PRE-FORMULATION

1. PREFORMULATION

2. NEW DRUG
• A change in a previously approved drug products formulation or method of
manufacture constitutes “newness”
• A combination of two or more old drugs or a change in the usual proportions of
drugs in an established combination product would be considered “new” if a
question of safety or efficacy is introduced by the change.
• A proposed new use for an established drug, a new dosage schedule or regimen
a new route of administration, or a new dosage form all cause a drug or drug
product to be “new” and reconsidered for safety and efficacy

3. SOME IMPORTANT FACTS OF NEW DRUG DISCOVERY
 Only one drug in ten thousand can be successful.
 ten to twelve years for a new drug to come in market.
 In special circumstances FDA encourages fast tracking for
search of effective drugs to treat AIDS.
 Drug discovery is designed to ensure that only safe and effective
pharmaceutical products are brought to market.

4. NEED TO DISCOVER NEW DRUG
 To decrease adverse effects in currently available drugs
 To increase bioavailability of existing drugs
 Resistant drugs
 Receptor based drugs
 Difference in pharmacokinetics in different zones of people

5. NEW DRUG DISCOVERED
 New drug discovery begins in lab with collective effort of scientists,
chemists and pharmacologists as they identify
Pharmaceutical Chemistry - Synthesis/modification
Pharmaceutical Analysis - Analytical method development
Pharmacology - Animal/Human volunteers study
Pharmaceutics - Formulation development

6. PREFORMULATION
Process of optimizing a drug through the determination and/or definition
of those physical and chemical properties considered important in the
formulation of a stable, effective and safe dosage form
Application of biopharmaceutical principles to physicochemical properties
Designing an optimum drug delivery system.
Characterization of drug molecule
Development of new dosage form.
First learning phase

7. INTRODUCTION
Late 1950’s and Early 1960 → Preformulation evolved
After 1960 → Pharmacokinetics and pharmacodynamics
developed, Analytical techniques were
improved and many organic compounds
were synthesized.

8. Long back
preformulation benefit of manufacturer.
Now → official requirement for IND (introductory new drug)
and NDA (New drug application)
IND involves description of the drug substance, and
its stability in the formulation.
IND required → approval by the FDA to market product.

9. GOALS OF PREFORMULATION
► To establish the physicochemical parameter of
new drug substances
► To establish the kinetic rate profile
► To establish physical characteristics
► To establish compatibility with the common excipients

10. The following events take place between the birth of
new drug molecule and marketing:
► Drug synthesized, tested for pharmacological activity
► Sufficient quantity is synthesized to
(i) perform initial toxicity studies
(ii) to do analytical work
(iii) to do initial preformulation studies
► Actual formulation is done

11. ► Formulation is subjected to phase 2 and phase 3 clinical
trials, during this period final formula is finalized
► NDA is submitted
► After approval of the NDA, production can be started

12. PRELIMINARY EVALUATION
1. Compound identity
2. Structure
3. Formula and molecular weight
4. Therapeutic indication
(a) Actual human dose
(b) Desired dosage form
(c) Bioavailability models
(d) Competitive products
5. Potential hazards

13. 6. Initial bulk lots
(a) Lot no.
(b) Crystallization solvent
(c) Particle size range
(d) Melting point
(e) % Volatile
(f) Observation

14. 7. Analytical measures
(a) HPLC assay
(b) UV/Visible spectroscopy
(c) TLC assay
(d) Synthetic rate
(e) Probable decay products

15. 8. Key dates
(a) Bulk scale up
(b) Toxicological start date
(c) Clinical supplies preparation
(d) IND filing
(e) Phase I testing
9. Critical development issue

16. MAJOR AREAS OF PREFORMULATION RESEARCH
I. Bulk characterization
Crystallinity and polymorphism
Hygroscopicity
Fine particle characterization
Powder flow properties

17. II. Solubility Analysis
Ionization Constant – pKa
pH Solubility Profile
Common Ion Effect – Ksp
Thermal Effects
Solubilization
Partition Coefficient
Dissolution

18. III. Stability Analysis
Stability in Toxicology Formulations
Solution Stability
pH Rate Profile
Solid State Stability
Bulk Stability
Compatibility

19. CRYSTALLINITIY AND POLYMORPHISM
Crystal habit and internal structure of a drug can affect
bulk and physicochemical properties, which ranges from
flowability to chemical stability.

