Polymorphism is the ability of a solid material to exist in two or more crystalline forms. The document discusses the different types of polymorphism, factors that influence polymorphism, and methods to identify and produce polymorphs. It also outlines several applications of polymorphism in pharmaceuticals and organic chemistry. Specifically, selecting the right polymorph is important for drug stability, solubility, and bioavailability.

1. Polymorphism in
organic chemistry

2. CONTENT
6. Methods to
identify
polymorphism
5.methods of
polymorphism
9. Conclusion
10. Reference
8.Pharmacetiucal
application
2. Need to study
polymorphism
1. Intro
4.types of
polymorphism
3.Properties of
polymorphism
8. Polymorphism of
organic chemistry
7. Applications

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 a quartz,
ß-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 consequencefor
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
 Stable form
 Meta form
 Solubility
ratio-
solubility of
metastable
form/
solubility of
stable form
 Stable form
having least
aqueous
solubility.
 Meta form
having high
aqueous
solubility.
Depending upon
relative stability there
are two form of
polymorphs::

9. Dissolution behavior of polymorphs
 Order of dissolution
rate:
amorphous>metastab
le>stable.
 As the thermodynamic
activity of polymorph is
lower there is lower
apparent solubility and
thus absorption is also
less.
Among which dissolution
rate is one of the most
important.
The abosrption rate and
bioavailability of drug administered
orally is controlled by many factor.
Behaviour

10. Polymorphs shows the same properties in the liquid or gaseous state but they behave differently in solid
state.
 Vapour
pressure
 Solubility and
dissolution
rate
 Hygroscopicity
 Stability
 Cryastal habit
 Optical and
electrical
property
 Melting and
sublimation
temperature
Properties of
polymorphism

11. Types of polymorphism
02
 Enantiotropic
polymorph
 Eg:Sulfur
01
 Monotropic
polymorph
 Eg:Glyceryl
stearate
 Monotrophs only one polymorph is
stable at all temperature below the
melting point, with all other
polymorph being unstable.
 Enantitrophs: if one form
stable over certain pressure
and temperature range. while
the other polymorph is stable
over different pressure and
temperature range.

13. Factors
affecting
polymorphism
 Effect of sovent
 gamma-unstable
 Effect of grinding
 Photostability
 Temperature and humidity
 Effect of tablet
compression

14. METHOD OF POLYMORPH
PREPARATION
 Solvent evaporation
method
 Slow cooling
approach
 Vapour diffusion
method
 Solvent diffusion
technique
 Vaccum
sublimation

15. 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.
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.
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.

16. 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.

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

18.  Used 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 or 3 different light velocity or refractive indices.
 Video recording system and polarizing microscope fitted during according to heating and cooling stage
for investigating polymorph.
Hot stage microscopy
 Fluid stage transformation as a function of temperature is observed.
 Silicon oil stage microscopy is used for detection of pseudopolymorph
X-ray diffraction method
 It provide the most complete information about solid state.
 This method is based on the scattering of x-ray by crystal.
Optical crystallography

19. Thermo gravimetric analysis
 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
changes.
 As many weight loss similar, the weight loss curve may require transformation before results may
be interpreted.

20. Applications
 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.

21.  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.
Eg:
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.
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.

22. 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.
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 a vehicle containing sufficient cosolvent to solubilize
the less soluble polymorphic form.

23.  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.
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.

24.  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.
 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.

25.  REFERENCES
 Karpinski PH. Polymorphism of active pharmaceutical ingredients. ChemEng Technol. 2006; doi:
10.1002/ceat.200500397.
 Chawla G, Bansal AK. Challenges in polymorphism of pharmaceuticals. CRIPS. 2004. . The theory
and practice of industrial pharmacy by - Leon Lechman, Joseph L Kanig.
 Biopharmaceutics and pharmacokinetics by- DM Bhramankar, Sunil Jaiswal.
 Physical pharmacy by- Alfred Martine. Sun C. Grant DJW. Influence of crystal structure on the
tableting properties of sulfamerazine polymorphs. Pharm Res. 2001; 18(3):274-80.
 Eyjolfsson R. Enalapril maleate polymorphs: instability of form II in a blet formulation. Phamazie. 2002;
57(5):347–48.
 Schmidt AC, Senfter N, Griesser UJ. Crystal polymorphism of local anaesthetic drugs. J Therm Anal
Calorim. 2003: 73:397-404.

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