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Seminar on polymorphism
1. Seminar on
POLYMORPHISM
(AS A PART OF PREFORMULATION STUDY)
Guided by : Prepared by :
Mrs. Hiral Shah Henil Patel
Assistant Professor M.Pharm Sem 1
Dept. Of Pharmaceutics Pharmaceutics.
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2. List of contents
1. Definition
2. Need to study polymorphism ( rational for selecting polymorph)
3. Properties
4. Types of polymorphism
5. How to differentiate them
6. Pseudopolymorphism.
7. Method for identify polymorphism
8. Parameter to be cared by preformulator
9. Factor affecting polymorphism
10. Effect of polymorphism on bioavailability
11. Application
12. Conclusion
13. references
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3. Definition
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. Cont…
Thus it is defined as the ability of substance to exist as two or more
Crystalline phase that have different Arrangements or conformations of
the molecule in the crystallatice .
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5. Need to study polymorphism
• Depending upon their relative stability, 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.
• Only 10% of the pharmaceuticals are present in their metastable form.
Cont..
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6. • Polymorphism is remarkably common particularly within certain structural
group.
• E.g. –
CLASS %OF POLYMORPHISM
Barbiturates 63
Steroids 57
Sulphonamides 40
Cont..
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7. • The effect of polymorphism on bioavailability is the most important
consequence for drug substance if the bioavailability is mediated via
dissolution.
• The example is chloramphenicol palmitate.
• Other like novobiocin , griseofulvine , Carbamazepine , aspirin and
ampicilline .
• The polymorphism of the excipients may also play an important role in
bioavailability.
Latest example is :- HYDOISOINDOLIN
( a tachykinine receptor antagonist )
Cont..
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8. Stability characteristics
• Depending upon relative stability there are two form of polymorphs 1)
stable form 2) meta form .
• Stable form having least aqueous solubility.
• Meta form having high aqueous solubility.
• Solubility ratio =solubility of metastable form/solubility of stable form.
• From below example, we can say that solubility ratio is higher than one just
because of …
• relative higher solubility of metastable form, that leads to increase
Cont..
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10. Dissolution behavior of the polymorphs
• the absorption rate and bioavailability of drug administered orally is
controlled by many factor.
• among which dissolution rate is one of the most important.
• as the thermodynamic activity of polymorph is lower there is lower
apparent solubility and thus absorption is also less.
• Order of dissolution rate: Amorphous>metastable> stable
cont..
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11. FORMATION OF METASTABLE POLYMORPHS:-
• Preparation of metastable polymorphs requires,
• Supersaturating conditions for the metastable form.
• Crystallization of the metastable state before the stable polymorph forms.
• Stable conditions for the metastable polymorph so that conversion to the
stable form is prevented .
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12. Properties of polymorphs
Polymorphs show the same properties in the liquid or gaseous state but they
behave differently in solid state.
Melting and sublimation temperature.
Vapour pressure
Solubility and dissolution rate
Stability
Optical and electrical property
Crystal habit
Hygroscopicity
Heat capacity
Solid-state reaction
Conductivity
Compression characteristics
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13. Type of polymorphism
TYPE
1. ENANTIOTROPIC POLYMORPH
2. MONOTROPIC POLYMORPH
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14. • Phase transition: the process of transformation of one polymorph into
another.
• which may also occur on storage or during processing, is called phase
transition.
• ENANTIOTROPHS:- If one form stable over certain pressure and
temperature range, while the other polymorph is stable over different
pressure and temperature range.
• eg, sulfur
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15. • MONOTROPHS:- only one polymorph is stable at all temperature below
the melting point, with all other polymorph being unstable.
• E.g. glyceryl stearate , chloramphenicol palmitate .
Both enantiotropism and monotropism are important properties of
polymorphs.
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16. Difference between enantiotropy and monotropy.
Enantiotropic pair monotropic pair
Reversible phase transition Irreversible phase transition
Metastable stable Metastable stable
Transition is endothermic Transition is exothermic
Lower melting form is Higher melting form is always
thermodynamically stable below the thermodynamically stable form.
transition temp.. And higher m.p .
form is stable above the transition
temp..
lower m.p. has lower heat of fusion. Higher m.p. has high heat of fusion.
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17. PSEUDOPOLYMORPHISM
• 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. Method to identify polymorphism
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
indices.
• Video recording system and polarizing microscope fitted during according
to heating and cooling stage for investigating polymorph.
cont…
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20. 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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21. Hot stage microscopy
• 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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22. 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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23. 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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24. Differential Thermal Analysis (DTA)
• The advantage is that the sample size required is only 2-5mg .
• DTA measures the tempt difference between sample and reference as a
function of temperature or time when heating at constant rate.