20. Chemical compound
Habit Internal structure
Amorphous
Crystalline
Single entity
Polymorphs
Molecular adducts
Stoichiometric
solvates (Hydrates)
Nonstoichiometric
inclusion compounds
Channel Layer Cage
(Clathrates)

21. Habit → outer appearance of a crystal
Internal structure → molecular arrangement within the solid
Changes with internal structure usually alter crystal habit.
Eg. Conversion of sodium salt to its free acid form produce
both a change in internal structure and crystal habit.

22. Crystals are characterized by repetitious spacing of constituent
atoms or molecules in a three dimensional array. In case of amorphous
forms atoms or molecules are randomly placed as in a liquid.
Amorphous forms - higher thermodynamic energy than the
crystalline form.
Upon storage, the amorphous forms tend to convert to more
stable crystalline forms.
Eg. Amorphous forms of Novobiocin was found to be well
absorbed, however when formulated into a suspension, convert into
more stable crystalline form and results in poor absorption

23. The parameters investigated are
Number of polymorphs that exist,
Relative degree of stability of various polymorphs,
Presence of a glassy state,
Stabilization of metastable forms,
Temperature stability ranges for each polymorph,
Solubility

24. Polymorphic stability - predicts long term physical stability of
dosage forms.
E.g.. Capping like cracking in tablets of anhydrous crystalline
carbochromen hydrochloride upon storage under high humidity
conditions. Due to transformation of the anhydrous form into a
dihydrate form.

25. The techniques used to study polymorphs are
1. Dissolution: Metastable forms are detectable because they
have a faster dissolution rate.
2. X ray diffraction:: Crystalline materials in powder form give
characteristic x ray diffraction patterns. Each powder pattern
of the crystal lattice is characteristic for a given polymorph.
3. Infra red spectroscopy: Different packing arrangements
will affect the energy of the molecular bonds thus altering
the IR spectra. Solid samples must be used since polymorphs
of a compound have identical spectra in solution.

26. 4. Differential scanning calorimetry and Differential thermal
analysis:
In these methods heat loss or gain resulting from physical
or chemical changes occurring in a sample is recorded as a
function of temperature as the substance is heated at uniform
temperature. Enthalpic changes i.e. both endothermic and
exothermic are caused by phase transitions. Fusion, sublimation,
solid-solid transition and water loss generally produce endothermic
effects while crystallization causes exothermic effects. Thermal
analysis enables evaluation of thermodynamic parameters
governing the system.

27. 5. Dilatometry:
Dilatometry measures the change in volume
caused by thermal or chemical effects. It has been used
to follow the melting behavior of theobroma oil by
measuring the specific volume of both rapidly and slow
cooled theobroma oil as function of increasing
temperature.
6. Hot stage microscope:
Upon heating to the phase transition point, the
crystal undergoes a change in the appearance.

28. Some problems in development that may result from inadequate
investigation of polymorphic drug forms are
1. Crystal growth in suspensions and creams, resulting in a product with
poor uniformity, appearance/bioavailability. E.g. Parenteral cortisone
acetate suspensions cake if prepared with the wrong polymorphic
form.
2. Precipitation of less soluble polymorphic form in liquid dosage forms.
3. Poor bioavailability from a less soluble polymorph, e.g.. Metastable
fluprednisolone implants has a higher absorption rate than the stale
form.
4. Crystal transitions resulting from milling or wet granulation, producing
changes in the physical nad biological characteristics of the dosage
form.
5. Poor chemical stability, eg. Amorphous penicillin is less stable than the
crystal salt.

29. Crystal habit may influence the properties as
1. Suspension stability and syringability: plate shaped crystals will
flow through a needle or orifice much more readily than needle
shaped crystals.
2. Tableting properties: Altered by crystal packing during
compression. E.g. particle size of lactose has a considerable
influence upon tablet strength.
3. Dissolution: Dissimilar crystalline habits may have different
dissolution rates depending on their surface area. Cubic and
spherical particles dissolve equally form all sides whereas other
habits change their shape factor during dissolution, altering the
dissolution rate.

