
Angle of repose is measured by the equation:
tanθ=h /r
here, h=height of conical heap &
r=radius of horizontal plane of powder

22. 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) X 100
TAPPED DENSITY
 It is simple, fast & popular method of predicting
powder flow characteristics.

23. Determination of PowderFlow 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
23

24. Particle size can influence variety of important
factors :
- Dissolution rate
- Suspendability
- Uniform distribution
- Penetrability
- Lack of grittiness
PARTICLE SIZE

25. PARTICLE SHAPE
Particle shape will influence the surface area, flow of
particles, packing & compaction properties of the
particles.
Cont…

27. Plasma Level Time Curve
It is a graph depicting drug concentration in
plasma as a function of time after dosing.
The plasma level time curve is generated by
obtaining the drug concentration in plasma
samples taken at various time intervals after
a drug product is administered.

28. General description: The concentration of drug
in each plasma sample is plotted on rectangular-
coordinate graph paper against the corresponding
time at which the plasma sample was removed. As
the drug reaches the general (systemic)
circulation, plasma drug concentrations will rise up
to a maximum. Usually, absorption of a drug is
more rapid than elimination. As the drug is being
absorbed into the systemic circulation, the drug is
distributed to all the tissues in the body and is also
simultaneously being eliminated. Elimination of a
drug can proceed by excretion, biotransformation,
or a combination of both.

29. Terminologies:
MSC (MTC): Maximum safe Concentration(
Minimum Toxic Concentration) is the concentration
of drug in plasma above which side effect or toxic
effect of drug occurs in patient.
MEC: Minimum Effective Concentration reflects the
minimum concentration of drug needed at the
receptors to produce the desired pharmacologic
effect.
Onset of Action: The onset of action corresponds
to the time required for the drug to reach the MEC.
Duration of drug action: The duration of drug
action is the difference between the onset time and
the time for the drug to decline back to the MEC.
Cmax: It is the maximum drug concentration in the
plasma.

30. tmax: The time of peak plasma level is the time
required to achieve the maximum drug
concentration in the plasma .
The intensity of Action: It is the measurement
of the pharmacologic response of the drug.
Generally the higher the plasma drug
concentrations the greater the pharmacologic
response, which reaches up to a maximum.
Duration of Drug Action: The duration of drug
action is the difference between the onset time
and the time for the drug to decline back to the
MEC.

31. Dissociation (or ionization) constants and
pKa
Many drugs are either weak acids or weak bases. In solutions of these drugs equilibria
exist between undissociated molecules and their ions. Thus, in a solution of a weakly acidic
drug HA the equilibrium may be represented by Eqn 1:
HA H++A- ……………………….(1)
Similarly, the protonation of a weakly basic drug B can be represented by Eqn 2:
--------------------------------------------------(2)
In solutions of most salts of strong acids or bases in water, such equilibria are shifted
strongly to one side of the equation because these compounds are completely ionized.
The ionization constant (or dissociation constant} Ka of a weak acid can be obtained by
applying the Law of Mass Action to Eqn 1 to yield:
----------------------------------------------(3)

32. Taking logarithms of both sides of Eqn 3 yields:
log Ka = log [H+] + log [A-] - log [HA]
The signs in this equation may be reversed to give:
-log Ka = -log [H+] - log [A-] + log [HA] -------------------------------------(4)
The symbol pKa, is used to represent the negative logarithm of the acid dissociation
constant Ka in the same way that pH is
used to represent the negative logarithm of the hydrogen ion concentration, and Eqn
4 may therefore be rewritten as:
pKa = pH + log [HA] - log [A-]
or,
----------------------------------------------------------(5)

33. A general equation may be written that is applicable to any acidic drug with
one ionizable group, where Cu and Ci represent the concentrations of the
unionized and ionized species, respectively.
This is known as the Henderson--Hasselbalch equation, (Eqn 6):
-----------------------------------------------------------------------(6)
The Henderson-Hasselbalch equation for any weak base with one ionizable
group may therefore be written as:
Or
where ci and cu refer to the concentrations of the protonated and unionized
species, respectively.

34. Crystallinity and polymorphism
Depending on internal structure compounds is
classified as
1. Crystalline
2. Amorphous
Crystalline materials are those in which the molecules
are packed in a defined order, and this same order
repeats over and over again throughout the particle.
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.

35. Solubility & dissolution rate are greater for amorphous
form then crystalline, as amorphous form has higher
thermodynamic energy.
Eg. Amorphous form of Novobiocin is well absorbed
whereas crystalline form results in poor absorption.

36. 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.

37. Different shapes of crystals

38. Techniques for studies of crystals
Microscopy
Hot stage microscopy
Thermal analysis
X-ray diffraction

39. 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
1. Enatiotropic
2. Monotropic

40. Polymorphism
The polymorph which can be changed from one form
into another by varying temp. or pressure is called as
Enantiotropic polymorph.
Eg. Sulfur.
One polymorph which is unstable at all temp. &
pressure is called as Monotropic polymorph.
Which means that only one polymorphic form is stable
and any other polymorph that is formed will eventually
convert to the stable form.
Eg. Glyceryl stearate.