• A DTA consists of a sample holder comprising thermocouples, sample
containers and a ceramic or metallic block; a furnace; a temperature
programmer; and a recording system.
• The key feature is the existence of two thermocouples connected to a
voltmeter.
• One thermocouple is placed in an inert material such as Al2O3, while the
other is placed in a sample of the material under study.
• As the temperature is increased, there will be a brief deflection of the
voltmeter if the sample is undergoing a phase transition.
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25. 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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27. Applications of DTA / DSC in preformulation studies
1. 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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28. Thermo Gravimetric Analysis (TGA)
• is a type of testing that is performed on samples to determine
changes in weight in relation to change in temperature.
• Such analysis relies on a high degree of precision in
measurements: weight and temperature change.
• As many weight loss curves look similar, the weight loss curve
may require transformation before results may be interpreted.
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29. • TGA is commonly employed in research and testing to determine
characteristics of materials such as polymers, to determine degradation
temperatures, absorbed moisture content of materials, the level of inorganic
and organic components in materials, decomposition points of explosives,
and solvent residues.
• It is also often used to estimate the corrosion kinetics in high temperature
oxidation.
• TGA Q 500.
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30. Dilatometry
• Measure change in volume caused by thermal or chemical effect.
• Using dilatometry the melting behaviour of Theobroma Oil was studied.
• Extremely accurate but tedious , time consuming and not widely used.
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31. 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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32. Parameter to checked by preformulator
1. No of polymorphs
2. Relative degree of stability
3. Presence of glassy state
4. Stabilization of metastable form
5. Temperature stability range
6. Solubility of each polymorph
7. Method of preparation
8. Effect of micronization
9. Excipients incompatibility
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33. Factor affecting polymorphism
A) Temperature and Humidity:-
• Storage conditions affect physicochemical reaction which are accelerated
at higher temperature.
• Humidity acts as a catalyst on the solid surface.
• E.g.
1. Zanoterone the solid degradation rate of form 4 is found to be greater
than that of form 3 at 40 C/ 25 %RH and 40 C/75% RH. At 40 C/ 25
%RH , the rate of degradation is 4 fold higher for form 4 vs 3.
2. Polymorphic transformation of cocoa butter occur after heating.
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34. B) Photostability
• Generally light sensitive drug are protected form the photolytic degradation
by packing them suitable in light resistant container.
• Stable crystalline form resist photochemical degradation and does not
require light resistant system.
E.g.
1) Acetametacin alpha, beta – stable
gamma - unstable.
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35. C) Effect of solvent
• Solvent can bring dramatic change in growth mechanism and morphology.
• Kinetic of crystal growing form solution was determined by two important
factors.
a. degree of molecular roughness
b. nature of absorption of the solvent from surface.
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36. D) Effect of grinding
• Grinding process reduces particle size, so increasing specific surface area
and that why direct effect on dissolution rate and bioavaibility of the
formulation.
• During process solid state polymorphic transformation in to non crystalline
or metastable form is caused by mechanical action.
• E.g.- dihydrate form is more stable than anhydrous form. With increasing
grinding time compound become unstable because grinding weakened
bonding crystals and water molecules.
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37. E) Effect of tablet compression:-
• Stability and compaction behavior form of of the polymorphic form of
drug is important
• Phenylbutazone in which form 3 converted to 2 form at >2000kg/cm2.
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38. Effect of polymorphism on
bioavailability
If the absorption of active ingredient in drug through G.I.T. is dissolution
rate dependent then 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
novobiocin is used as sodium salt which is active orally but unstable
chemically while insoluble form is stable chemically and orally
inactive.(unabsorbable )
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39. APPLICATION
1. The knowledge of solid-state properties in an early stage of drug development helps to
avoid manufacturing problems, to fine-tune the performance of drugs and provides space
for innovations .
e.g.- Famotidine which is an excellent histamine
H2 receptor antagonist is also found to exist in two different polymorphic forms,
metastable polymorph B and stable polymorph A.
2. For improvement of therapeutic activity of drug.
3. To prevent loss of raw material.
4. For better bioavailabity of drug.
.
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40. 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 sable form .
• As polymorphism can have such serious consequences for the
bioavailability of drugs with low aqueous solubility.
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41. Study Question
1. What is polymorphism? Discuss its significance in dissolution.
Enumerate the methods to identify polymorphs. 6 mark ( GTU July
2012 )
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42. References
1. The theory and practice of industrial pharmacy by- Leon Lechman ,
Joseph L Kanig .
2. Biopharmaceutics and pharmacokinetics by- DM Bhramankar , Sunil
Jaiswal .
3. Physical pharmacy by- Alfred Martine.
4. The science of dosage form design by Michael E Alton .
5. Encyclopedia of pharmaceutical technology .
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