30. Polymorphism effects on Dissolution:
Dissolution data for two polymorphs will be different when
more discriminating solvent is used. E.g. indole derivatives,
Crystal Characteristics and Bioavailability:
Different polymorphic forms of a given drug, show
difference in the dissolution rates and solubility. When absorption
of a drug is dissolution rate limited as more soluble and faster
dissolving form may be utilized to improve the rate and extent of
bioavailability.

31. E.g. Chloramphenicol palmitate
Comparative blood level data obtained in human following oral
administration of 1.5gm of pure A and pure B forms of chloramphenicol palmitate
and their mixtures chloramphenicol palmitate suspension containing varying ratios
of A and B polymorphs following single oral dose equivalent to 1.5 gm of
chloramphenicol.
Polymorph A 100% Polymorph B 0%
Polymorph A 75% Polymorph B 25%
Polymorph A 50% Polymorph B 50%
Polymorph A 25% Polymorph B 75%
Polymorph A 0% Polymorph B 100%
Among these pure polymorphic form B was most bioavailable.

32. Alpha and beta chlortetracycline hydrochloride
More soluble beta form is more bioavailable. The effect of
polymorphism on bioavailability is mediated via enhanced dissolution.

33. Crystal characteristics and chemical stability:
For drugs in solid state, the physical form of the drug
influences the rate of degradation.
For eg. Aztreonam, a monobactam antibiotic exists as needle like
and dense spherical beta crystalline forms. In the presence of high
humidity (37%°C / 75% RH). The crystalline forms undergoes beta
lactam hydrolysis more readily with shelf life of about 6 months
where as the beta form under identical condition is stable for
several years. Under stress condition anhydrous crystalline form of
the experimental drug degraded rapidly with a half life of 18
weeks. Solvate form of the drug under some condition was
essentially stable. The desolvated form degraded most rapidly.

34. Crystal characteristics and tabletting behavior
In a typical tableting operation, flow and compaction behaviors of the
powder mass to be tableted are important. These properties among
others are related to morphology, tensile strength, and density of the
powder bed. Two polymorphic forms of the same drug could differ
significantly respect to these properties. The morphology of a crystal also
depends on crystal habit. Crystal habit is a description of the outer
appearance of a crystal when the environment in which crystal grow
changes the external shape of the crystals without altering their internal
structure. The a different habit result. Crystal’s habit is influenced by the
presence of an impurity, concentration, rate of crystallization, and
hydrodynamics in crystallizer.

35. Crystal characteristic and physical stability
One form of the polymorphic form is thermodynamically stable at a
given temperature and pressure. The other forms would convert to the
stable form with time. This transformation may be rapid or slow. When
the transformation is not stable the thermodynamically is unstable form
is referred to us metastable form. The stable polymorph exhibits
highest melting point, the lowest solubility and the maximum chemical
and physical stability under shelf conditions to justify its use for reasons
of better dissolution or ease of tableting. Wherever metastable form is
remanded a Preformulation scientist must assure its integrity under a
variety of processing conditions.

36. Polymorphic transformation can occur during grinding,
granulating, drying and compressing. Digoxin, spironolactone, and
estradiol are reported to undergo, Polymorphic transformation during
size reduction. Phenylbutazone under goes polymorphic
transformation as a result of grinding and compression. Granulation
since it make use of a solvent molecule, can lead to solvate, formation.
A solvate molecule may change to anhydrous crystalline form, or
amorphic form in drying step.

37. HYGROSCOPICITY
THE AMOUNT OF MOISTURE ABSORBED BY THE FIXED WEIGHT OF ANHYDROUS
SAMPLE IN EQUILIBRIUM WITH THE MOISTURE IN THE AIR AT A GIVEN TEMPERATURE IS
REFERRED AS EQUILIBRIUM MOISTURE CONTENT. IT MAY INFLUENCE THE FLOW AND
COMPRESSION CHARACTERISTICS OF POWDER AND THE HARDNESS OF THE FINAL TABLET
AND GRANULATION PROCESS. MANY OF THE DRUG SUBSTANCES EXHIBIT A TENDENCY OF
ABSORBING MOISTURE. SO THESE HYGROSCOPIC COMPOUNDS SHOULD BE STORED IN A
WELL CLOSED CONTAINER. AND ALSO DURING PRODUCTION OF DOSAGE FROM USING
THESE COMPOUNDS THE HUMIDITY SHOULD BE MAINTAINED AT A CONTROLLED MANNER.
E.G. DURING CAPSULE FILLING 30-50% RELATIVE HUMIDITY IS MAINTAINED.

