2. AFTER THIS LECTURE, YOU ALL SHOULD
KNOW:-
❖ DEFINATION AND IMPORTANCE OF
PREFORMULATION IN PHARMACY.
❖ STEPS INVOLVED IN PREFORMULTION.
❖ ORGANOLEPTIC PROPERTIES.
❖ PURITY, PARTICLE SIZE SHAPE AND
SURFACE AREA.
❖ SOLUBILITY AND DISSOLUTION OF DRUG
SUBSTANCE
❖ CHEMICAL REACTION INVOLVING DRUG
EXCIPIENT INTERACTIONS AND FACTORS
AFFECTING ABSORPTION OF DRUGS.
3. INTRODUCTION
Definition
It is defined as the phase of R&D in which
preformulation studies characterize physical and
chemical properties of a drug molecule in order to
develop safe,effective and stable dosage form.
Goals of preformulation
⮚ Quantization of physical and chemical
properties will assist in developing a;
a. Stable
b. Safe
c. Effective formulation
4. IMPORTANCE OF PREFORMULATION IN
PHARMACY:-
❖ Preformulation testing is the first step in the rational
development of dosage form of a drug substance.
❖ Preformulation forms an indespensible part of the
inovator company as well as generic companies.
❖ Preformulation testing generate information useful
to the formulator in developing stable and bioavilable
dosage forms.
❖ The necessity of preformulation is not only
acknowledged by most companies it is to a
certain extent prerequisite and forms back bone
for R&D.
5. A- Physical description and Bulk
Characterization
1. Crystallinity and polymorphism
2. Hygroscopicity
3. Fine particle characterization
4. Powder flow properties
B- Solubility analysis
1. Ionization constant (pKa)
2. Partition coefficient
3. Aquous solubility
4. pH-Solubility Profile
C- Stability analysis
1. Photolytic stability
2. Stability to Oxidation
3. Compatibility studies
Major areas of preformulation
studies
6. A. Physical description and Bulk
Characterization:
1- CRYSTALLINITY AND POLYMORPHISM
⮚ Solid drug materials may occur as:
a. Amorphous (higher solubility)
b. Crystalline (higher stability)
Scientists prefer crystalline form due to stablility.
e.g Crystalline form of penicilline G is more stable
But sometime it is necessary to use amorphus
form as in the case of Novobiocine
7. Polymorphism
⮚ Different polymorphs exhibits different
solubilities,therapeutic activity and
stability.
✔ Companies prefer to develop the most
stable polymorph
⮚ Pseudopolymorphism
Solvates
Hydrates
Determination method:
Thermodyanamically-van,t Hoff plot(solubility vs
temperature)
Directly – by microscopic determination
8. 2- HYGROSCOPICITY
Ability of substance to absorb moisture
from environment.
⮚Changes in moisture level can
greatly influence many parameters
such as; chemical stability ,
flowability , and compatibility.
Methods
I. Gravimetric method
II. Karl Fischer titration
9. 3- FINE PARTICLE
CHARACTERIZATION
⮚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 , and
sedimentation rates.
10. METHODS TO EVALUATE PARTICLE
SIZE
1.Sieving or screening
2.Optical microscopy
3.Sedimentation
4.Coulter counter method .
11. 1. Sieving and screening
● Sieving is a separation technique based on the difference in
particle size. The sieve is responsible for retaining the larger
particles.
● Sieving is a traditional and a very easy method of separation
since it doesn’t require much of your skills.
● It is a cheap method as the installation cost is very low.
● It takes lesser time in comparison to other methods of
separation.
12. 2. Optical Microscopy
● The optical microscope, also referred to as a light
microscope, is a type of microscope that commonly
uses visible light and a system of lenses to generate
magnified images of small objects. Optical microscopes are
the oldest design of microscope and were possibly invented
in their present compound form in the 17th century. Basic
optical microscopes can be very simple, although many
complex designs aim to improve resolution and
sample contrast.
13. 3. Sedimentation
● Sedimentation is the tendency for particles in
suspension to settle out of the fluid in which they are
entrained and come to rest against a barrier.
● This is due to their motion through the fluid in
response to the forces acting on them: these forces can
be due to gravity, centrifugal acceleration, or
electromagnetism.
14. 4. Coulter Counter Method
● Wallace H. Coulter developed a technology for counting and sizing
particles using impedance measurements.
● The technology was principally developed to count blood cells
quickly by measuring the changes in electrical conductance as cells
suspended in a conductive fluid passed through a small orifice. In the
past seventy-five years, the technology has also been used to
characterize thousands of different industrial particulate materials.
● The particles to be measured must be suspended at low
concentration in an electrically-conductive fluid, usually a solution of
electrolyte in water or in an organic liquid.
15. 4- POWDER FLOW PROPERTIES
Flow properties are significantly affected
by:
Changes in particle size,
density,
shape,
adsorbed moisture
Methods of determination
⮚ Angle of repose
⮚ Compressability index
⮚ Hausner’s Ratio
which may arise from
processing or formulation.
