Preformulation study ppt

Presented By: Dinesh Kumar
M. Pharma. (Pharmaceutics),

 These studies should focus on physicochemical properties of new
compound that affect drug performance & development of efficacious
dosage form.
 Mostly investigation of physical and chemical property of a drug .

 To establish the physicochemical parameters of a new drug.
 To establish its physical characteristics .
 To establish its compatibility with common excipients.
 Providing a scientific data to support the dosage form design and
evaluation of the product efficacy and stability.
3

 Drugs can be used therapeutically as solids, liquids and gases.
 Liquid drugs are used to a much lesser extent than solid drugs
and even less frequently thangases.
 Solid materials are preferred in formulation work because of
their ease of preparation into tablets and capsules.
 The majority of drug substances in use occur as solid
materials.
 Most of them are pure chemical compounds of either:
Amorphous or Crystalline in nature
7

CRYSTALLINITY AND POLYMORPHISM
 Solid drug materials may occur as:
a. Amorphous (higher solubility)
b. Crystalline(higher stability)
 The amorphous or crystalline characters of drugsare of
great importance to its ease of formulation and handling, its
chemical stability and its biological activity.
9

 Amorphous drugs have randomly arranged atoms or
molecules.
 Amorphous forms are typically prepared by ;
precipitation, lyophilization, or rapid cooling method.
Advantage:
 Amorphous forms have higher solubilities as well as
dissolution rates as compared to crystalline forms.
Disadvantage:
 Upon storage, sometimes amorphous solids tend to
revert to more stable forms. This instability can occur
during bulk processing or within dosageforms. 10

 It is inactive when administered in crystalline form, but
when they are administered in the amorphous form,
absorption from the gastrointestinal tract proceeds
rapidly with good therapeutic response.
11

 Crystals are characterized by repetitious spacing of constituent
atoms or molecules in a three dimensional array.
 Crystalline forms of drugs may be used because of greater
stability than the corresponding amorphous form.
 For example: the crystalline forms of penicillin G as
potassium or sodium salt is considerably more stable and
result in excellent therapeutic response than amorphous forms.
12

 identical depending on the variation in;
a. Temperature
b. Solvent
c. Time
 Polymorphism is the ability of a compound to
crystallize as more crystalline
different internal
than one distinct
lattices or crystalspecies with
packing arrangement even they are chemically
13

 Different polymorphs exhibits different solubilities,
therapeutic activity and stability.
 Chemical stability and solubility changes due to
polymorphism can have an impact on drug’sactivity.
14

 Differential scanning calorimetry and Differential
thermal analysis: [DSC & DTA]
Measure the heat loss or gain resulting from physical or
chemical changes within a sample as function of temperature.
 Thermo gravimetric analysis (TGA):
It measure changes in sample weight as a function of time
(isothermal) or function of time (isothermal) or temperature.
 Desolvation and decomposition processes are frequently
monitored by TGA.
17

 Purity, polymorphism, solvation, degradation, and
excipient compatibility.
 Thermal analysis can be used to investigate and
predict any physicochemical interactions between
components in the formulation.
 It is used for selection of chemically compatible
excipients.
18

 It is an important technique for establishing the batch- to batch
reproducibility of a crystallineform.
 Each diffraction pattern is characteristic of a specific
crystalline lattice for a givencompound.
Applications:
 Quantitative ratios of two polymorphs and their
percentages of crystallinity may be determined.
crystalline forms can be Mixtures of different
analyzed using normalized intensities at specific
angles, which are unique for each crystallineform.
19

 Many drugs , particularly water-soluble salts, have a
tendency to adsorb atmospheric moisture.
 Changes in moisture level can greatly influence many
parameters such as ; chemical stability, flowability, and
compatibility.
 Adsorption and equilibrium of moisture content can
depend upon ; atmospheric humidity, temperature,
surface area, exposure, and the mechanism for moisture
uptake.
20

It adsorbs water because of hydrate formation or
specific site adsorption.
Deliquescent materials:
Adsorb sufficient water to dissolve completely,
as observed with sodium chloride on a humidday.
 Analytic methods for monitoring the moisture level
are ; gravimetric (weight gained), Karl Fischer
titration, or gas chromatography) according to the
desired precision & the amount of moisture adsorbed
onto the drug sample.
21

 Certain physical and chemical properties of drug
substances are affected by the particle size
 Size, shape & surface morphology of drug particles
affect the flow property, dissolution &chemical
reactivity of drugs.
Significance of Particle Size:
 Particle size of drugs may affect formulation and
product efficacy.
distribution including; drug dissolution rate, content
uniformity, texture, stability, flow characteristics, and22
sedimentation rates.