38. During reformulation the moisture content range should be
specified. If the granules have more moisture content it lead to poor
flow and excess hardness of the tablet. If the granules contain less
moisture, the compressed tablet may face problem of less hardness
and more friability. In such cases good packing like E.g. Strip or Blister
packing is essential. It is better to add silica gel packs in the bulk
container of tablet or capsules.
Deliquescent substances absorb water to dissolve completely.
E.g. sodium chloride. This hygroscopicity influence many important
parameters like chemical stability, flowability, and compatibility.

39. Test to find out hygroscopicity
1.Open containers :
Bulk drug is placed in open containers with a thin powder bed to assure
maximum atmospheric exposure. These samples are then exposed to a range of
controlled relative humidity. Moisture up-take should be monitored at time
points representative of handling (0 to 24 hrs) and storage (0 to 12 weeks).
2. Analytical method:
Gravimetry, Karl fisher titration gas chromatography etc

40. Types
1. Non hygroscopic  If stored at RH < 90%, No moisture content increase.
If stored at RH > 90% for one week, moisture content increase up to < 20%.
2. Slightly hygroscopic  If stored at RH < 80% No moisture content
increase. If stored at RH > 80% for one week, moisture content increase up to
< 40%.
3. Moderately hygroscopic  If stored at RH < 60%, moisture content does
not increase above 5%. If stored at RH > 60% for one week, moisture content
increase up to < 50%.
4. Very hygroscopic  If stored at RH as low as 40-50%, moisture content
may increase. If stored at RH > 90% for one week, moisture content may
exceed 30%.

41. BULK DENSITY
Bulk density of a compound varies with the method of
crystallization, milling, or formulation., Bulk density is of
importance in capsule filling and in selection of appropriate size
of the empty capsule and also in tablet granules flows into the
die. Usually bulk density is fo great importance when one
considers size of a high dose capsule product or homogeneity of
a low dose formulation in which there are large differences in
drug and excipients densities.

42. TYPES OF DENSITIES
1. True density: It is the ratio of weight to volume. It is
determined by liquid displacement method. (Helium
displacement method)
2. Granule density: The powder volume includes volume of
the particles with the intraparticle voids and this is
determined by mercury displacement method.
3. Bulk density: It is the weight of the powder divided by the
volume of the particle includes intra and inter particle voids.
Measured by tapping method.

43. PARTICLE SIZE
Particle size is characterized using these terms :
Very coarse
Coarse
Moderately coarse
Fine
Very fine

44. Particle size can influence variety of important factors :
- Dissolution rate
- Suspendability
- Uniform distribution
- Penetrability
- Lack of grittiness

45. Methods to Determine Particle Size
Sieving
Microscopy
Sedimentation rate method
Light energy diffraction
Laser holography
Cascade impaction

46. PARTICLE SHAPE

47. ORGANOLEPTIC PROPERTIES
COLOR ODOUR TASTE
OFF-WHITE PUNGENT ACIDIC
CREAM-YELLOW SULFUROUS BITTER
SHINY FRUITY SWEET
AROMATIC TASTELESS
ODOURLESS TASTELESS

48.  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 conjugated
unsaturation as well as the presence of chromophores.
 Some compound may appear to have color although
structurally saturated.
COLOR

49.  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.
ODOUR

50. 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.

51. 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

52. 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
DETERMINATION OF POWDER FLOW PROPERTIES

53. SOLUBILIZATION
“ Solubilization is defined as the spontaneous passage
of poorly water soluble solute molecules into an
aqueous solution of a soap or detergent in which a
thermodynamically stable solution is formed ”.

