PREFORMULATION.ppt

CONTENTS
 Introduction
 Organoleptic properties
 Purity
 Particle size, shape and surface area
 Solubilisation, or solubility, Surfactants and its importance
 Temperature, pH, co-solvency, solid dispersion, β-
cyclodextrin drug-dispersion system
 Crystal properties and polymorphism
 Compatibility studies
 Preformulation stability studies
A consideration of physico-chemical characteristics of new
drug molecules with respect to different dosage forms
4/25/2023
MMCP 2

Preformulation
 Preformulation is 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.
4/25/2023
MMCP 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”.
Preformulation commences when a newly
synthesized drug shows a sufficient pharmacologic
promise in animal model to warrant evaluation in
man.
4/25/2023
MMCP 4

Introduction
 The preformulation is the first step in the rational
development of a dosage form of a drug substance
alone and when combined with excipients.
 Objective :
To generate useful information to the
formulator to design an optimum drug delivery
system.
4/25/2023
MMCP 5

Introduction
 Before embarking on a formal programme of
preformulation, scientist must consider the following
:
1. Available physicochemical data (including
chemical structure, different salt available).
2. Anticipated dose.
3. Supply situation and development schedule.
4. Availability of stability – indicating assay.
4/25/2023
MMCP 6

GOALS OF PREFORMULATION
 To establish the necessary physicochemical
parameters of new drug substances.
 To determine kinetic rate profile.
 To establish physical characteristics.
 To establish compatibility with common
excipients.
4/25/2023
MMCP 7

Preliminary Evaluation
a) Compound identity.
b) Formula and molecular weight.
c) Structure.
d) Therapeutic indications:
- Probable human dose.
- Desired dosage form(s)
- Bioavailability model
- Competitive products
4/25/2023
MMCP 8

Preliminary Evaluation
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
4/25/2023
MMCP 9
Contd…

ORGANOLEPTIC PROPERTIES
COLOR ODOUR TASTE
OFF-WHITE PUNGENT ACIDIC
CREAM-YELLOW SULFUROUS BITTER
SHINY FRUITY SWEET
AROMATIC TASTELESS
ODOURLESS TASTELESS
4/25/2023
MMCP 10

COLOR
 Color is generally a function of a drug’s inherent
chemical structure relating to a certain level of
unsaturation.
 Color intensity relates to the extent of unsaturation as
well as the presence of chromophores.
 Some compound may appear to have color although
structurally saturated.
4/25/2023
MMCP 11

ODOUR
 The substance may exhibit an inherent odor
characteristic of major functional groups present.
 Odor greatly affects the flavor of a preparation or
food stuff.
TASTE
 If taste is considered as unpalatable, consideration is
to be given to the use of a less soluble chemical form
of the drug.
 The odour and taste may be suppressed by using
appropriate flavors and excipients or by coating the
final product.
4/25/2023
MMCP 12

PURITY
 Designed to estimate the levels of all known &
significant impurities & contaminates in the drug
substance under evaluation.
 Study performed in an analytical research &
development group.
 It is another parameter which allows for comparison
with subsequent batches.
 Occasionally, an impurity can affect stability.
e.g.
- Metal contamination
- Appearance
4/25/2023
MMCP 13

PURITY
 The techniques used for characterizing the purity of a
drug are the same as those used for other purpose in a
preformulation study.
 Thin layer chromatography is a wide ranging
applicability & is an excellent tool for characterizing
the purity.
 HPLC, paper chromatography & gas
chromatography are also useful.
 More quantitative information can be obtained by
using quantitative differential scanning calorimetry.
4/25/2023
MMCP 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)
4/25/2023
MMCP 15

PARTICLE SIZE
 Particle size can influence variety of
important factors :
- Dissolution rate
- Suspendability
- Uniform distribution
- Penetrability
- Lack of grittiness
4/25/2023
MMCP 16

Methods to Determine Particle Size
 Sieving
 Microscopy
 Sedimentation rate method
 Light energy diffraction
 Laser holography
 Cascade impaction
4/25/2023
MMCP 17

