micromeritics polymorphs mmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmm

1. Mr. Sagar Kishor Savale
Department of Pharmaceutics
avengersagar16@gmail.com
2015-016
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2. List of contents:-
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1. Definition
2. Need to study polymorphism ( rational for selecting
polymorph)
3. Types of polymorphism
4. How to differentiate them
5. Pseudo polymorphism
6. Properties
7. Method for identify polymorphism
8. Significance of polymorphism
9. Conclusion
10. References

3. Definition
1,2
When a substance exists in more than one crystalline form, the different form
are designated as polymorphs and the phenomenon as polymorphism.
e.g.:-
 carbon: diamond in a cubic ( tetrahedral lattice arrangement )
 Graphite in sheet of a hexagonal lattice.
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4. True polymorphs can be classified into two
different types
2
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1. Enantiotropic— one polymorph can be reversibly changed
into another one by varying the temperature or pressure.
eg. sulfur
2. Monotropic— the change between the two forms is
irreversible. eg. Glyceryl stearates

5. Difference between enantiotropy and monotropy.
3
Enantiotropic pair monotropic pair
Reversible phase transition Irreversible phase transition
Metastable stable Metastable stable
Transition is endothermic Transition is exothermic
Lower melting form is
thermodynamically stable below the
transition temp.. And higher m.p .
form is stable above the transition
temp..
Higher melting form is always
thermodynamically stable form.
lower m.p. has lower heat of fusion. Higher m.p. has high heat of fusion.
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6. Method to identify polymorphism.
3
Optical crystallography:
 Use in the identification of polymorphs crystal exist in isotropic and
anisotropic form
 Isotropic examine the velocity of light is same in all direction
 Anisotropic crystal have 2 or3 different light velocities or refractive index.
 Video recording system and polarizing microscope fitted during according
to heating and cooling stage for investigating polymorph.
cont…
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7. Application
 To study of degree of stability of metastable form.
 Transition temperature
 Melting point
 Rate of transition under various thermal and physical condition.
 Whether to peruse polymorphism as a route to an improved dosage form.
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8. Hot stage microscope
 Fluid stage transformation as a function of temperature is observed
 Silicon oil stage microscopy is used for detection of pseudopolymorph.
APPLICATION:
 in the study of solid-state active pharmaceutical ingredients
(APIs), EXCIPIENTS and pharmaceutically relevant polymers and lipids.
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9. x ray diffraction method
 It provide the most complete information about solid state (identification &
description)
 This method is based on the scattering of x-ray by crystals
 By this method one can identify the unit cell dimensions & conclusively
establish the crystalline lattice system & provide specific differences between
crystalline forms of given compound.
 In an X-ray diffraction measurement, a crystal is mounted on a goniometer and
gradually rotated while being bombarded with X-rays, producing a diffraction
pattern of regularly spaced spots known as reflections.
 It is tedious time consuming so it is not used or unsuitable for routine use.
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10. 4/21/2016 Sagar Kishor Savale 10
 X ray diffraction pattern

11. Application
 many materials can form crystals—such as salts, metals, minerals,
semiconductors, as well as various inorganic, organic and biological
molecules—X-ray crystallography has been fundamental in the
development of many scientific fields
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12. Melting point
 M.P. determination are often useful technique, but only when substance
undergoing investigation heated through phase transition without
decomposition.
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13. Differential Scanning Calorimetric (DSC)
 DSC is also like to DTA except that the instrument measures the amount of energy
required to keep the sample at the same temperature as the reference i.e. it measures
the enthalpy of transition.
 When no physical or chemical changes is occurring within the sample then there is
neither a temperature change nor the need to input energy to maintain an isotherm.
 Samples that may be studied by DSC or DTA are:
Powders, fibers , single crystals, polymer films, semi-solids.
 DSC measures endothermic and exothermic transitions as a function of temperature.
 –Endothermic heat flows into a sample.
 –Exothermic heat flows out of the sample.
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14. 4/21/2016 Sagar Kishor Savale 14
Differential
Scanning
Calorimeter
(TA Instruments
Q10, Q 100,Q
1000)

