Polymorphisms

PREM (2015A5PS862H)
BITS PILANI HYDERABAD CAMPUS
 Definition:
• Derived from Greek word
Poly means many & morph means shapes

• When a substance exist in more than one crystalline form, the

different forms are designated as polymorphs and the
phenomenon is known as Polymorphisms.

• due to different arrangements or conformations of the

molecules in the crystal lattice.

• More than 50% of active pharmaceutical ingredients (APIs)

are estimated to have more than one polymorphic form
Examples:
• Mercuric iodide crystals, when heated above 126 ̊C, forms
yellow laminar crystals. On cooling, the yellow form reverts to
red form.

• Paracetamol exist in two polymorphic forms. One is

monoclinic Form-I, which is marketed whereas Form-II is
orthorhombic.

• Piroxicam, a nonsteroidal, anti-inflammatory drug widely

prescribed all over the world exists in three forms I, II and III.
• Polymorphism is remarkably common particularly within some
structural group
e.g
Physical Properties Differ Among Various
Polymorphs
Difference in crystalline structure will leads to difference in
various physical properties

• packing properties
• thermodynamic properties such as free energy, solubility,
melting point, etc
• kinetic properties such as rate of dissolution, stability
• mechanical properties such as compatibility, hardness,
tensile strength, flow of material etc.
 Stablity characterstics:
• Depending on their relative stability, one of the several
polymorphic form is more stable.

 Stable polymorphisms
 Metastable form

• Metastable to Stable due to their higher energy state.

 Types of Polymorphisms
Polymorphism can be classified in to two types according to their
stability with respect to the different range of temperature and
pressure.
• Enantiotropic polymorph
If one form is stable over certain pressure and temp range,
while the form is stable over different pressure and temp range
e.g : sulfur
one polymorphs can change reversibly into another at
definite transition temp below the melting point
 Types of Polymorphisms

• Monotropic polymorph
Only one polymorph is stable at all temperature below melting
point, with all other polymorph being unstable
e.g: chloramphenicol palmitate

No reversible transition is possible

Methods to identify Polymorphism

• X-ray diffraction method

• Dilatometry
• Differential scanning Calorimeter
• Differential gravimetric Analysis (DGA)
• Optical Crystallography
• Hot stage microscopy
• Differential thermal Analysis (DTA)
Applications
• influence variety of API properties including flowability,
tableting, dissolution rate, solubility, stability and even
biological performance including efficacy and toxicity.
eg: six polymorphs of cocoa butter and all the polymorphs
have significantly different melting points

• enhance the shelf-life of the product & will help to

maintain the potency, as planned/desired

• Metastable form shows better bioavailability and therefore

preferred in formulations. Only 10% are in metastable
form
• The effect of polymorphisms on bioavailability, if bioavailability
is mediated by dissolution
e.g: chloramphenicol palmitate, aspirin, novobiocin etc

• polymorphisms of excipients in bioavailability

References:
1 Raza K, Kumar P, Ratan S, Malik R, Arora S (2014)
Polymorphism: The Phenomenon Affecting the
Performance of Drugs. SOJ Pharm Pharm Sci, 1(2), 10.

• Grant DJW. [Chapter 1]. Theory and origin of

polymorphism. Polymorphism in pharmaceutical solids. In:
Brittain Harry G, editor. Marcel Dekker, Inc; 1999.

• www.wikkipedia.com
Thank you