This document provides an overview of preformulation studies for drug development. It discusses the importance of characterizing key physicochemical properties of drug substances such as solubility, ionization constants, melting point, and polymorphism. It also covers the role of excipients and how drug-excipient interactions can impact stability. The document concludes with sections on stability studies, factors that influence stability, and guidelines for stability testing procedures and frequencies.

1. 1
FACILITATED BY:
Mr. Avinash.S.G
Asst. professor
Dept. of Pharmaceutics
HSKCOP , Bagalkot.
PRESENTED BY:
Supriya Hiremath
M. Pharm I semester
Dept. of Pharmaceutics
HSKCOP, bagalkot

2. CONTENTS:
• Preformulation
• Drug excipient interactions
• Stability studies
• Kinetics of stability
• Stability testing
• Theories of dispersion
• Emulsion
• Suspension
2

3. Preformulation
• Preformulation is the stage of development
during which the physicochemical properties of
the drug substance are characterized and
established.
• Knowledge of the relevant physiochemical and
biopharmaceutical properties determines the
appropriate formulation and delivery method for
preclinical and phase first studies.
• DEFINITION:- Investigation of physico-chemical
properties of the new drug compound that could
affect drug performance and development of an
effective dosage form”.
3

4. The physiochemical properties are:
1. Solubility
2. Ionization constant (pKa and pKb)
3. Melting point,
4. Solid-state properties,
5. Partition co-efficient ,
6. Surface characteristics,
7. Dissolution,
8. Flow properties of powder drug,
9. Vapour pressure.
4

5. The solubility of every new drug i.e., acidic or
basic, must be determined over pH range 1 to 8.
• It has been investigated that unless a compound has an
aqueous solubility in excess of 1% (10mg/ml) over the
pH range 1-7 at 370 C, then potential bioabsorption
problems may occur
• A solubility of less than 1 mg/ml indicates the need for a
salt. In the range of 1-10 mg/ml, serious consideration
should be given to salt formation.
5
1. Solubility

6. 2. Ionization constant
• 75% of drugs are weak bases;
• 20% weak acids and
• 5% non- ionic, amphoteric.
Factors usually important in the absorption of
weakly acidic and basic are :
1. pH at the site of absorption
2. Ionization constant (Pk )
3. Solubility of un-ionized species
6

7. The ionization constant refers to equation---
HB +H2O  H3O+ + B-
This relationship can be given by Henderson-
Hesselbalch equation which shows the concentrations of
un- ionised and ionised species…….
For bases -> pH = pKa + log [unionised] / [ionised]
For acids -> pH = pKa + log [ionised] / [unionised]
7

8. 3.Melting point
• Melting point:- Determination of M.P. of solids further
confirms the properties of formulated compound and
conditions to be maintained in formulation process.
• So, determination of M.P. is essential for
preformulation process. Because when heat is
supplied to the formulated compound on above M.P.
range, leads to phase changes sometimes .
• This may leads to conversion of active compound to
inactive / toxic form. E.g : Metastable (low M.P.)
stable (high M.P.)
8

9. 4. Solid state properties
• Solid-State Properties:- Solids usually exists in crystalline, amorphous
or a combination of both.
• There are 6 crystal systems…. Cubic, tetragonal, orthorhombic,
monoclinic, triclinic and hexagonal. (differ in internal structure)
• Crystal habit is of 5 types…. Tabular, platy, prismatic, acicular, bladed,
equant. (differ in external structure) crystal can exist in different
states and these includes:
A) Polymorphism
B) Pseudo- polymorphism
C) Isomorphous crystal forms
A) POLYMORPHISM: Many drug substances can exist in more than
one crystalline form with different space lattice arrangements. This
property is known as ”polymorphism” and crystals are termed as”
Polymorphs”. Many solids may be prepared in a particular
polymorphic form via. Appropriate manipulation of conditions of
crystallization such as……
9

10. • Changing the nature of solvent, temp, rate of cooling etc.
Polymorphism is common particularly with certain structural
groups.
• 63% of barbiturates, 7% of steroids, and 40% of
sulphonamides.
B) PSEUDO-POLYMORPHISM: Occasionally, a solid crystallizes,
entrapping solvent molecules in a specified lattice position
and in a fixed stoichiometry, resulting in a solvate, or pseudo
polymorph.
• The solvents includes– water, methanol, ethanol, acetone,
chloroform, benzene, toulene, etc. The distinction between
these forms and true forms can be obtained by determining
the melting point.
10

