Preformulation unit i uips (2)

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PREFORMULATION
Physical properties
Mr. Tarun Parashar
Asst. prof.
Uttaranchal University
Dehradun

INTRODUCTION
WHAT IS PREFORMULATION?
“It is the study of the physical and chemical properties of the
drug prior to compounding process”.
• Objective :
To generate useful information to the formulator to design
an optimum drug delivery system.
• Prior to the development of any dosage form new drug, it is
essential that certain fundamental physical & chemical
properties of drug powder are determined.
• These studies should focus on physicochemical properties of
new compound that affect drug performance & development of
efficacious dosage form.

Goals of preformulation
 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.
In short
 Quantization of physical and chemical properties will assist in
developing a;
a. Stable
b. Safe
c. Effective formulation
3

THE MAJOR AREAS OF PREFORMULATION
STUDY
I. Physical description and Bulk Characterization:
 Crystallinity and Polymorphism
 Hygroscopicity
 Fine Particle Characterization
 Thermal Effects
 Powder Flow Properties
5

II. Solubility Analysis :
 Ionization Constant pKa
 pH Solubility Profile
 Common Ion Effect
 Solubilization
 Partition Coefficient
 Dissolution
III. Stability Analysis :
 Solid-State Stability
 Solution-Phase Stability
 Compatibility Studies: Stability in the Presence of
Excipients 6

PHYSICAL CHARACTERIZATION
 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 than gases.
 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

PHYSICAL DESCRIPTION AND BULK
CHARACTERIZATION
 Bulk properties for the solid form such as particle size,
bulk density and surface morphology are likely to
change during process of development.
 The various physical and bulk characteristics are
explained as follows:
8

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

AMORPHOUS DRUGS
 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 less stable forms. This instability can occur
during bulk processing or within dosage forms. 10

E.g. Novobiocin :
 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

CRYSTALLINE DRUGS
 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

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

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

THERMAL ANALYSIS
 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

Applications:
 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

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

HYGROSCOPICITY
 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

Hygroscopic substances:
It adsorbs water because of hydrate formation or
specific site adsorption.
Deliquescent materials:
Adsorb sufficient water to dissolve completely
 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
into the drug sample. 21

FINE PARTICLE CHARACTERIZATION
 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.
 Certain physical and chemical properties of drug
substances are affected by the particle size
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.
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)

Particle size can influence variety of important
factors:
- Dissolution rate
- Suspendability
- Uniform distribution
- Penetrability
- Lack of grittiness
Methods to Determine Particle Size
• Sieving
• Microscopy
• Sedimentation rate method
• Light energy diffraction
• Laser holography
• Cascade impaction

1. Sieving method :
• Range : 50 – 150 µm
• Simple, inexpensive
• If powder is not dry, the apertures get clogged.
2. Microscopy :
• Range : 0.2 – 100 µm
• Particle size can be determined by the use of
calibrated grid background.
• Most direct method.
• Slow & tedious method.
3. Sedimentation method :
• Range : 1 - 200 µm
• Andreasen pipette is used.
4. Cascade impaction :

• The principle that a particle driven by an
airstream will hit a surface in its path, provide
that its inertia is sufficient to overcome the drug
force that tends to keep in it in airstream.
5. Light energy diffraction :
• Range : 0.5 – 500 µm
• Particle size is determined by the reduction in
light reaching the sensor as the particle,
dispersed in a liquid or gas, passes through the
sensing zone.
• Quick & fast.
6. Laser holography :
• Range : 1.4 – 100 µm

• A pulsed laser is fired through an aerosolized
particle spray & photographed in three
dimensional with holographic camera, allowing
the particles to be individually imaged & sized.
23
27

SURFACE MORPHOLOGY
 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
 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

POWDER FLOW PROPERTIES
 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

The Angle Of Repose:
 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 of repose.
 Lower values indicates better flow characteristics.
31

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

 Compressibility:
It can be characterized by the following methods;
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

The acceptance criteria for carr`s index are :
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

2. Hausner `s ratio:
 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

SOLUBILITY
 The solubility of drug is an important
physicochemical property because it affects the rate of
drug release into the dissolution medium and
consequently, 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 polar solvents 36
➢ 2. Non-polar solutes dissolve in non-polar solvents

Common solvents used for solubility determination are:
 Water

 Polyethylene Glycols

 Propylene Glycol

 Glycerine

 Sorbitol

 Ethyl Alcohol

 Methanol

 Benzyl Alcohol

 Isopropyl Alcohol

 Tweens

 Polysorbates

 Castor Oil

 Peanut Oil
 Sesame Oil
37
Buffers at various pHs

SOLUBILITY DETERMINATION
Description Approximate Solubility(%w/v)
weight of
solvent(g)
necessary to
dissolve 1g of
solute
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

Ionization constant (pKa)
 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 is
dependent on the pH of the solution.
 The method for the determination of pKa according
to the nature of drug can be explained as:
39

pKa Determination By Nature of
Drug
Nature of drug Ionization pKa
Very weak acid Unionized at all pH >8
Moderately weak Unionized at 2.5-7.3
acid gastric pH-1.2
Strong acid Ionize at all pH <2.5
Very weak base Unionize at all pH <5
Moderately weak Unionize at 5-11
base intestinal pH
Strong base Ionize at all pH >11
40

 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 = pKb + log ([ionized drug]/[un-ionized drug])

Methods for determination of pKa:
The various methods for the determination of pKa are;
a. Potentiometric method
b. Spectrophotometric method
c. Solubility method
d. Conductometric method
42

Partition coefficient
 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.
Drugs having values of P much greater than 1 are
classified as lipophilic, whereas those with partition
coefficients much less than 1 are indicative of a43
hydrophilic drug

Stability studies
 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.
 Factors affecting chemical stability critical in
rational dosage form design include ;
➢ Temperature
➢pH
➢Dosage form diluents

 The effect of pH on drug stability is important in the
development of both oral and parenteral dosage
forms
 Buffer selection for parenteral dosage forms will
also be largely based on the stability characteristics
of the drug.

Preformulation unit i uips (2)

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