15. Applications of DTA / DSC in preformulation studies
1. To determine the purity of a sample
2. To determine the number of polymorphs and to determine
the ratio of each polymorph
3. To determine the heat of solvation .
4. To determine the thermal degradation of a drug or
excipients .
5. To determine the glass-transition temperature(tg) of a
polymer.
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16. Effect of polymorphism on bioavailability
 If the absorption of active ingredient in drug through G.I.T polymorphism is
an important preformulation tool.
 Here successful utilization of polymorph having significant greater
thermodynamic activity (solubility)may provide good therapeutic blood
level from otherwise inactive drugs. Eg novobiocin .
 two different forms : crystalline and amorphous. In tablet or capsule
formulation
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17. PSEUDO POLYMORPHISM
4
 Term - pseudo means = false
 The phenomenon in which solvent molecules get incorporated into crystal
lattice of solid are known as solvates.
 This solvates exist in different crystal form called pseuodopolymorph and
the phenomenon is called as Pseudopolymorphism .
 also known as a hydrate when water is solvent.
 E.g.- synthetic estrogen ‘ethynylestradiol ’ is crystallized from the solvent
acetonitrile , methanol , chloroform and saturated with water four different
crystalline solvates are form.
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18. Differentiate pseudopolymorph form true polymorph.
 By observing melting behavior in silicon oil using hot stage microscopy.
 Here in this technique pseudopolymorph evolve the gas causing bubbling of
the oil.
 While true polymorphs merely melts, forming second globular phase.
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19. Application
1. For improvement of therapeutic activity of drug.
2. To prevent loss of raw material.
3. For better bioavailabity of drug.
.
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20. Need to study polymorphism.
5
 One of the several polymorphic form will be physically more stable than
others.
 Stable polymorph represent s the lowest energy state, has highest melting
point and least aqueous solubility.
 Metastable form represent the higher energy state, have lower melting point
and high aqueous solubility .
 Metastable form converted to the stable form due to their higher energy state.
 Metastable form shows better bioavailability and therefore preferred in
formulations.
Cont..
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21.  Polymorphism is remarkably common particularly within certain structural
group.
 E.g. –
Cont..
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CLASS %OF POLYMORPHISM
Barbiturates 63
Steroids 57
Sulphonamides 40

22. Significance of studying polymorphism
 Different polymers exhibits different solubility, therapeutic & stability.
 The desire forms consistently manufactured.
 The effect of pharmaceutical manipulations are understood.
E.g. granulation, milling & compression.
 Effect of storage condition on the dosage form can be evaluated &
predicated. E.g. crystal growth in suspension, cream.
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23. Properties of polymorphs.
5
Polymorphs show the same properties in the liquid or gaseous state but they
behave differently in solid state.
 Melting and sublimation temperature.
 Solubility and dissolution rate
 Stability
 Crystal habit
 Hygroscopicity
 Compression characteristics
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24. Conclusion
 Differences in the solubility and melting point must also be assessed and
then a decision can be made to determine which form to progress through to
the next stage.
 Metastable form may lead to a preferential choice of a polymorph other than
stable form .
 As polymorphism can have such serious consequences for the
bioavailability of drugs with low aqueous solubility.
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25. References
1. M.E. Aultan, The science of dosage form design, 2nd
edition 2002, p.no
8,26,124-126,142-144.
2. Brahmankar D. M., Sunil B. Jaiswal, Biopharmaceutics &
Pharmacokinetics- A Treatise,1st edition, Vallabh Prakashan, New Delhi
2007, p.no-27-29.
3. Leon Lachman, Herbert A. Lieberman, The Theory Practice Of Industrial
Pharmacy, 3rd edition, Varghese Publication, Bombay 1987, p.no. 178-
181, 230-231.
4. Alfred Martin, James Swarbrick, Physical Pharmacy,3rd , Varghese
Publication, Bombay 1991, p.no. 72-73, 575-76.
5. Encyclopedia of Pharmaceutical Technology
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