11. C) ISOMORPHOUS CRYSTALS: Isomorphism is the
ability of forming crystals of similar shape by
different chemical substances. Such
substances are said to be Isomorphous( same
shape). Isomorphism is due to same chemical
constitution.
E.g. Magnesium sulphate, MgSO4.7H2O and
Zinc sulphate , ZnSO4.7H2O
11

12. 5. Partition co-efficient
• Lipid solubility of a drug is an important factor in the
assessment of its absorption potential, because GI
membranes are largely lipoidal in nature. This lipid
solubility can be obtained by determining how a drug
substance distributes itself between water and an
immiscible organic solvent. This is referred as “Partition
coefficient”.
• APPLICATIONS :
A) Solubility both in aqueous and in mixed solvents.
B) Drug absorption in vivo
C) Partition chromatography : In making choice of column
(Hplc / Tlc) & choice of mobile phase (eluent).
12

13. 6. Surface characteristics
The surface characteristics of drug are the:
• Particle size
• Surface area
13

14. Particle size
• • Particle size is characterized using these
terms :
i. Very coarse (#8)
ii. Coarse (#20)
iii. Moderately coarse (#40)
iv. Fine (#60)
v. Very fine (#80)
14

15. A. PARTICLE SHAPE AND SIZE:
• Poorly soluble drugs in a finely sub divided
state shows more bioavailability than that of
coarse material. It can be attained by grinding.
• Should reduce coarse material to
approximately 10-40 microns range.
15

16. • The determination of particle area shows an inverse relationship with
particle size.
The theory involved in this BET theory of adsorption.
• The theory states that most substances will adsorb a monomolecular layer
of a gas under certain conditions of partial pressure (of gas) & temp.
By knowing-
a) the monomolecular capacity of adsorbent
b) Area of the adsorbate molecule.
Surface area can be calculated.
• Most commonly used adsorbate is nitrogen. Methods employed :-
• The techniques used for this are
a) volumetric technique
b) Gravimetric technique
c) Dynamic method
B. Surface area
16

17. • Usually, the absorption of solid drugs adminstered orally can be
depicted as-
• Solid drug in
kd -Drug in solution
ka-Drug in systemic aqueous solution
• If kd << ka = Absorption is dissolution rate limited
• It is therefore essential to investigate the dissolution behaviour of
drug sub’s especially with moderate and poor solubility.
• The knowledge of comparitive dissolution rates of different
chemical ( salt, ester, prodrug) & physical ( polymorph, solvates
etc), forms of a drug is necessary in selecting the optimum form
for further development.
17

18. 8. Powder flow properties:
• It includes:
a) BULK DENSITY
b) ANGLE OF REPOSE
A) BULK DENSITY:
The flow ability of a powder is evaluated by comparing the poured
density and tapped density of a powder and the rate at which it packed
down.
 It is expressed by Carr’s Compressibility index and Hausner ratio
Carr’s index % = [(Tapped density – Poured density)/ Tapped density]*100
Hausner index = Tapped density / Poured density
18

19. Type of flow Carr’s index(%)
Excellent flow 5-10
Good flow 12-16
Fair to passable 18-21
Poor flow 23-25
Very poor flow 33-38
Extremely poor flow >40
Hausner index
<1.25 Good flow (=20% carr’s index)
1.25 Poor flow (=30% carr's index)
1.25 -1.5 Glidant is to be added
19

20. B) ANGLE OF REPOSE:
• A Static heap of powder, when only gravity acts upon it, will tend to
form a conical mount. One limitation exists, the angle to the
horizontal cannot exceed a certain value and this is known as the “
angle of repose ”.
• If any particle temporarily lies outside this limiting angle, it will slide
down the adjacent surface under the influence of gravity until the
gravitational pull is balanced by the function caused by
interparticulate forces.
• The following values of angle of repose represent the type of flow.
• Angle of repose Type of flow
<25 Excellent
25-30 Good
30-40 Passable
>40 Very poor
20

21. 9. Vapour pressure :
• A substance must possess low vapour
pressure and if it is high it may leads to
stability problems and content uniformity
problems and sometimes interaction with
other compounds may take place.
21