41. Polymorphism
Polymorph differ from each other with respect to their physical
property such as
Solubility (the stable polymorphic form will have the slowest
dissolution rate)
Melting point
Density
Hardness
Compression characteristic
During preformulation it is important to identify the polymorph that
is stable at room temp.
Eg. 1)Chloromphenicol exist in A,B & C forms,
of these B form is more stable & most
preferable.
2)Riboflavin has I,II & III forms, the III form
shows 20 times more water solubility than
form I.

42. Hygroscopicity
A substance that absorbs sufficient moisture
from the atmosphere to dissolve itself is known
as a hygroscopic or deliquescent materials.
For this reason pharmaceutical air conditioning
is usually set below 50% RH, and very
hygroscopic products, e.g. effervescents, which
are particularly moisture sensitive, are stored
and made below 40% RH.

43. Solubility analysis
A solution may be denned as a homogeneous
mixture of two or more components that form a
single phase .
The component that determines the phase of the
solution is termed the solvent and usually
constitutes the largest proportion of the system.
The dispersed as molecules or ions throughout
the solvent are termed solutes
The transfer of molecules or ions from a solid
state into solution is known as dissolution. The
extent to which the dissolution proceeds under a
given set of experimental conditions is referred
to as the solubilityof the solute in the solvent.

44. Aqueous solubility:
Dictates the ease with
which formulations
for oral gavage and
intravenous injection
studies in animals are
obtained.
Intrinsic solubility (C0)
: Dictates the fundamental solubility when
completely unionized.

45. In many instances, dissolution rate in the fluids
at the absorption site is the rate limiting step in
the absorption process.
Dissolution rate can affect
- Onset of action.
- Intensity of action.
- Duration of response.
- Control the overall Bioavailability of drug form.

46. The solubility should ideally be measured at two
temperatures:
1. 4°C to ensure physical stability and extend
short-term storage and chemical stability until
more definitive data are available.
The maximum density of water occurs at
4°C.This leads to a minimum aqueous solubility.
2. 37°C to support biopharmaceutical
evaluation.

47.  Addition of co-solvent
 pH change method
 Reduction of particle size
 Temperature change method
 Hydotrophy
 Addition of Surfactant
 Dielectrical Constant
 Complexation
General Method of Increasing
the Solubility

48. DISSOLUTION
An equation known as the Noyes-Whitney
equation was developed to define the dissolution
from a single spherical particle. The rate of mass
transfer of solute molecules or ions through a
static diffusion layer (dm/dt) is directly
proportional to the area available for molecular
or ionic migration (A), the concentration
difference (∆C) across the boundary layer, and is
inversely proportional to the thickness of the
boundary layer (h).

50. 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 is formed ”.
It is the process by which apparent
solubility of an otherwise sparingly
soluble substance is increased by the
presence of surfactant micelles .

51.  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

52. Step2: Molecules of the solid breaks away from the
bulk
Step 3: The free solid molecule is intergraded into
the hole in the solvent

53. Description Parts of solvent required for
one part of solute
Very soluble < 1
Freely soluble 1 - 10
Soluble 10 - 30
Sparingly soluble 30 - 100
Slightly soluble 100 - 1000
Very slightly soluble 1000 - 10,000
Insoluble > 10,000

54.  Aqueous concentrates of volatile oils can be
prepared by solubilization.
 Example: soaps used for solubilising phenolic
compounds for use as disinfectants- Lysol, Roxenol
etc.
 Barbiturates, anticoagulant, alkloidal drugs are
dissolved with polysorbate by solubilization.
Applications of solubilization

55. ThermalAnalysis
It is used to study the physico-chemical
interactions of two or more components.
Differential thermal analysis (DTA):DTA
measures the temperature difference between
the sample and a reference as a function of
temperature or time when heating at a constant
rate.
Differential scanning calorimetry (DSC): It
measures the enthalpy of transition

56. Effect of temperature on the solubility of drug
can be determined by measuring heat of
solution. (∆Hs).
ln S = -∆Hs/RT + C.
where, S = Molar solubility at temperature T
(K).
R = Gas constant.
Heat of solution represents the heat released or
absorbed when a mole of solute is dissolved in
a large quantity of solvent.

57. Mostly solution process is endothermic (∆Hs =
+ve) & thus increasing the solution
temperature increase the drug solubility.
Typical temp. range should include 5°C, 25°C,
37°C & 50°C
Importance:
Determination of temperature effect on
solubility helps in predicting storage condition
& dosage form designing

58. Partition Coefficient
Partition coefficient is generally defined as the
fraction of drug in an oil phase to that of an
adjacent aqueous phase.
P o/w = (C oil / C water) equilibrium
Accordingly compounds with relatively high
partition coefficient are predominantly lipid
soluble and consequently have very low aqueous
solubility.
Compounds with very low partition coefficients
will have difficulty in penetrating membranes
resulting poor bioavailability.