 Particle size significantly influences the oral
absorption profiles of certain drugs.
 Satisfactory content uniformity in solid dosage
forms depends to a large degree on particle size and
the equal distribution of the active ingredient
throughout the formulation.
23

1. Sieving or screening
2. Optical microscopy
3. Sedimentation
4. Stream scanning.
a relatively large sample
Sieving or screening:
Disadvantage: It requires
size.
Advantage: Simplicity in technique and equipment
requirements.
24

Disadvantage: Quantitative evaluations need minimum
1000 particles (tedious and time consuming). The slide
must be representative of the bulk of thematerial.
Sedimentation:
 It utilize the relationship between rate of fall of
particles and their size.
Disadvantage:
 Proper dispersion, consistent sampling temperature
control, must be carefully controlled to obtain
consistent and reliable results.
25

 Technique utilizes a fluid suspension of particles which
pass the sensing zone where individual particles are
sized, counted & tabulated.
 Sensing units are based on ; light scattering
transmission, as well as conductance.
 The popular unit in the pharmaceutical industry for this
purpose is the Coulter Counter
Advantages:
 The unit electronically size, count and tabulate the
individual particles that pass through the sensing zone
and data is obtained in a short time with reasonable
accuracy. 26

 Thousands of particles can be counted in seconds and
used to determine the size distributioncurve.
 It is a powerful tool and can be used for evaluation of
parameters as crystal growth in suspension
formulation.
27

 It is observed by Scanning Electron Microscopy (SEM),
which serves to confirm the physical observations related to
surface area.
 Surface morphology of drug can provide greater area for
various surface reactions such as; degradation, dissolution, or
hygroscopicity.
 Surface roughness leads to poor powder flow characteristics
of powders due to friction and cohesiveness
28

 Bulk density of a compound varies with the method
of crystallization, milling, or formulation.
Importance of bulk density:
 Knowledge of the true and bulk densities of the drug
substance is useful in forming idea about the size of
the final dosage form.
 The density of solids also affects their flow
properties.
29

 Flow properties are significantly affected by:Changes in
particle size, density, shape, and adsorbed moisture, which
may arise from processing or formulation.
 The powder flow properties can be characterized by the
following methods:
30

 It is the maximum angle between the surface of a pile
of powder and horizontal plane
Tan θ= h/r
 The rougher and more irregular the surface of the
particles, the higher will be the angle ofrepose.
 Lower values indicates better flow characteristics.
31

Angle of repose Type of flow
< 20 Excellent flow
20-30 Good flow
30-34 Passable
>40 Poor flow
The acceptance criteria for angle of reposeare:
32

 Compressibility:
It can be characterized by the followingmethods;
1. Carr’s compressibility index
2. Hausner`s ratio
1. Carr’s compressibility index:
Carr’s index (%) =Tapped density–bulk density x100
Tapped density
 By decreasing the bulk and tapped density good flow
properties can be obtained. 33

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 34

 Hausner `s ratio = Tapped density X 100
bulk density
The acceptance criteria for Hausner`s ratio are:
:
Hausner`s ratio Type of flow
< 1.25 Good flow
> 1.5 Poor flow
1.25-1.5 Glidant addition required
>1.5 Glidant doesn’t improve
flow
35

 The solubility of drug is an important
physicochemical property because it affects the rate of
drug release
consequently,
into the dissolution medium and
the therapeutic efficacy of the
pharmaceutical product.
 The solubility of a material is usually determined by
the equilibrium solubility method, which employs a
saturated solution of the material, obtained by stirring
an excess of material in the solvent for a prolonged
period until equilibrium is achieved.
 General rules –
 1. Polar solutes dissolve in polarsolvents
 2. Non-polar solutes dissolve in non-polarsolvents
36

 Water
 Polyethylene Glycols
 Propylene Glycol
 Glycerine
 Sorbitol
 EthylAlcohol
 Methanol
 BenzylAlcohol
 IsopropylAlcohol
 Tweens
 Polysorbates
 Castor Oil
 Peanut Oil
 Sesame Oil
 Buffers at various pHs
37