22. • Excipients play an important role in formulating a dosage
form. These are ingredients which along with active
pharmaceutical ingredients make up the dosage forms.
• Excipients act as protective agents, bulking agents and
can also be used to improve bioavailability of drug.
• Excipients as like other active pharmaceutical
ingredients need to be stabilized and standardized.
22

23. • “An excipient is an inactive substance formulated
alongside the active ingredient of a medication, for
the purpose of bulking-up formulations that
contain potent active ingredients”.
• The resultant biological, chemical and physical
properties of the drug product are directly
affected by the excipient chosen, their
concentration and interactions with the API:
 Consistency of drug release and bioavailability.
 Stability including protection from degradation.
Ease of administration to the target patient
population by the intended route.
23

24. Ideal properties of Excipient
• No interaction with drug
• Cost effective
• Pharmacologically inert
• Stable for handling
24

25. • Excipient are inactive ingredients used as
carriers for the active ingredients in a
pharmaceutical product.
• These may be classified into the following
categories:
 Anti adherents.
Binders.
Disintegrants.
Preservatives.
 Sweeteners.
25

26. Types of drug excipient Interactions
1.Physical interactions.
2.Chemical interactions.
3.Biopharmceutical interactions.
4. Excipient –Excipient interactions.
26

27. 1. Physical interactions.
• physical interactions alter the rate of
dissolution , dosage uniformity ,etc. physical
interactions do not involve chemical changes
thus permitting the components in the
formulation to retain their molecular
structure .physical interactions are difficult to
detect .
27

28. 28

29. 2. Chemical interactions
• Active pharmaceutical ingredients and
excipients react with each other to form
unstable compounds.
29

30. 30
Oxidation Oxidative reactions are
catalyzed by oxygen,
light, heavy metal
ions, fumed metal
oxides, fumed silica,
fumed, zirconia etc.
Steroids, Vitamins,
Antibiotics,
Epinephrine,
Aldehydes, Alcohols,
Phenols.

31. 3. Biopharmaceutical interactions
• These are the interaction observed after
administration of the medication. Interaction
within the body is between medicine and
body fluids which influence the rate of
absorption . All excipient physiological way
when they are administered along with active
pharmaceutical ingredients.
31

32. Examples
32

33. 4. Excipient –Excipient interactions
Excipient –excipient interaction though
observed very rarely. These are prime importance
in determining the stability of the dosage forms
excipient –excipient interactions can be
undesirable as well as some interactions are used
in the formulations to get the desired product
attributes.
33

34. STABILITY STUDIES.
 Preformulation stability studies are usually the
primary quantitative assessment of chemical
stability of new drug which includes,
 Solution state stability.
 Solid state stability.
 Solution state stability: the objective of carrying out
solution studies is to identify conditions necessary to
form a stable solution.
 this includes effect of pH,ionic strength, & oxygen on
solution.
34

35. Eg. Degradation of thiamine in acetate buffer
is unaffected at PH 3.9 ,but at higher PH
degradation rate increases.
Solid state stability: It is carried to find out a
stable storage conditions for the drug in sold
state & identification of compactable
excipients for the formulation.
on contrary to the liquid/solution stability this
study is affected by changes in purity and
crystallinity and the solid state reactions are
much slower and more difficult to interpret
than solution state stability studies.
35

36. STABILITY
• The state or quality of being steady and not
changing.
Def: The ability of the pharmaceutical dosage
form to maintain the physical, chemical,
therapeutic and microbial properties during the
time of storage and usage by the patient.
It is
measured by the rate of changes that take place
in the pharmaceutical dosage form.
36

37. Three types of stability concern the pharmacists:
• l. Chemical: Each active ingredient retains its
chemical integrity within the specified limits.
• 2. Physical: The original physical properties
(including appearance, taste, color and odor)
are retained.
• 3. Biological: Sterility is retained (No microbial
growth).
37

38. Degradative reactions in pharmaceutical formulation
takes place at definite rates and an chemical in nature,
they depends on such conditions as-
1. Concentration of reaction
2. PH
3. Temperature
4. Radiation & catalyst
38

39. Mechanism that effect the tablet
stability
1. Oxidation: this is one of the major cause of tablet
instability ,This oxidative reaction are influence
by light & metal ions (ion, co, Ni,).
39
 This cause the tablet to produce coloured
products or produce objectionable odours.

