What is Polymorphism?

A substance’s capacity to crystallise into various crystalline forms is known as polymorphism. These crystal changes are also referred to as polymorphs. Polymorphs behave differently in the solid state even though they are the same in the liquid or gaseous states.

The ritonavir problem was caused by a change in the solubility of ritonavir that caused the drug to precipitate from the capsule formulation, and reduced its bioavailability to less than 5%. The reason for this change is a phenomenon known as polymorphism. This phenomenon was discovered in the early nineteenth century, but only since the middle of the twentieth century have its wider implications been appreciated by scientists investigating the crystallization, properties and interconversion of solid phases.

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These implications stem from the fact that different polymorphs of a given substance may display very significant differences in physical properties such as melting point, colour, hardness, density, electrical conductivity, heat of fusion, solubility and dissolution rate, as well as differences in chemical reactivities.

Types of Polymorphism

Solids can exist as crystalline, amorphous, solvate (hydrate), and desolvated (dehydrated) forms. Complicating this situation is the fact that crystalline solids (and solvates/hydrates and desolvated/dehydrated solvates/hydrates) can exist in what is known as polymorphs. Crystals exist with the molecules arranged in a repeating pattern with an identifiable symmetry.

However, there can be more than one possible repeating pattern for many drugs. This can be demonstrated by visualizing a number of identical Lego pieces of a specific shape. Each Lego piece represents a drug molecule. These individual Lego pieces can be assembled in several ways to form different symmetrical patterns. Each of the different patterns contains the same number and type of individual Lego pieces.

Polymorphism is quite common for the same material to crystallize in different (more than one) arrangements of molecules in the crystal. Polymorphism can be classified into two types according to their stability with respect to the different ranges of temperature and pressure.

1. Monotropic System

Only one polymorph is stable at all reasonable temperatures.

e.g. metolazone

2. Enantiotropic system

One polymorph is stable over one temperature range, another polymorph is stable over a different temperature range – e.g. carbamazepine and acetazolamide.

Relationship between Polymorphs and Solvates

  • The thermodynamically most stable anhydrous form may no longer be the most stable: it will convert to solvate in the presence of the right amount of solvent.
  • The thermodynamically most stable solvate is not necessarily associated with the lowest degree of a solvate.
  • A particular solvate may have polymorphs. e.g. Nedocromil Zinc

Key Points about Polymorphs

  • Pharmaceutical solids may be crystals, crystal solvates or hydrates, crystal desolvated solvates or dehydrated hydrates, or amorphous solids
  • All crystal forms described can exist in different forms called polymorphs
  • Polymorphs can have significant differences in their physical properties even though they are chemically identical. Physical properties include solubility, melting point, particle size, dissolution rate, hygroscopicity, and others.
  • Polymorphs may interconvert depending on conditions. Usually, the metastable kinetic form converts to the stable thermodynamic form.
  • Laboratory studies are key to determining the potential of a compound to form multiple polymorphs, determining under what conditions the polymorphs are formed, what are the physical properties of each polymorph, and what is the stability of each polymorph
  • The primary analytical method to characterize polymorphs is x-ray diffraction. Other methods used include solid state NMR, Raman and NIR spectroscopy, and thermal methods such as DSC and TGA.
  • Seeding is used to facilitate manufacturing of the desired polymorph.

Crystallization Chemistry Experiment

Frequently Asked Questions – FAQs


What is polymorphism in chemistry?

A solid chemical substance having the ability to exist in more than one crystalline form is known as polymorphism in chemistry.

What is a polymorph and example?

The chemical composition of two or more minerals that vary in terms of atomic arrangement and crystal structure. Diamond and graphite, two separate minerals made of the same substance but crystallising differently, are a well-known example.

What is the difference between allotropes and polymorphism?

Although allotropy is the ability of some chemical elements to exist in two or more different forms, in the same physical state, known as allotropes of these elements, polymorphism is the capacity of a solid material to exist in more than one form or crystal structure.

What is an example of polymorphism in chemistry?

The minerals calcite and aragonite, which are both variations of calcium carbonate, are classic example of polymorphism. Graphite and diamond are two polymorphs of carbon that are possibly the most well-known examples.

Is polymorphism a physical or chemical property?

In crystallography, polymorphism is the phenomenon in which a solid chemical compound exists in more than one crystalline form; the forms have identical solutions and vapours but have slightly different physical and, in some cases, chemical properties.
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