Description Approximate
weight of
solvent(g)
necessary to
dissolve 1g of
solute
Solubility(%w/v)
Very soluble <1 10-50
Freely soluble 1-10 3.3-10
Soluble 10-30 1-3.3
Sparingly soluble 30-100 0.1-1
Slightly soluble 100-1000 0.01-.1
Very slightly soluble 1000-10000 0.01-0.1 38
Poorly soluble >10000 <0.01

 For a compound containing basic or acidic functional
groups, solubility at a given pH is influenced by the
compound’s ionization characteristics.
 The solubility of a compound in aqueous media is
greater in the ionized state than in the neutral state.
 Thus, solubility of ionizable compounds isdependent
on the pH of the solution.
 The method for the determination of pKaaccording
to the nature of drug can be explainedas:
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Nature of drug Ionization pKa
Very weak acid Unionized at all pH >8
Moderately weak
acid
Unionized at
gastric pH-1.2
2.5-7.3
Strong acid Ionize at all pH <2.5
Very weak base Unionize at all pH <5
Moderately weak
base
Unionize at
intestinal pH
5-11
Strong base Ionize at all pH
40
>11

 Determination of the dissociation constant for a drug
capable of ionization within a pH range of 1 to
10 is important since solubility, and consequently
absorption, can be altered by changing pH.
 The Henderson-Hasselbalch equation provides an
estimate of the ionized and un-ionized drug
concentration at a particular pH.
 For acidic compounds:
pH = pKa + log ([ionized drug]/[un-ionized
drug])
 For basic compounds:
pH = pKa + log ([un-ionized drug]/[ionized
drug])
41

The various methods for the determination of pKaare;
a. Potentiometric method
b. Spectrophotometric method
c. Solubility method
d. Conductometric method
42

 Partition coefficient (oil/water) is a measure of a
drug's lipophilicity and an indication of its ability to
cross cell membranes.
Define:
It is defined as the ratio of un-ionized drug
distributed between the organic and aqueous phases at
equilibrium.
Po/w = (Coil/C water)equilibrium
Drugs having values of P much greater than 1 are
classified as lipophilic, whereas those withpartition
coefficients much less than 1 are indicative of a
hydrophilic drug
43

 Preformulation stability studies are usually the first
quantitative assessment of chemical stability of a
new drug.
 These studies include both solution and solid state
experiments under conditions typical for the
handling, formulation, storage, and administration of
a drug candidate as well as stability in presence of
other excipients.
critical in Factors affecting chemical stability
rational dosage form design include;
 Temperature
pH
Dosage form diluents
44

e.g. acid labile drugs intended for oral
administration must be protected from the highly
 The effect of pH on drug stability is important in the
development of both oral and parenteral dosage
forms
acidic environment of the stomach.
 Buffer selection for parenteral dosage forms will
also be largely based on the stability characteristics
of the drug.
45

 PHARMACEUTICAL DISPERSION
 The term "Disperse System" refers to a system in which one
substance (the dispersed phase) is distributed, in discrete units,
throughout a second substance (the continuous phase or
vehicle). Each phase can exist in solid, liquid, or gaseous state.
 COARSE DISPERSION SYSTEM
• Emulsion
• Colloids
• Suspension
 EMULSION
 An emulsion may be defined as a biphasic system
consisting of two immiscible liquids, one of which
(the dispersed phase) is finely and uniformly dispersed
as globules throughout the second phase (the
continuous phase). Since emulsions are a
thermodynamically unstable system, a third agent, the
emulsifier is added to stabilize the system. The particle
size of the dispersed phase commonly ranges from 0.1 to
100 µm

•Oil in water emulsion
•Water in oil emulsion
•Multiple emulsion
PREPARATION OF EMULSION
General method
Generally, an O/W emulsion is prepared by dividing the oily
phase completely into minute globules surrounding each globule
with an envelope of emulsifying agent and
finally suspends the globules in the aqueous phase. Conversely,
the W/O emulsion is prepared by dividing aqueous phase
completely into minute globules surrounding each globule with an
envelope of emulsifying agent and finally suspending the
globules in the oily phase.