40. 2. Hydrolysis: Reaction between organic
compounds & water ,it is characterized by the
splitting of water molecule to form the positively
charged ( H+) & negatively charged hydroxide
(OH).
Drug with functional group such as ester,
amides, lactones may be susceptible to
hydrolysis or degradation.
40

41. STABILITY TESTING
Purpose
• To ensure the efficacy, safety and quality of
active drug substance and dosage forms.
• To establish shelf life or expiration period and
to support label claims.
41

42. Factors affecting stability
1) Storage time
2) Storage conditions
3) Types of dosage form
4) Container & closure system
42

43. 1) Storage time
• The longer the storage time, the more the
degradation of drug and the more the deterioration
of dosage forms.
2) Storage conditions
• Storage conditions such as storage temperature and
percentage relative humidity at the storage place
affect the stability of dosage forms adversely.
43

44. Climate zones
The design of the stability testing programme
should take into account the intended market and
the climatic conditions in the area in which the
medicinal products will be used.
4 climate zones can be distinguished
1) Zone 1: Temperature
2) Zone 2: Subtropical with possible high humidity
3) Zone 3: Hot or dry
4) Zone 4: Hot or humid.
44

45. The shelf life should be established with due
regard to the climatic zones in which the products
are to be marketed.
45
Zone Mean kinetic
temperature
Yearly average
humidity (% RH)
Zone : 1 (Moderate) 21 C 45%
Zone : 2 (Mediterranean) 25 C 60%
Zone : 3 (Hot, Dry) 30 C 35%
Zone : 3 (Very hot, Moist) 30 C 70%

46. Stability storage conditions for zone 1 & 2
46

47. Stability storage conditions for zone 3 & 4
47

48. Testing Frequency
According to ICH guidelines, for routine time testing
during first year, sampling should be done every 3 month
during 2nd year. Sampling should be done for every 6
month and after that sampling should be done once in a
year.
 Accelerated testing should be done once in a year six
months and it suggests sampling points of 0, 3 & 6
months for stable products
 The FDA guidelines suggest sampling intervals of 0, 2, 4
& 6 months
 WHO guidelines suggest 0, 1, 2, 3 & 6 months sampling
intervals.
48

49. Intermediate Testing
FDA and WHO guidelines do not suggest
intermediate testing intervals. Only ICH suggest 0, 6,
9 & 12 months sampling points for these.
Parameters checked during testing
1) Dissolution or release of pharmaceutical product
2) Assay or percentage purity of pharmaceutical
product
3) Physical characters of pharmaceutical product
4) pH (in case of liquid)
49

50. Accelerated Test For Stability
• When determining the chemical stability of a
product, assay employed should be sufficiently
specific to distinguish between the drug and its
decomposition product.
• Acceleration of chemical decomposition is
achieved by raising the temperature of the
preparation.
• The order of reaction for the decomposition
process is determined by plotting the appropriate
function of concentration against time and
obtaining a linear relationship.
50

51. • The reaction velocity constant, k, for the
decomposition at each of the elevated
temperature can be calculated from the slope of
the line.
• The Arrhenius relationship is then employed to
determine the reaction velocity constant ,k, at
room temperature.
• This is obtained from the linear plot of the log of
determined reaction velocity constant, k,
against the reciprocal of absolute temperature,
which is extrapolated to room temperature 25 C
51

52. Arrhenius equation
Where,
K = Rate constant
A = Frequency factor
e = Mathematical quantity
E = Activation energy
R = The gas constant
T = Kelvin temperature
52

53. Estimation of shelf life
• The value of k at 25 C substituted in the
Arrhenius equation and an estimate obtained of
the time during which the product will
maintained the required quality or potency (shelf
life)
• Limitations: the predicted shelf life of a
preparation will only be valid if the accelerated
test is carried out on the final packaged product.
• Applied only those form of decomposition which
increase with rise in temperature.
53

54. 54
THEORIES OF DISPERSION AND
PHARMACEUTICAL DISPERSION

55. Emulsion
A thermodynamically unstable system
consisting of at least 2 immiscible liquid phases,
1 of which is dispersed as globules in the other
liquid phase.
• The dispersed liquid is known as the internal
or discontinuous phase
• Where as the dispersed medium is known as
the external or continuous phase
55