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.
4/25/2023
MMCP 18

3. Sedimentation method :
 Range : 1 - 200 µm
 Andreasen pipette is used.
 Particle size is calculated by Stoke’s law :
dst =
Where,
h = distance of fall in time, t
n = viscosity of the medium
ρs = density of the particles
ρ0 = density of the dispersion medium
g = acceleration due to gravity
4/25/2023
MMCP 19
18 η h
(ρs -ρ0) gt

4. 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.
5. 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.
4/25/2023
MMCP 20

6. 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.
4/25/2023
MMCP 21

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.
4/25/2023
MMCP 22

Determination Of Powder Flow Properties
 By determining Angle Of
Repose.
 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
4/25/2023
MMCP 23

 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.
4/25/2023
MMCP 24

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
4/25/2023
MMCP 25

PARTICLE SHAPE
4/25/2023
MMCP 26
Cont…

PARTICLE SHAPE
 Particle shape will influence the surface area, flow of
particles, packing & compaction properties of the
particles.
 A sphere has minimum surface area per unit volume.
 Therefore, these properties can be compared for
spheres & asymmetric particles, in order to decide
the shape.
 The following expression can be obtained:
Property Sphere particle
surface area πds
2 αs x dp
2
volume (1/6)πds
3 αv x dp
3
4/25/2023
MMCP 27
Cont…

PARTICLE SHAPE
 Therefore,
surface area = πds
2 = αs x dp
2
Volume = (1/6)πds
3 = αv x dp
3
 Solving for αs & αv by equating the appropriate properties
provides:
αs =
πds
2 & αv =
πds
3
 When particle shape is spherical, the ds = dp
 Thus, αs = π = 3.124 & αv = π/6 = 0.524
 Therefore, Shape factor = αs = 3.124 = 6
αv 0.524
4/25/2023
MMCP 28
dp2 6 dp3

SURFACEAREA
 Particle size & surface area are inversely related
to each other.
 Smaller the drug particle, greater the surface area.
 Specific surface is defined as the surface area per
unit weight (Sw) or unit volume (Sv) of the
material.
4/25/2023
MMCP 29

SURFACEAREA
 Estimation of Sw:
Sw = Surface area = Surface area
Weight density x volume
= Sv
ρ
= 6
ρ . d
4/25/2023
MMCP 30

Methods for determining
surface area
1. Adsorption method :
 Particles with a large specific surface are good
adsorbents for the adsorption of gases & of solutes
from solution.
 The volume of nitrogen gas, Vm, in cm3 that 1 g of the
powder can adsorb when the monolayer is complete is
more accurately given by using the BET equation,
however, which can be written as:
P = 1 + (b-1) . P
V(P0 – P) Vmb Vmb P0
4/25/2023
MMCP 31
Cont….

Methods for determining
surface area
 Where,
V = Volume of gas in cm3 adsorbed per gram of powder
at pressure P.
P = Pressure of the adsorbate, in mmHg.
Po= Saturation vapor pressure (monolayer)
Vm= Amount of vapor adsorbed per unit mass adsorbent,
when the surface is covered with monomolecular
layer
b = Constant that express the difference between the
heat of adsorption & heat of liquefaction of the
adsorbate (nitrogen).
4/25/2023
MMCP 32

Air permeability method :
4/25/2023
MMCP 33

HOWEVER SIZE REDUCTION
IS NOT REQUIRED IN FOLLOWING CASES
 WHEN DRUG IS UNSTABLE.
 DEGRADE IN SOLUTION FORM.
 PRODUCE UNDESIRABLE EFFECTS.
 WHEN SUSTAINED EFFECT IS DESIRED.
4/25/2023
MMCP 34

 The amount of substance that passes into
solution in order to establish equilibrium at
constant temperature and pressure to
produce a saturated solution.
4/25/2023
MMCP 35

 If solubility is <1mg/ml indicates need for salt
formation to improve solubility.
 If solubility is <1mg/ml in pH= 1 to 7,
preformulation study should be initiated.
 Solubility should ideally be measured at two
temperatures: 4°C and 37°C.
 4°C to ensure Physical stability.
 37°C to support Biopharmaceutical evaluation.
4/25/2023
MMCP 36