 Phase inversion method
 In this method, the aqueous phase is first added to the
oil phase so as to form a W/O emulsion. At the
inversion point, the addition of more water results in
the inversion of emulsion which gives rise to an O/W
emulsion.
 Continental and dry gum method
 Extemporaneously emulsions are usually made by
continental or dry gum method. In this method, the
emulsion is prepared by mixing the emulsifying
agent (usually acacia) with the oil which is then mixed
with the aqueous phase. Continental and dry gum
methods differ in the proportion of constituents.

In this method, the proportion of the constituents is same as
those used in the dry gum method; the only difference is the
method of preparation. Here, the mucilage of the emulsifying
agent (usually acacia) is formed. The oil is then added to the
mucilage drop by drop with continuous titration.
Membrane emulsification method
It is a method, which is based on a novel concept of
generating droplets “drop by drop” to produce emulsion.
Here, a pressure is applied direct to the dispersed phase which
seeps through a porous membrane into the continuous phase
and in this way the droplets formed are then detached from
the membrane surface due to the relative shear motion
between the continuous phase and membrane surface.

 Stability of emulsions A very important parameter for emulsion
products is their stability; however, the evaluation of emulsion
stability is not easy. Pharmaceutical emulsion stability is
characterized by the absence of coalescence of dispersed phase,
absence of creaming and retaining its physical characters like
elegance, odour, colour and appearance. The instability of emulsion
may be classified into four phenomenons Flocculation,
creaming, coalescence and breaking.
 Creaming is the phenomenon in which the dispersed phase
separates out, forming a layer on the top of the continuous phase.
It is notable that in creaming, the dispersed phase remains in
globules state so that it can be redispersed on shaking. Creaming can
be minimized if the viscosity of the continuous phase is increased.

EMULSION STABILITY ASSESSMENT
Emulsion stability must be regarded in terms of physical
stability of emulsion system examined and the physical and
chemical stability of the emulsion components .
Macroscopic examination
The degree of creaming or coalescence occurring per unit
period of time can give the assessment of emulsion physical
satiability. This procedure is carried out by calculating the
ratio of the volume of the creamed part (separated part) of
the emulsion and the total volume of
the product.
Determination of particle size and particle count/globule
size analysis
Determination of changes in the average particle size is one
of the parameters used for assessing emulsion stability.
Optical microscopy, Andreasen apparatus and Coulter
counter apparatus are used for this purpose.

Determination of viscosity/viscosity changes
A change in the globule size or number or migration of
emulsifying agent during aging may be detected by a
change in apparent viscosity. Emulsions follow non-Newtonian
flow characteristics. Flocculation in O/W emulsions results in an
immediate increase in Viscosity.
Determination of electrophoretic properties
Zeta potential is an important parameter used for assessing
emulsion stability, since electric charges on the particles
affect the rate of flocculation. Electrostatically emulsion
stabilization is due to the mutual repulsion between electrical
double layer of both phases. Such type of stability is very
sensitive to the ionic strength of solution, as the concentration
of electrolyte increases the electrical double layer compressed
and the distance of electrostatic repulsion is reduced resulting in
flocculation.

 Dilution test/miscibility test
 Miscibility test involves the addition of continuous phase, e.g.
in case of O/W emulsion; the emulsion remains stable upon
unlimited addition of water but will become unstable upon
unlimited addition of oil, that is, the oil will separate. Vice
versa is the case with W/O emulsion
 Electrical conductivity test
 Water is a good conductor of electricity; hence, an emulsion
with water continuous phase will readily conduct electricity
while that with oil continuous phase will not.
 Staining test/dye-solubility test
 In this test, a small amount of water soluble dye, such as
methylene blue is added to the emulsion, now if water is the
continuous phase (O/W emulsion), dye will dissolve uniformly
throughout the system. If oil is the continuous phase (W/O
emulsion), dye will remain as cluster on the surface of the
system.

A Pharmaceutical suspension is a disperse system in which
internal phase is dispersed uniformly as finely divided
insoluble particles throughout the external phase. The internal
phase consisting of insoluble solid particles having a specific
range of size which is maintained uniformly throughout the
suspending vehicle with aid of single or combination of
suspending agent.The external phase (suspending medium) is
generally aqueous in some instance, may be an organic or oily
liquid for non oral use.
FORMULATION OF SUSPENSIONS
The three steps that can be taken to ensure formulation of an
elegant pharmaceutical suspension are:
1.CONTROL PARTICLE SIZE. On a small scale, this can be
done using a mortar and a pestle to grind down ingredients to
a fine powder.
2. Use thickening agent to increase viscosity of the vehicle by
using suspending agents or viscosity increasing agents.
3. Use of a wetting agent/ surfactants

Factors that contribute to appreciable stability of a suspension
include:
a)Small particle size- reduce the size of the dispersed particle
increases the total surface area of the solid. The greater the
degree of subdivision of a given solid the larger the surface
area. The increase in surface area means also an increase in
interface between the solids and liquids leading to an increase in
viscosity of a system.
b). Increasing the viscosity – increasing the viscosity of the
continuous phase can lead to the stability of suspensions. This is
so because the rate of sedimentation can be reduced 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 preparation.