56. Theories of Emulsification
Many theories have been advanced to account for
the way or means by which the emulsion is
stabilized by the emulsifier.
1) Electric Double Layer Theory.
2) Phase Volume Theory.
3) Hydration Theory of Emulsions
4) Oriented wedge theory.
5) Adsorbed Film and Interfacial tension Theory
56

57. 1) Electric Double Layer Theory:
• The oil globules in a pure oil and pure water emulsion
carry a negative charge. The water ionizes so that both
hydrogen and hydroxyl ions are present.
• The negative charge on the oil may come from
adsorption of the OH ions.
• These adsorbed hydroxyl ions form a layer around the
oil globules. A second layer of oppositely charged ions
forms a layer in the liquid outside the layer of negative
ions.
• The electric charge is a factor in all emulsions, even
those stabilized with emulsifying agents
57

58. 2) Phase Volume Theory
• If spheres of same diameter are packed as closely
as possible, one sphere will touch 12 others and
the volume the spheres occupy is about 74 per
cent of the total volume.
• Thus if the spheres or drops of the dispersed phase
remain rigid it is possible to disperse 74 parts of
the dispersed phase in the continuous phase; but if
the dispersed phase is increased to more than 74
parts of the total volume, a reversal of the
emulsion will occur.
• However, the dispersed phase does not remain
rigid in shape but the drops flatten out where they
come in contact with each other, nor are all the
dispersed particles the same. 58

59. • Fischer and Hooker state that hydrated
colloids make the best emulsifiers.
• Fischer states the emulsifying agent, by which
a permanent emulsion is obtained,"proves to
be a hydrophilic colloid when water and oil
emulsions are concerned
• Fischer and Hooker have found albumin,
casein, and gelatin to be good emulsifying
agents.
59
3) Hydration Theory of Emulsions:

60. 4) Oriented wedge theory:
• This theory deals with formation of monomolecular
layers of emulsifying agent curved around a droplet of
the internal phase of the emulsion.
Example:
• In a system containing 2 immiscible liquids, emulsifying
agent would be preferentially soluble in one of the
phases and would be embedded in that phase.
• Hence an emulsifying agent having a greater hydrophilic
character will promote o/w emulsion and vice-versa.
• Sodium oleate is dispersed in water and not oil. It forms a
film which is wetted by water than by oil. This leads the
film to curve so that it encloses globules of oil in water.
60

61. 5) Adsorbed film & interfacial tension
theory:
61
Lowering interfacial tension is one way to decrease the
free surface energy associated with the formation off
droplets. Assuming the droplets are spherical,
ΔF= 6 γV
D
V= volume of the dispersed phase in ml,
D= is the mean diameter of the particles.
γ= interfacial tension
It is desirable that: The surface tension should be reduced
below 10dynes/cm by the emulsifier and it should be
absorbed quickly.

62. Methods of Preparation Of Emulsions:
Commercially, emulsions are prepared in large
volume mixing tanks and refined and stabilized by
passage through a colloid mill or homogenizer.
Extemporaneous production is more concerned
with small scale methods.
1) Dry Gum Methods
2) Wet Gum Methods
3) Bottle Method
4) Beaker Method.
5) In situ Soap Method.
62

63. DRY GUM Method
• Dry gum method is used to prepare the initial
or primary emulsion from oil, water, and a
hydrocolloid or "gum" type emulsifier.
Dry Gum Methodology
• (4 parts oil, 2 parts water, and 1 part
Emulsifier).
63

64. Procedure:
• Take mortar, 1 part gum is levigated with the 4
parts oil until the powder is thoroughly wetted;
then the 2 parts water are added all at once, and
the mixture is vigorously triturated until the
primary emulsion formed is creamy white and
produces a "cliking" sound as it is triturated.
• Active ingredients, preservatives, color, flavors are
added as a solution to the primary emulsion.
• When all agents have been incorporated, the
emulsion should be transferred to a calibrated
vessel, brought to final volume with water.
64