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
4/25/2023
MMCP 37

SOLUBILITY ANALYSIS
 Preformulation solubility studies focus on drug
solvent system that could occur during the delivery of
drug candidate.
 For e.g. A drug for oral administration should be
examined for solubility in media having isotonic
chloride ion concentration and acidic pH.
4/25/2023
MMCP 38

 Analytic method that are particularly useful
for solubility measurement include HPLC, UV
spectroscopy, Fluorescence spectroscopy and
Gas chromatography.
 Reverse phase HPLC offer accurate and
efficient mean of collecting solubility data of
drug.
4/25/2023
MMCP 39
SOLUBILITY ANALYSIS

 Ionization constant (pKa)
Can be calculated by Henderson Hasselbach
equation-
For acidic drugs….pH= pKa+ log [ionized drug]
[unionized drug]
For basic drugs….pH= pKa+ log[unionized drug]
[ionized drug]
4/25/2023
MMCP 40

 pH Solubility Profile
 The solubility of acidic or basic drug will show
difference in solubility with changes in pH.
 pH solubility profile of a drug can be established
by running the equilibrium solubility experiment
within pH range of 3-7.
4/25/2023
MMCP 41

 Partition Coefficient
 It is the ratio of unionized drug distributed
between organic and aqueous phase at equilibrium.
P o/w = ( C oil / C water )equilibrium
4/25/2023
MMCP 42

 Effect Of Temperature
 The heat of solution Hs, represents the heat
released or absorbed when a mole of solute is
dissolved in large quantity of solvent.
 Endothermic reaction
 Exothermic reaction
4/25/2023
MMCP 43

Determination of solubility
 The following points should be considered
 The solvent & solute must be pure.
 A saturated solution must be obtained before any
solution is removed for analysis.
 The method of separating a sample of saturated
solution from undissolved solute must be
satisfactory.
 The method of analyzing solution must be reliable
 Temperature must be adequately controlled .
4/25/2023
MMCP 44

 Addition of co-solvent
 pH change method
 Reduction of particle size
 Temperature change method
 Hydotrophy
 Addition of Surfactant
 Dielectrical Constant
 Complexation
4/25/2023
MMCP 45
General Method of Increasing
the Solubility

• Weak Electrolyte :- Phenobarbitone
• Non polar :- Nitro Cellulose
 These are poorly soluble in given solvent.
 For such poorly soluble materials, to enhance
their solubility, the water miscible solvents are used
in which the drug has good solubility.
 This process of improving solubility is known as
co-solvency and the solvent used is known as co-
solvents.
4/25/2023
MMCP 46
Addition Of Co-Solvent

e.g. Phenobarbitone is insoluble in water. A clear
solution is obtained by dissolving in mixture of
Alcohol, Glycerin, Propylene glycol.
e.g. Cosolvents:-
PG, glycerin, sorbitol, PEG, Glyceryl formal,
glycofurol, ethyl carbamate, ethyl lactate and
dimethyl acetamide.
4/25/2023
MMCP 47
Addition Of Co-Solvent

pH change Method
 Weak base:- Alkaloids, Local Anaesthesia
 Weak acid:- Sulphonamides, Barbiturates
 In aqueous medium they dissociate poorly and
undissociated portion is insoluble.
e.g. Benzoic acid, Phenobarbitone
 So, solubility of the undissociated portion is
improved by pH control.
For weak acidic drug:- increase pH, solubility is
increase.
 For weak base drug:- decrease pH, increase
solubility.
4/25/2023
MMCP 48

 Reduction in Particle size improve solubility of
drug.
 Basically reduction in particle size increase contact
surface area of the particle, there by ultimately it
increase rate of solubility of drug.
Reduction Of Particle size
4/25/2023
MMCP 49

 In endothermic reaction by increasing temperature
solubilityisincrease.
 In exothermic reaction by increasing temperature
solubility is decrease.
e.g. Methyl Cellulose when mixed with water and
temperature is raised, it becomes insoluble. To
dissolve it cold water is added.
4/25/2023
MMCP 50
Temperature Change Method

The term Hydotrophy has been used to designate the
increase in solubility in water of various substances
due to the presences of large amount of additives.
e.g. Solubilization of Benzoic acid with Sodium
benzoate.
4/25/2023
MMCP 51
Hydotrophy

