Polymorphism

1. Polymorphism in Pharma
Chemistry
Presented by:
MAHENDRA G. S.
M Pharm
Department of pharma
chemistry

2. Content
• Introduction
• Need to study polymorphism
• Properties of polymorphism
• Types of polymorphism
• Methods of polymorph preparation
• Methods to identify polymorphism
• Applications
• Polymorphism in organic chemistry
• Pharmaceutical application of polymorphs
• Conclusion
• Referance

3. Introduction
The term polymorph has been derived from Greek word “poly” which means
“many” and “morph” implying “form”. Hence, polymorphism refers to different
structural forms of a chemical substance.
It is defind as the ability of a solid material to exist in two or more
crystalline forms with different arrangements or conformations in the crystal
lattice.
Polymorphism can potentially be found in any crystalline material including
polymers, minerals, and metals, and is related to allotropy, which refers to
chemical elements. The complete morphology of a material is described by
polymorphism and other variables such as crystal habit, amorphous fraction or
crystallographic defects. Polymorphism is relevant to the fields of pharmaceutics,
agrochemicals, pigments, dyestuffs, foods and explosives.

4. More than 50% of active pharmaceutical ingredients (APIs) are estimated to
have more than one polymorphic form . Polymorphism and pseudomorphism are very
common amongst drugs and are responsible for differences in many properties.
The first observation of polymorphism is attributed to Friedrich Wohler and
Justus Von Liebig, in 1832. He was examining a boiling solution of organic solid
benzamide. During cooling, initially the benzamide is crystallized in the form of silky
needles but on standing they were slowly transformed or replaced into another form
like rhombic crystals.
The different crystal types are the result of hydration or salvation, in pseudo
polymorphism. Glycine is example for organic polymorph and is able to form mono
clinic and hexagonal crystals

5. Silica is the example for polymorphism and it forms many polymorphs such as α-
quartz, β-quartz, tridymite, cristobalite, coesite, and stishovite. A classic example
for polymorph are the minerals calcite and agagonite, both forms of calcium
carbonate.
Polymorphism is exhibited in diamonds and graphite. Both diamond and graphite
are polymorphs of the same element carbon. Both the elements entirely consist of
carbon but they have different crystalline structures and physical properties, since the
structure determines the properties of the compounds

6. Need to Study Polymorphism
• Depending upon their relative stability, one of the several polymorphic form will be physically
more stable than others.
• Stable polymorph represents 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.

7. • Only 10% of the pharmaceuticals are present in their metastable form.
• The effect of polymorphism on bioavilability is the most important consequence
for drug substaces if the bioavailability is mediated via dissolution.
• The example is chloramphenicol palmitate. Other like novobiocin, griseofulvine,
carbanazepine, aspirin and ampiciline.
• The polymorphism of the excipients may also play an important role in
bioavailability.
latest example: HYDOISOINDOLIN

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.

9. Dissolution behavior of the polymorhs
• The abosrption 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.

10. Properties of Polymorphism
Polymorphs shows 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
Cryastal habit
Hygroscopicity
Heat capacity

11. Types of polymorphism
1. Monotropic polymorph
2. Enantiotropic polymorph
Monotrophs : only one polymorph is stable at all temperature below the melting
point, with all other polymorph being unstable.
Eg. Glyceryl stearate, chloramphenicol palmitate.
Enantitrophs : if one form stable over certain pressure and temperature range,
while the other polymorph is stable over different pressure and temperature
range.
Eg. Sulfur

13.  Types of polymorphism are explained by using the graphs shown
above.
Graph (a) explains the enantiotropic system and graph (b) explains the monotropic
system.
• With reference to the graph (a) the polymorph ‘A’ is stable at below transition
temperature Tt, and it has lesser free energy GA compared with polymorph B, which
has high free energy.
• But the temperature increases to above transition temperature Tt, free energy GB of
polymorph B is lesser than free energy GA of polymorph A, thus polymorph B
becomes more stable than polymorph A.
• This gives rise to an enantiotropic system of solid phases. For enantiotropic system, a
reversible transition (any transition from one polymorph to another will be reversible)
can observed at a definite transition temperature Tt at which the free energy curve
cross, before the melting point reached.

14. • With reference to the graph (b), the polymorph A has less free energy than other
polymorphs throughout the range below the melting point.
• For monotropic system, an irreversible transition (any transition from one polymorph
to another will be irreversible) can be observed, since the free energy curves do not
cross below the melting point.
• The polymorphs which have the higher free energy curve and higher solubility is
called as unstable polymorph. It is possible to distinguish between monotropes and
enantiotropes from their heats of fusion.
Enantiotropes are indicated by an endothermic polymorphic transition and whereas
monotropes are indicated by an exothermic polymorphic transition.

15. Factors affecting polymorphism
Temperature and humidity:
e.g: polymorphic transformation of cocoa butter occur after heating.
Photostability:
e.g: acetometacin alpha, beta – stable
gamma-unstable.
Effect of sovent:
Effect of grinding:
e.g: dihydrate form is more stable than anhydrous form. With increasing
grinding time compuond become unstable because grinding weakened bonding
crystals and water molecules.
Effect of tablet compression:
e.g: phenylbutazone in which form 3 converted to 2 form at >2000kg/cm2.