16. Types of different densities:-
● Bulk density is the amount of powder by weight that is present in a defined volume. It is usually
expressed as g ml−1 and is obtained by measuring the volume of a fixed weight of powder after it has
been tapped for a defined number of times.
● The tapped density (ρT) is determined by tapping the cylinder 300 times, followed by the measurement
of compacted volume (VT) .
17. 1. Angle of Repose
● The angle of repose, or critical angle
of repose, of a granular material is the
steepest angle of descent
or dip relative to the horizontal plane
to which a material can be piled
without slumping.
● At this angle, the material on the slope
face is on the verge of sliding. The
angle of repose can range from 0° to
90°.
● The morphology of the material
affects the angle of repose; smooth,
rounded sand grains cannot be piled as
steeply as can rough, interlocking
sands
18.
19. 2. Compressibility index
● The Compressibility Index is measure of the propensity of a powder to be
compressed
● it is measure of the powder’s ability to settle, and it permit an assessment of
the relative importance of inter-particulate interactions.
● Compressibility index and flow ability is related.
● In a free-flowing powder, such interactions are less significant, and the bulk
and tapped densities will be closer in value.
● For poorer flowing materials, there are frequently greater interparticle
interactions, and a greater difference between the bulk and tapped densities
will be observed.
20. 3. Hausner’s ratio
● The Hausner ratio is a number that is correlated to the flowability of
a powder or granular material. It is named after the engineer Henry H.
Hausner (1900–1995).[1][2]
● The Hausner ratio is calculated by the formula
21.
22. Steps in Preformulation Process Pharmaceutical Research
1. Stability
a. Solid State
(1) Temperature
(2) Light
(3) Humidity
b. Solution
(1) Solvent
(2) pH
(3) Light
2. Solid State Compatibility
a. TLC Analysis
b. DRS Analysis
3. Physico-chemical Properties
b. Molecular Structure and Weight
c. Color
d. Odor
e. Particle size, Shape, and Crystallinity
f. Melting Point
g. Thermal Analysis Profile
(2) DTA
(3) DSC
(4) TGA
23. Cont.
4. Physico-mechanical Properties
a. Bulk and Tapped Density
b. Compressibility
c. Photomicrograph
5. In Vitro Availability Properties
a. Dissolution of Drug Crystal Per sec.
b. Dissolution of Pure Drug Pellet
c. Dissolution Analysis of Pure Drug
d. Rat Everted Gut Technique
6. Other Studies
a. Plasma Protein Binding
b. Effect of Compatible Excipients on Dissolution
c. Kinetic Studies of Solution
● Degradation
d. Use of Radio-labeled Drug
24. Cont...
b. Hygroscopicity Potential
c. Absorbance Spectra
(2) UV
(3) IR
i. Solubility
(1) Water and Other Solvents
(2) pH-Solubility Profile
(3) Salt Forms
(4) Cosolvents
(5) Complexation
(6) Prodrug
j. Effect of pH on UV Spectra
k. Ionization Constant
l. Volatility
m. Optical Activity
n. Polymorphism Potential
o. Solvate Formation
25. B- Solubility analysis
1. Ionization constant (pKa)
⮚ The dissociation constant (Ka) is a value used to
describe the tendency of compounds or ions to
dissociate.
⮚ Determination of the Pka for a drug capable of
ionization within a pH range of 1to10 is important since
solubility, and consequently absorption, can be altered
by changing pH.
Methods for determination of pKa:
a. Potentiometric method
b. Spectrophotometric method
c. Solubility method
d. Conductometric method
26. 2- Partition coefficient
●The concentration ratio of a substance distributed between two phases
(i.e., octanol and water) at equilibrium:
●P = Co/Cw
●Determined by Shak Flask Method
⮚Partition Coefficient is usefull because:
• It measure lipophilicity
• Major role in drug transport
• Analytical separation
27. 3- Aqueous solubility
The concentration at which the solution phase is in equilibrium
with a given solid phase at a stated temperature and pressure.
Determination
Aquous solubility is determined when excess of drug is added to
certain aqueuous media, and agitated until equilibrium is achieved.
General Method of Increasing the Solubility
❖ Addition of co-solvent
❖ pH change method
❖ Reduction of particle size
❖ Temperature change method
❖ Addition of Surfactant
❖ Complexation
28. 4- pH-Solubility Profile
. Excess drug
powder
Stir in beaker
with distilled
water
Continuous
stirring of
suspension
Add
acid/base
Measure
pH of
suspension
Determine the
concentration
of drug in
the filtrate
SOLUBILITY pH
29. C- Stability analysis
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
31. Compatibility studies
1. The knowledge of drug excipients interaction is useful
for the formulation to select appropriate excipients.
2. 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 .
3. 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.