 C). TEMPERATURE.
 Another factor which negatively affects the stability and
usefulness of pharmaceutical suspensions is fluctuation of
temperature.
 Temperature fluctuations can lead to caking and claying.

Self-microemulsifying drug delivery (SMEDDS) is the one of
the method for the improvement of oral bioavailability.
SMEDDS are class of emulsion that has received particular
attention as a means of enhancing oral bioavailability of
poorly absorbed drugs. These systems are essentially mixes of
oil and surfactant (sometimes with added co surfactant) that
form emulsion on mixing with water with little or no energy
input.
SMEDDS or self-emulsifying oil formulations (SEOF) are
defined as isotropic mixtures of natural or synthetic oils,
solid or liquid surfactants, or alternatively, one or more
hydrophilic solvents and co-solvents/surfactants. Upon mild
agitation followed by dilution in aqueous media, such as GI
fluids, these systems can form fine oil-in-water (o/w)
emulsions or microemulsions. Self-emulsifying formulations
spread readily in the GI tract, and the digestive motility of
the stomach and the intestine provide the agitation necessary
for self-emulsification.

Viscosity Theory
As per this theory, an increase in viscosity of emulsions will lead
to an increase in stability.
Film theory Or absorption theory
As per this theory an added emulsifying agenagent forms a
mechanical film by getting adsorbed at Interfaces of liquid. This
offers stability to the emulsions.
Wedge theory
As per this theory monovalent soaps like sodium sterate gives o/w
type emulsions and divalent soaps like calcium sterate gives w/o
type emulsions. This was successfully explained by
accommodation of soap molecules at the interface and subsequent
possible orientation of the soap molecule to give the type of
emulsions. Limitation of this theory is that it could not explain the
stability of emulsions.
Interfacial tension theory
Initially when the oil and water are mixed together they will
become immiscible due to interfacial tension. The added
emulsifying agent reduce the interfacial tension and hence a stable
emulsion is formed.

 Parenterals are the sterile dosage form intended for
administration other than enteral route and extent
their action by directly entering into systemic
circulation.
 CLASSIFICATION :
Based on volume they are classified into two types :
Small volume parenterals (SVP’s)
E.g. Paracetamol IP150 mg(2ml)
Large volume parenterals (LVP’s)
E.g. Piracetam I.P. -200 mg /ml15 ml(20ml)/ 60
ml(100ml)

Based on volume they are classified into two types :
Small volume parenterals (SVP’s)
E.g. Paracetamol IP150 mg(2ml)
Large volume parenterals (LVP’s)
E.g. Piracetam I.P. -200 mg /ml15 ml(20ml)/ 60
ml(100ml)

 Leakage test
The leaker test is intended
to detect incompletely
sealed ampoules, so that
they may be discarded.
 Tip sealed ampoules are
more prone to leak than
pull sealed. ... The visual
inspection is done by
holding the ampule by its
neck against highly
illuminated screens.

1.Membrane Filtration Method
2.Direct Inoculation Method

 30 Sterile units are selected from each batch.
 The weight of 10 individual sterile units is noted and
the content is removed from them and empty
individual sterile units is weighed accurately
 Then net weight is calculated by subtracting empty
sterile unit weight from gross weight.
PYROGEN TEST : The test involves measurement of the
rise in body temperature of rabbit following the IV
injection of a sterile solution into ear vein of rabbit
 Dose not exceeding 10ml per Kg injected intravenously
within a period of not more than 10 min

1. Handbook of preformulation by Srafaraz K. niazi
2. Dosage form design by Dr. Javed ali, Dr. khar
,Dr.Ahuja,1st edition ,2004-2005
3. H. Brittain, Polymorphism in Pharmaceutical Solids,
Marcel Dekker, Inc., 1999.
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