16. Methods of polymorph preparation
• Solvent evaporation method
• Slow cooling approach
• Solvent diffusion technique
• Vapour diffusion method
• Vaccum sublimation
1. Solvent evaporation method (Rota Evaporation) :
In this approach, the saturated solution of the drug is prepared in an
appropriate solvent and the solvent is removed by rotatory evaporation. Air drying at
various temperatures, can also be employed to obtain different potential polymorphs .

17. 2. Slow cooling approach :
This technique is frequently employed for the polymorphic forms of less
soluble drugs in the solvent systems having boiling point range of 30 to 90°C. In
brief, the solute is heated in the solvent just above the boiling point of the latter to
produce the saturated solution. This solution is transferred to a stoppered tube and is
connected to a Dewar flask containing water at a temperature just below the boiling
point of the solvent. The Dewar flask is left in these conditions for several days. This
technique may further be improved to obtain better crystal forms using different
solvent mixtures of different polarities. Variation in the solvent composition may
inhibit or promote growth of particular crystal faces and hence, can yield crystals of
the desired morphology. This approach is also called the solution growth approach .

18. 3. Solvent diffusion technique :
This method is employed when the amount of drug available is less, and the
drug is sensitive to air and/or solvent(s). In this option, the solution is placed in a
sample tube; subsequently a less dense solvent is carefully dripped down the sides of
the tube using either a pipette or a syringe to form a discreet layer. The slow diffusion
of the solvent results in the crystallization of API at the interface. Most employed
solvent combination is CH2 Cl2 / ethanol and is preferred one, provided the sample is
insoluble in ether .

19. 4. Vapor diffusion method :
This method is analogous to the previous one and is also applicable for the
less quantities of the sample. In this case, the concentrated drug solution (0.5 μL to
approximately 20 μL) is placed as a drop hanging on the underside of a microscope
cover slip.
The cover slip with the hanging drop is sealed with silicon oil over a solution
(approx. 1 mL; reservoir) containing high concentration of precipitant. Due to higher
precipitant concentration, the latter has lower vapor pressure than the drug solution.
This results in diffusion of the solvent from the drop towards the reservoir and
subsequent crystallization of the API within hours to weeks .

20. Methods to identify polymorphism
• 0ptical crystallography
• Hot stage microscopy
• X-ray diffraction method
• Differential thermal analysis (DTB)
• Differential scanning calorimetric (DSC)
• Thermo gravimetric analysis (TGA)

21. •0ptical crystallography
1) Used in the identification of polymorphs crystal exist in isotropic and
anisotropic form.
2) Isotropic examine the velocity of light is same in all direction.
3) Anisotropic crystal have 2 or 3 different light velocity or refractive
indices.
4) Video recording system and polarizing microscope fitted during according
to heating and cooling stage for investigating polymorph.
• Hot stage microscopy
1) Fluid stage transformation as a function of temperature is observed.
2) Silicon oil stage microscopy is used for detection of pseudopolymorph

22. •X-ray diffraction method
1) It provide the most complete information about solid state.
2) This method is based on the scattering of x-ray by crystal.
3) By this method one can identify the unit cell simensions and conclusively
establish the crystalline lattice system and provide specific differences
between crystalline forms of given compound.
4) In an x-ray diffraction measurement, a crystal is mounted on a gonipmeter
and gradually rotated while being bombarded with x-rays, producing
diffraction pattern of regularly spaced spots known as reflections.
5) It is tedious time consuming so it is not used or unsuitable for routine use.

23. •Thermo gravimetric analysis
1) Is a type of testing that is performed on samples to determine changes in
weight in relation to change in temperature.
2) Such analysis relies on a high degree of precision in measurements;
weight and temperature changes .
3) As many weight loss similar, the weight loss curve may require
transformation before results may be interpreted.

24. APPLICATION
• The knowledge of solid-state properties in an early stage of 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.
• For improvement of therapeutic activity of drug.
• To prevent loss of raw material.
• For better bioavailability of drug.

25. • Pharmaceutical application of polymorphs
Suspension :
In preparation of suspension use of a wrong polymorph of a drug, a phase
conversion from the metastable to stable polymorph may occur. This results in
crystal growth and caking of suspension.
e.g: cortisone acetate was one of the most difficult polymorphic problems to solve.
Macek obtained the first patent on stable noncaking aqueous suspension of cortisone
acetate and methods of preparing the same. He describe the early attempts to obtain a
stable aqueous suspension, where cortisone acetate, in the form of crystals stable in
the dry state, was suspended in the aqueous medium and allowed to remain in the
medium for a few hours. It was observed that crystals growth of the cortisone acetate
invariably occurred with subsequent caking and sedimentation.