65. Wet Gum Method
Methodology
• (Oil 4 parts + Water 2 parts + Emulsifier 1 parts)
Procedure:
In this method, the proportions of oil, water, and emulsifier are
the same (4:2:1), but the order and techniques of mixing are
different.
• The 1 part gum is triturated with 2 parts water to form a
mucilage; then the 4 parts oil is added slowly, in portions,
while triturating.
• After all the oil is added, the mixture is triturated for several
minutes to form the primary emulsion.
• Then other ingredients may be added as in the continental
method.
65

66. Bottle Method
• This method may be used to prepare emulsions of
volatile oils, Oleaginous substances of very low
viscosities.
• This method is a variation of the dry gum method.
• One part powdered acacia (or other gum) is placed in
a dry bottle and four parts oil are added.
• The bottle is capped and thoroughly shaken.
• To this, the required volume of water is added all at
once, and the mixture is shaken thoroughly until the
primary emulsion forms.
66

67. Beaker Method
• Dividing components into water soluble and oil soluble
components.
• All oil soluble components are dissolved in the oily
phase in one beaker and all water soluble components
are dissolved in the water in a separate beaker.
• Oleaginous components are melted and both phases
are heated to approximately 70°C over a water bath.
• The internal phase is then added to the external phase
with stirring until the product reaches room
temperature.
67

68. In situ Soap Method:
Two types of Soaps developed by this Methods:
1) Calcium Soaps
2) Soft Soaps
1) Calcium Soaps: W/O type Emulsions.
• E.g. Oleic acid + Lime water. Prepared by simple
mixing of equal volumes of Oil and Lime water.
• Emulsifying agent used is Calcium salt of free
fatty acids.
E.g. Olive Oil + Oleic acid (FAA)
68

69. Instability in Emulsion:
69

70. 70

71. 71

72. 72

73. Suspension
• A pharmaceutical suspension is a coarse
dispersion in which internal phase is
dispersed uniformly throughout the
external phase
73

74. Preparation of suspension
Two main methods are used:
• Precipitation methods:
• Dispersion method:
74

75. Precipitation methods:
Three main methods
• Organic solvent precipitation
• Precipitation effected by changing pH of the
medium
• Double decomposition
75

76. Organic solvent precipitation
76

77. Precipitation effected by changing pH
of the medium
77

78. Double decomposition
78

79. Dispersion method:
79

80. Preparation techniques of suspension
• Small scale preparation of suspensions
• Large scale preparation of suspensions
80

81. Small scale preparation of suspensions
81
Grinding the insoluble materials with a vehicle containing
the wetting agent
soluble ingredients are dissolved in same portion of the
vehicle
Added to the smooth paste to step1 to get
slurry.
Make up the dispersion to the final volume

82. Large scale preparation of suspensions
• If suspension is made by dispersion process it
is best to achieve pulverization of solid by
micronization technique or spray drying
• If suspension is made by controlled
crystallization, a supersaturated solution
should be formed and then quickly cooled
with rapid stirring.
82

83. Stability of suspension
1. Small particle size:
Reduce the size of the dispersed particle increase
the total surface area of the solid. The greater the degree
the subdivision of a given solid the larger the surface area
The increase in surface in surface area means also
an liquids leading to an increase in viscosity of a system
2. Temperature:
Another factor which negatively affects the stability and
usefulness of pharmaceutical suspensions is fluctuation of
temp..
Temp fluctuations can lead caking of claying.
83

84. 3. Increasing the viscosity:
• Increasing the viscosity of the continuous phase can lead to the
stability of suspension this is so because the rate of
sedimentation can be reduce by increase in viscosity
• viscosity increase is brought about by addition of thickening
agents to the external phase. In water these must be either
soluble or swell
• it is important to note that the rate of release of a drug from a
suspension is also dependent on viscosity of a product
• the more viscous the preparation, the slower Is likely to be the
release of a drug sometimes this property may be desirable for
depot preparations
84

85. REFERENCE
1. Leon Lachman,HerbertA. Lieberman. The
Theory & Practice of Industrial Pharmacy. 2009
Edition.
2. Text book of Physical Pharmacy by Alfred
Martin, Varghese publication.
3. Text book of Modern Pharmaceutics by Gilbert
&Banker.
4. Text book of pharmaceutical practice by M .Alton.
Pharmaceutical dosage forms.
5. Pharmaceutical preformulation by J.T.Carstensen,
Ph.D
85

86. 86