 Surfactants are molecules with well defined polar
and non-polar region that allow them to aggregate in
solution to form micelles. Non polar drugs can
partition into micelles and be solubilized.
e.g. Surfactant based solution of Taxol, that is
solubilized in 50% solution of Cremophor.
4/25/2023
MMCP 52
Addition of Surfactant

Dielectrical Constant is the effect that substances
has, when it acts as a solvent on the case with which it
separates oppositely charged atoms.
e.g. DEC of Water- 80
Kerosene- 2
Glycerine- 48
.2
4/25/2023
MMCP 53
Dielectrical Constant

Complexation
 For the Complexation occur both drug and ligand
molecule should be able to donate or accept
electrons.
 The solubility of compound is the sum of solubility
of the compound and its complex.
e.g. HgI2 (Mercuric Iodide) is sparingly soluble in
water. Its solubility in water is increased by forming
complex with KI.
HgI2 +2KI K2HgI4 (water soluble)
4/25/2023
MMCP 54

SURFACTANT
 Surfactants:-
are wetting agents that lower the surface
tension of a liquid, allowing easier spreading,
and lower the interfacial tension between two
liquids.
 Classification
Some commonly encountered surfactants of
each type include:
1. Ionic 2. Non ionic
 Cationic
 Anionic
 Zwitterionic
4/25/2023
MMCP 55

IONIC
 Cationic Surfactants:-
 Quaternary ammonium salts are more preferred
because they are less affected by pH.
e.g. Cetyl Trimethyl Ammonium Bromide (CTAB)
Hexadecyl Trimethyl Ammonium Bromide, and other
Alkyltrimethyl Ammonium Salts, Cetylpyridinium
Chloride (cpc)
4/25/2023
MMCP 56

Anionic Surfactants:-
 They are the most commonly used surfactants,
containing Carboxylate, Sulfonate, Sulfate ions.
e.g. Sodium Dodecyl Sulphate (SDS), Ammonium
Lauryl Sulphate and other alkyl sulfate salts, Sodium
Laureth Sulphate, also known as Sodium Lauryl
Ether Sulphate (SLES).
4/25/2023
MMCP 57
IONIC

 Zwitterionic:-
 When a single surfactant molecule exhibit both
anionic and cationic dissociations it is called
amphoteric or Zwitterionic.
The anion include carboxylates and phosphate
group and the cation include quaternary
ammonium group.
e.g. Dodecly Betamine
Dodecly Dimethylamine Oxide
4/25/2023
MMCP 58
IONIC

NONIONIC
 These are most widely used because they are
free from non compatability, stability and
potential toxicity and classified as water soluble
and water insoluble non ionic surfactants.
e.g. Long chain fatty acids, fatty alcohols
 Water solubility of these agents is further
increased by addition of polyoxyethylene groups
through ether linkage with one of the alcohol
group.
e.g. spans
4/25/2023
MMCP 59

4/25/2023
MMCP 60
STABILITY
TESTING….

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
4/25/2023
MMCP 61

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…….
 controlled and documented determination of
acceptable changes of the drug substance or drug
product
4/25/2023
MMCP 62

What are 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
4/25/2023
MMCP 63

Forced degradation studies
 Acidic & Basic conditions.
 Dry heat exposure
 UV radiation exposure
 Influence of pH
 Influence of temperature
 Influence of ionic strength
4/25/2023
MMCP 64

Arrhenius Equation
 K = Ae-Ea /RT
where..k = specific rate of degradation.
R = gas constant ( 1.987 calories degree -1mole)
T = absolute temperature.
A = frequency factor.
4/25/2023
MMCP 65

Arrhenius Equation
 Plot of log K v/s 1/T….yields a slope equal to -Ea/2.303 R ….. From
which heat of activation (Ea) can be calculated.
 Log k2/k1 = ΔHa/2.303 R . (T2 –T1 )/T2.T1
4/25/2023
MMCP 66

Chemical degradation studies
 Hydrolysis
 Oxidation
 Reduction
 Decarboxylation
 Photolysis
4/25/2023
MMCP 67

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)
4/25/2023
MMCP 68
Tablet & Capsule