59. MEASUREMENTOFPARTITIONCOEFFICIENT:
It can be measured by using following methods.
Shake flask (or tube) method.
HPLC method.
Electrochemical method.
Slow-Stirring Method.
Estimation method based on individual solubilities.

61. Common-ion effect
The common-ion effect is used to describe the
effect on an equilibrium involving a substance
that adds an ion that is a part of the equilibrium.
Adding a common ion prevents the weak acid or
weak base from ionizing as much as it would
without the added common ion.
A common ion often significantly reduces the
solubility of a slightly soluble electrolyte.

62. Common-ion effect
For example, silver chloride, AgCl, is a slightly soluble
salt that in solution dissociates into the ions Ag+ and
Cl - , the equilibrium state being represented by the
equation AgClsolid ⇒Ag++Cl -
According to Le Châtelier's principle, when a stress is
placed on a system in equilibrium, the system responds
by tending to reduce that stress. If another solute
containing one of those ions, e.g., sodium chloride,
NaCl, is added which supplies Cl - ions, the solubility
equilibrium of the solution will be shifted to remove
more Cl - from the solution i.e. right to left by forming
more solid AgCl. The net result is the decrease in the
solubility of AgCl.

63. Addition of common ion reduces the solubility of
slightly soluble electrolyte.
The “salting out” results from the removal of water
molecules as solvent due to the competing hydration
of other ions.
So weakly basic drug which are given as HCl salts
have decreased solubility in acidic solution.
E.g. Chlortetracycline, Papaverine, Bromhexine,
Triamterene, etc.
The reverse process “salting in” arises with larger
anions. (E.g. Benzoate, salicylate) which can open the
water structure.
These hydrotropes increase the solubility of poorly
water soluble compounds

65. Why Stability?
Provide a evidence on how the quality of a drug
substance or drug product varies with time under the
influence of a variety of environmental factors such
as….. temperature, Humidity and light.
Establish a re-test period for the drug substance or a shelf
life for the drug product and recommended storage
conditions.
Because physical, chemical or microbiological changes
might impact the efficiency and security of the final
product

66. Where and Why?
Stability Studies are preformed on ...
• Drug Substances (DS)  The unformulated drug
substance that may subsequently be formulated with
excipients to produce the dosage form.
• Drug Products (DP)  The dosage form in the final
immediate packaging intended for marketing…….

67. Development of a drug substance into a suitable
dosage form requires the
Preformulation stability studies of drug under
the following categories:-
[1] Solid state stability.
[2] Solution state stability

68. 1] Solid state stability
• Solid state reactions are much slower & more
difficult to interpret than solution state reactions
because of reduced no. of molecular contacts
between drug & excipient molecules &
occurrence of multiple reactions.
 Techniques for solid state stability studies:
Solid State NMR Spectroscopy. (SSNMR)
Powder X-ray diffraction. (PXRD)
Fourier Transform IR. (FTIR)
Raman Spectroscopy.
Differential Scanning Calorimetry (DSC).

69. [2] Solution State Stability
• The primary objective is identification of conditions
necessary to form a solution.
• These studies include the effects of
- pH - Temperature.
- Light - Oxygen.
- Cosolvents - Ionic Strength.
- Solution Stability investigations usually commence
with probing experiments to confirm decay at the
extremes of pH & temperature.
- If the results of this solution stability studies dictate
the compound as sufficiently stable, liquid formulation
can be developed.

70. Whatare changes?
Physical changes
• Appearance
• Melting point
• Clarity and color of solution
• moisture
• Crystal modification (Polymorphism)
• Particle size
Chemical changes
• Increase in Degradation
• Decrease of Assay
Microbial changes

71. Forced degradation studies
Acidic & Basic conditions.
Dry heat exposure
UV radiation exposure
Influence of pH
Influence of temperature
Influence of ionic strength

72. Chemical degradation studies
Hydrolysis
Oxidation
Reduction
Decarboxylation
Photolysis

73. Testing scope for Solid dosage
Physical-chemical properties
– Appearance
– Elasticity
– Mean mass
– Moisture
– Hardness
– Disintegration
– Dissolution
Chemical properties
– Assay
– Degradation
Microbial properties
Container closure system properties
– Functionality tests (e.g. extraction from blister)
Tablet & Capsule

74. Testing scope for Oral liquid form
Physical-chemical properties
– pH
– Color & clarity of solution
– Viscosity
– Particle size distribution (for oral suspensions only)
Chemical properties
– Assay
– Degradation products
– Degradation preservatives
– Content antioxidants
Microbial properties
Container closure system properties
– Functionality tests

75. Testing scope for
LIQUID FORMS for inj. and PARENTRAL
Physical-chemical properties
– pH
– Loss on weight
– Color & clarity of solution
Chemical properties
– Assay
– Degradation products
– Degradation preservatives
– Content antioxidants
Microbial properties
Container closure system properties
– Functionality tests