33. ORGANOLEPTIC PROPERTIES:-
❖ “Organoleptic Properties are those properties
which are evaluated after an impression on the
organs of sense”
❖ It refers to the evaluation of drugs by properties like
–colour, odour, taste, size, shape and special
features like touch, texture, etc..it is a technique of
qualitative evaluation based on the study of
morphological and sensory profile of whole drugs.
❖ The aromatic odour of fruits, sweet taste of
liquorice, the ovoid tears of gum acacia are some
examples of this type of evaluation.
36. Colour testing:
❖ Colour can be useful, while describing different
batches of drug, it can sometimes be used as an
indicator of solvent presence or more importantly of
degradation.
❖ In addition subtle difference in colour due to
particle size distribution.
❖ Colour of various drug formulation may indicate
the degradation process,the colour of certain types
of formulation can be improved by adding certain
dyes.
37. Taste testing:
⮚Taste of the formulated drug plays an important role in
consumers acceptance.
⮚ Unpalatable drugs which do not have good taste,
problem may be solved by incorporation of-
● Flavouring
agents.
● Excipients.
● Coating.
38. Odour testing:
⮚Odour plays an important role in drug formulation and
any strong odour should not be present for consumers
acceptance of the consumers finished product.(such as
capsules, tablets, syrups etc..)
⮚Odour provides an indication of the quality of
formulation.eg:-characteristic odour of acetic acid in
degradation of aspirin.
⮚Presence of odour may also be the characteristic of the
drug.eg:- vitamins
40. Oxidation:
●It is very common pathway for drug degradation in both liquid and solid formulation.
⮚ Oxidation is the gain of oxygen, loss of hydrogen and/or loss of
electrons
● When iron reacts with oxygen it forms a chemical called rust. The iron is
oxidized and the oxygen is reduced.
❑ Oxidation occurs in two ways
⮚ Auto oxidation
⮚ Free radical oxidation
41. Functional group having high susceptibility
towards oxidation:-
⮚ Substituted aromatic group (Toluene, Phenols,
Anisole).
⮚ Alkenes
⮚ Ethers
⮚ Thioethers
⮚ Amines
Commonly viewed example of
oxidation in daily life
42. FACTORS AFFECTING OXIDATION PROCESS
1) Oxygen concentration
2) Light
3) Heavy metals particularly those having two or
more valence state
4) Hydrogen & Hydroxyl Ion
5) Temperature
43. PREVENTION OF OXIDATION
1) Reducing oxygen content
2) Storage in a dark and cool condition
3) Addition of chelating agent (Eg. EDTA, Citric acid,
Tartaric acid)
4) Adjustment of pH
5) Changing solvent (Eg. Aldehydes, ethers, Ketones,
may influence free radical reaction)
6) Addition of an antioxidant or reducing agent
(e.g. H2, CO, Zn etc.).
44. HYDROLYSIS
o It is the cleavage of chemical bonds by the addition of water.
o The reaction of water with another chemical compound
to form two or more products, involving ionization of the
water molecule usually splitting the other compound.
● Examples include :
o the catalytic conversion of starch to glucose, saponification, and
the formation of acids or bases from dissolved ions.
● When this attack is by a solvent other than water than it is known as solvolysis
45. Conditions that catalysis the breakdown
• Presence of hydroxyl ion
• Presence of hydride ion
• Presence of divalent ion
• Heat
• Light
• Ionic hydrolysis
• Solution polarity and ionic strength
• High drug concentration
46. PHOTOLYSIS:
⮚ Photo dissociation, photolysis,
or photodecomposition is a
chemical reaction in which a
chemical compound is broken
down by photons.
⮚ Since a photon's energy is
inversely proportional to its
wavelength, electromagnetic
waves with the energy of visible
light or higher, such as ultra violet
, X-rays and gamma rays are
usually involved in such
reactions.
47. PREVENTION OF PHOTODECOMPOSITION
o Suitable packing.
o Eg. Yellow-green glass gives the best protection in U.V. region while
Amber gives considerable
●protection against U.V. radiation but little from I.R.
o Protection of drug from light
● Eg. Nifedipine is manufactured under Na light.
o Avoiding sunbath.
48. RACEMIZATION
⮚ Racemization is the process in which one enantiomer of a compound, such as an L-
amino acid, converts to the other enantiomer.
⮚ The compound then alternates between each form while the ratio between the (+) and
(–) groups
● approaches 1:1, at which point it becomes optically inactive.
⮚ If the racemization results in a mixture where the enantiomers are present in equal
quantities, the resulting sample is described as racemeric or a racemate.
49. ⮚ The inter-conversion from one isomer to another can lead to
o different pharmacokinetic properties (ADME) as well as
o different pharmacological &
o toxicological effect.
⮚ Example: L-epinephrine is 15 to 20 times more active than D-
form, while activity of
racemic mixture is just one half of the L-form.
⮚ It depends on
o temperature,
o solvent,
o catalyst &
o presence or absence of light