Testing scope for Oral liquid form
– pH
– Color & clarity of solution
–Viscosity
– Particle size distribution (for oral suspensions only)
– Assay
– Degradation products
– Degradation preservatives
– Content antioxidants
– Functionality tests
4/25/2023
MMCP 69

Testing scope for
LIQUID FORMS for inj. and PARENTRAL
– pH
– Loss on weight
– Color & clarity of solution
– Assay
– Degradation preservatives
4/25/2023
MMCP 70

Testing scope for
SEMI LIQUID FORMS
– Appearance, odor, homogenesity, consistency
– Loss on weight,Viscosity
– Content uniformity (within the container)
– Assay
– Content preservatives
4/25/2023
MMCP 71

Climatic Zones / Storage conditions
Climatic Zone
Countries
Calculated data
Temp. humidity
°C % r.h.
Derived data
Temp humidity
°C % r.h.
Climatic Zone I
"Temperate"
Japan, United Kingdom,
Northern Europe,
Canada, Russia, United
States
20 42 21 45
Climatic Zone II
"Mediterranean,
Subtropical"
Japan, United States,
Southern Europe
26.4 52 25 60
4/25/2023
MMCP 72

Climatic Zones / Storage conditions
Climatic Zone
Countries
Calculated data
Temp. humidity
°C % r.h.
Derived data
Temp humidity
°C % r.h.
Climatic Zone III
"Hot, dry"
Iran, Iraq, Sudan
26,4 35 30 35
Climatic Zone IV
"Hot, humid"
Brazil, Ghana, Indonesia,
Nicaragua,
Philippines
26,7 76
30 70
4/25/2023
MMCP 73

What is ICH?
 ICH stands for International Conference on Harmonization
of
Technical Requirements for Registration of Pharmaceuticals for
Human use
 Objectives of ICH
• Harmonization of registration applications within the three
regions of the EU, Japan and the United States.
• ICH is a joint initiative involving both regulators and industry
as equal partners in the scientific and technical discussions of
the testing procedures which are required to ensure and assess
the safety,quality and efficacy of medicines.
4/25/2023
MMCP 74

What or Who is ICH?
There are Six Parties directly involved in the decision making process
• EU: European Commission - European Union
• EFPIA: European Federation of Pharmaceutical Industries and
Associations
• MHLW: Ministry of Health, Labor andWelfare, Japan
• JPMA: Japan Pharmaceutical Manufacturers Association
• FDA: US Food and Drug Administration
• PhRMA: Pharmaceutical Research and Manufacturers of America
4/25/2023
MMCP 75

 There are additionally observers installed to act as a link
with non-ICH countries and regions
• WHO
•The European FreeTrade Area (EFTA),
represented by Swissmedic Switzerland
• Health Canada
٠Global guidelines
4/25/2023
MMCP 76

ICH Guidelines
• QualityGuidelines “Q” (chemical and pharmaceuticalQA)
– details see next slide
• Safety Guidelines “S” (in vitro and in vivo pre-clinical studies)
– covering CarcinogenicityTesting, GenotoxicityTesting,
Toxicokinetics and Pharmacokinetics ….. etc.
• Efficacy Guidelines “E” (clinical studies in human subject)
– Covering clinical safety, Dose Response Studies, Good
Clinical Practices, Clinical evaluation …. etc.
• Multidisciplinary Guidelines “M”
– Covering MedicalTerminology, Electronic Standards for
Transmission of Regulatory Information …… etc.
– Important for Stability !
» Guideline M4:The CommonTechnical Document (CTD)
4/25/2023
MMCP 77

ICH Q-Guidelines (Quality)
 Stability Testing in Climatic Zone I and II (Q1A)
 Photostability Testing (Q1B)
 Stability Testing for New Dosage Forms (Q1C)
 Bracketing and Matrixing Designs (Q1D)
 Evaluation of Stability Data (Q1E)
 Stability Testing in Climatic Zones III and IV (Q1F)
 Validation of Analytical Procedures (Q2)
 Impurities (Q3)
 Biotechnological Products (Q5)
 Specifications (Q6)
4/25/2023
MMCP 78