26. A physically stable aqueous suspension was obtained by ball-milling cortisone
acetate powder, in the aqueous vehicle where a polymorphic phase transition occurred.
In a later patent, Magerlein described two new polymorphs of cortisone acetate, Form A
,which is not stable in the dry state, and Form B, which is stable in the dry state. Both
crystal forms when used in aqueous suspensions gave physically stable, noncaking
aqueous suspension.
Creams :
When creams are prepared with the active ingredient suspended in the cream base,
use of the wrong polymorph can result in a phase inversion to a more stable phase. As a
consequence, crystal growth can occur in the vehicle yielding gritty, cosmetically
unacceptable creams or products in which the active ingredient is unevenly distributed.
During the preparation of a topical cream it is necessary to select the correct polymorph
of the active ingredient, which when suspended is least susceptible to growth in the
cream base.

27. Solution :
Flynn has reported some problem in the formulation of a parenteral
solution of a drug. In this instance, determination of the water solubility of
the compound indicated the drug to be adequately soluble for the
concentration required in the formulation. Stability studies on the
formulation quickly turned up the presence of a precipitate. An investigation
of the problem showed the precipitate to consist of a less soluble polymorph
of the compound. The problem was solved by formulating the product in a
vehicle containing sufficient cosolvent to solubilize the less soluble
polymorphic form.

28. Polymorphism in organic chemistry
• Active pharmaceutical ingredients (APIs), frequently delivered to the patient in the
solid-state as part of an approved dosage form, can exist in such diverse solid forms
as polymorphs, pseudopolymorphs, salts, co-crystals and amorphous solids. Various
solid forms often display different mechanical, thermal, physical and chemical
properties that can remarkably influence the bioavailability, hygroscopicity, stability
and other performance characteristics of the drug. Hence, a thorough understanding
of the relationship between the particular solid form of an active pharmaceutical
ingredient (API) and its functional properties is important in selecting the most
suitable form of the API for development into a drug product.

29. In past decades, there have been significant efforts on the discovery, selection and
control of the solid forms of APIs and bulk drugs. This contribution discusses the
thermodynamics and kinetics of polymorphic systems, the characterization of
polymorphs, and the transformation between polymorphs.

30. Case studies:
• In the case of the antiviral drug ritonavir, not only was one polymorph virtually
inactive compared to the alternative crystal form, but the inactive polymorph was
subsequently found to convert the active polymorph into the inactive form on contact,
due to its lower energy and greater stability making spontaneous interconversion
energetically favourable. Even a speck of the lower energy polymorph could convert
large stockpiles of ritonavir into the medically useless inactive polymorph, and this
caused major issues with production which ultimately were only solved by
reformulating the medicine into gelcaps and tablets, rather than the original capsules.

31. • Cefdinir is a drug appearing in 11 patents from 5 pharmaceutical companies in which
a total of 5 different polymorphs are described. The original inventor Fujisawa now
Astellas (with US partner Abbott) extended the original patent covering a suspension
with a new anhydrous formulation. Competitors in turn patented hydrates of the drug
with varying water content.
• Acetylsalicylic acid has an elusive second polymorph that was first discovered by
Vishweshwar et al.;fine structural details were given by Bond et al.A new crystal type
was found after attempted co-crystallization of aspirin and levetiracetam from hot
acetonitrile. In form I, two aspirin molecules form centrosymmetric dimers through
the acetyl groups with the (acidic) methyl proton to carbonyl hydrogen bonds, and, in
form II, each aspirin molecule forms the same hydrogen bonds, but then with two
neighbouring molecules instead of one. With respect to the hydrogen bonds formed
by the carboxylic acid groups, both polymorphs form identical dimer structures. The
aspirin polymorphs contain identical 2-dimensional sections and are therefore more
precisely described as polytypes.

32. • Paracetamol powder has poor compression properties; this poses difficulty in making
tablets, so a new polymorph of paracetamol was found which is more compressible.
• Due to differences in solubility of polymorphs, one polymorph may be more active
therapeutically than another polymorph of same drug.
• Cortisone acetate exists in at least five different polymorphs, four of which are
unstable in water and change to a stable form.
• Carbamazepine (used in epilepsy and trigeminal neuralgia) beta-polymorph
developed from solvent of high dielectric constant ex aliphatic alcohol, whereas alpha
polymorph crystallized from solvents of low dielectric constant such as carbon
tetrachloride.
• Estrogen and chloroamphenicol also show polymorphism.

33. Conclusion
• In the present era of evolving understanding, it is accepted that not merely
chemical purity/integrity of the API is the sole dependable and formulation
influential parameter. The physical arrangements of the constituents in the crystal
lattice have immense potential to influence the physicochemical properties of the
drugs and subsequently the therapeutic outcomes. Therefore, the study of
polymorphic forms has become as important as any other branch of
pharmaceutical sciences, as the former helps to embark upon the proper
API/excipient form selection.

34. • with the foregoing discussion, it is clear that probably every organic medicinal
can exist in different polymorphs and the choice of the proper polymorph will
determine if a pharmaceutical preparation will be chemically or physically stable,
or if a powder will tablet or not tablet well, or if the blood level obtained will be
the therapeutic level to give the pharmacologic response desired. Thus, it is time
that pharmaceutical companies, as a part of their pre- formulation studies, identify
and study the stability of different polymorphs of each potential new drug, as they
do the melting points or other physical characteristics.

35. Referances
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37. THANK YOU