Polymorphism

What is Polymorphism?

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.

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.

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 are 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.

Types of Polymorphism

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

Monotropic System

Only one polymorph is stable at all reasonable temperatures.

e.g. metolazone

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

• Thermodynamically most stable anhydrous form may no longer be most stable: will convert to solvate in the present of the right amount of the solvent.

• The thermodynamically most stable solvate is not necessarily associated with the lowest degree of 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