Study Storage condition
Minimum time period
covered by data at
submission
Long term 25°C ± 2°C / 60% ± 5% r.h or
30°C ± 2°C / 65% ± 5% r.h.
12 months
Intermediate 30°C ± 2°C / 65% ± 5% r.h. 6 months
Accelerated 40°C ± 2°C / 75% ± 5% r.h. 6 months
4/25/2023
MMCP 79
Drug substances - General case
Drug substances - intended for storage in a Refrigerator
Study Storage condition Minimum time period
covered by data at
submission
Long term 5°C ± 3°C 12 months

Drug substances/Product- intended for storage in Freezer
covered by data at
submission
Long term -20°C ± 5°C 12 months
4/25/2023 MMCP 80
Drug products - General case
covered by data at
submission
Long term 25°C ± 2°C / 60% ± 5% r.h. or
30°C ± 2°C / 65% ± 5% r.h.
12 months

Drug products - packaged in Semi-permeable containers
covered by data at
submission
Long term 25°C ± 2°C / 40% ± 5% r.h. or
30°C ± 2°C / 35% ± 5% r.h.
12 months
4/25/2023 MMCP 81
Drug products - intended for storage in a Refrigerator
covered by data at
submission
Long term 5°C ± 3°C 12 months

. From the graph : time period to have 90% potency for each temperature namely
37°c, 45°c and 60°c were ascertained for Formulation F3 which are depicted in the
following table
Temperature under study Time required to have a 90%
potency (days) i.e.‘t’ 90%
37°C 262
45°C 192
60°C 95
4/25/2023 MMCP 82
CALCULATIONS FOR SHELF LIFE PREDICTION
‘t’ 90% values from the above table then convert into log ‘t’ 90% and their
coresponding temperature (t) into absolute temperature (‘T’). Then reciprocal of
absolute temperature 1/T was calculated at each temperature.

TABLE DEPICTING ‘t’90% ,1/TAND LOG ‘t’90%
VALUES FOR FORMULATION F3AT 37°C, 45°C
AND 60°C
Temperature
under study
‘t’ 90% (days) 1/T Log ‘t’ 90%
37°C 262 3.225*10-3 2.41
45°C 192 3.14*10-3 2.28
60°C 95 3.000*10-3 1.97
4/25/2023
MMCP 83

TABLE DEPICTING ‘t’90% ,1/TAND LOG ‘t’90%
VALUES FOR FORMULATION F3AT 37°C, 45°C
AND 60°C
 At 30°C(RoomTemperature)
T = ‘t’ +273
= 30+273
T = 303 1/T=1/303=3.30*10-3
Depicts a plot between log t 90% and 1/T10-3 Formulation F3 at 37°C ,
45°C,60 °C.The straight line so obtained was extra plotted to 1/T
value at 30°C & the corresponding log ‘t’ at 30°C on y axis was noted
down. It was found to be 2.69.
Now log’ t’ 90% at 30°C = 2.69
‘t’ 90°C at 30°C = 490 days.
Therefore shelf life of formulation F3 in years = 490/365 = 1.342 years
or = 1.3 years.
4/25/2023
MMCP 84

REFERENCES
1. Ansel’s pharmaceutical Dosage forms & Drug delivery
systems, 8th edition by Loyd V. Allen, Nicholas G.popovich,
Howard C. Ansel, publised by B.I.Publication pvt. Ltd.,
page no:- 187-193,42 & 43,126-133.
2. Pharmaceutical preformulation by J.T.Cartensen published
by technomic publishing Co., page no:- 1-6, 211-212.
3. Textbook of physical pharmaceutics by C.V.S.
Subrahmanyam, published by Vallabh prakashan, page no:-
182-208, 222-226.
4/25/2023
MMCP 88

REFERENCES
4. The theory & practice of industrial pharmacy by
Leon Lachman, Herbert A. Lieberman, Joseph L.
kenig, 3rd edition, published by Varghese Publishing
house, page no:- 171-184.
5. Martin’s Physical pharmacy & Pharmaceutical
science, 5th edition by Patrick J. Sinco, Published by
Lippincott williams & wilkins, page no:- 547-550.
6. Pharmaceutical dosage forms : Tablet volume1,
edited by Herbert A. Lieberman & Leon Lachman,
published by Marcel dekker, page no:- 1-10.
4/25/2023
MMCP 89

PREFORMULATION.ppt

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PREFORMULATION.ppt