54.  When surfactants are added to the liquid at low
concentration they tend to orient at the air-liquid
interface .
 On further addition of surfactant the interface
becomes completely occupied and excess molecules are
forced into the bulk of liquid.
 At very high concentration surfactant molecules in the
bulk of liquid begin to form micelles and this
concentration is know as CRITICAL MICELLE
CONCENTRATION {CMC}
SOLUBILIZATION

55.  The process of solubilization involves the breaking
of inter-ionic or intermolecular bonds in the solute,
the separation of the molecules of the solvent to
provide space in the solvent for the solute,
interaction between the solvent and the solute
molecule or ion.
Step 1: Holes opens in the solvent

56. Step2: Molecules of the solid breaks away from the
bulk
Step 3: The free solid molecule is intergraded into
the hole in the solvent

57. 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

58.  Addition of co-solvent
 pH change method
 Reduction of particle size
Hydotrophy
 Addition of Surfactant
 Dielectrical Constant
 Complexation
General Method of Increasing
the Solubility

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

60. 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.

61.  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

62. 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.
Hydotrophy

63.  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.
Addition of Surfactant

64. 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
Benzene- 2.2
Dielectrical Constant

65. 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)

66. 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

67. HLB SCALE
 Griffin in 1947 developed the system of the
hydrophilic-lipophilic balance [ HLB ] of surfactant.
 The higher the HLB of the an agent, the more
hydrophilic it is.
 Tween, polyoxyethylene derivative of the spans are
hydrophilic and have high HLB value (9.6-16.7)
 The lower the HLB of the agent, the more lipophilic
it is.
 The sorbitan ester are lipophilic and have low HLB
value (1.8-8.6)

68. HLB SCALE
Most antifoaming agents
W/O Emulsifying agents
Wetting and Spreading agents
O/W Emulsifying agents
Detergents and Solubilizing agents
0
3
6
9
12
15
18

69. 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
04/05/2012

70. 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

71. 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

72. FORCED DEGRADATION STUDIES
 Acidic & Basic conditions.
 Dry heat exposure
 UV radiation exposure
 Influence of pH
 Influence of temperature
 Influence of ionic strength

73. STABILITY STUDIES AT DIFFERENT STAGES
 Stress- and accelerated Testing with drug substances
 Stability on pre-formulation batches
 Stress testing on scale-up Batches
 Accelerated and long term testing for registration
 On-going Stability testing
 Follow-up Stabilities

74. Scope
• Solubility Profile
• Hygroscopicity
• Thermal stability
(Melting point,
Polymorphism)
• Chemical stability
􀂄 1 Batch
􀂄 Up to 3 month
Scope
• Determination of expire date
• Determination of preliminary
specifications
• Release of clinical batches
• Monitoring of samples during the clinical
phases
• Definition of storage conditions
• Definition of Tests for registration
stability
􀂄 Up to 36 month
􀂄 Selection of samples
• API, excipient, batches
􀂄 Scope
• Appearance
• Appropriate physical-chemical parameter
• Assay / Degradation products
􀂄 Up to 3 month
STABILITY STUDIES AT DIFFERENT STAGES

75. 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)
Tablet & Capsule

76. TESTING SCOPE FOR ORAL LIQUID FORM
 Physical-chemical properties
– pH
– Color & clarity of solution
– Viscosity
– Particle size distribution (for oral suspensions only)
 Chemical properties
– Assay
– Degradation products
– Degradation preservatives
– Content antioxidants
 Microbial properties
 Container closure system properties
– Functionality tests

77. TESTING SCOPE FOR
LIQUID FORMS FOR INJ. AND PARENTRAL
 Physical-chemical properties
– pH
– Loss on weight
– Color & clarity of solution
 Chemical properties
– Assay
– Degradation products
– Degradation preservatives
– Content antioxidants
 Microbial properties
 Container closure system properties
– Functionality tests

78. TESTING SCOPE FOR
SEMI LIQUID FORMS
 Physical-chemical properties
– Appearance, odor, homogenesity, consistency
– Loss on weight, Viscosity
– Content uniformity (within the container)
 Chemical properties
– Assay
– Degradation products & preservatives
– Content preservatives
– Degradation– Content antioxidants
 Microbial properties
 Container closure system properties
– Functionality tests

79. 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
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
Accelerated 25°C ± 2°C / 60% ± 5% r.h. 6 months

80. Drug substances/Product- intended for storage in Freezer
Study Storage condition Minimum time period
covered by data at
submission
Long term -20°C ± 5°C 12 months
Drug products - General case
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

81. Thank you