Polymorphism

Polymorphism definition in chemistry states that polymorphism is the condition in which a solid chemical substance exists in more than one crystalline form. When given a set of building blocks, you can make the various structures with the same blocks. Now, think of the blocks as molecules and the structures as crystals. A crystal of a solid is formed when the molecules are arranged symmetrically in a repeating pattern. However, for a combination of drugs, there can be more than one repeating pattern in which they can arrange themselves. This leads to the condition called polymorphism in chemistry, where the same chemical compound exists in different crystalline forms.  

Polymorphism: An Overview

In materials science, polymorphism refers to the existence of solid material in several forms or crystal structures. Isomerism is a type of polymorphism. Polymorphism is a phenomenon that can occur in any crystalline substance. Polymorphism in chemical elements is defined by allotropy. Agrochemicals, dyestuffs, medicines, foods, pigments, and explosives all benefit from polymorphism.

A polymorphic transition is a reversible transition, according to the International Union of Pure and Applied Chemistry. It's a reversible transition from one solid crystalline phase to another with the same chemical makeup but a different crystal structure at a specific temperature and pressure. Dimorphic materials have two polymorphs, trimorphic materials have three polymorphs, and so on.

Which Properties can Differ Due to Polymorphism? 

The various polymorphs of a compound possess distinct physical and sometimes chemical properties, although the solutions and vapours appear identical. Various polymorphs of a substance may exhibit substantial differences in physical properties such as melting point, colour, hardness, density, electrical conductivity, hygroscopicity, latent heat of fusion, solubility, and dissolution rate, as well as variance in chemical reactivity. 

Types of Polymorphism

It is quite common for the molecules of a substance to rearrange themselves in different forms, to make polymorphism a common occurrence. Considering the stability of the solid crystals concerning temperature and pressure, we can classify polymorphism into two broad categories. 

Polymorphism is a regular occurrence in which the molecules of a substance rearrange themselves into new forms. Polymorphism can be divided into two groups based on the stability of solid crystals at different temperatures and pressures.

1. Mono-tropic Polymorphism: In the mono-tropic system of polymorphism, only one polymorph is stable for all acceptable temperatures. The compound metolazone exhibits this type of polymorphism. 

Only one polymorph is stable at all tolerable temperatures in the mono-tropic system of polymorphism. This polymorphism can be found in the chemical metolazone.

2. Enantiotropic Polymorphism: In the enantiotropic system of polymorphism, there are different polymorphs, and each polymorph is stable under a specific range of temperature. So, one polymorph can be stable at a low-temperature range; one can be stable at a high-temperature range and so on. The compounds carbamazepine and acetazolamide exhibit this type of polymorphism. 

There are multiple polymorphs in the enantiotropic system of polymorphism, and each polymorph is stable across a certain temperature range. As a result, one polymorph may be stable at low temperatures, while another may be stable at high temperatures, and so on. This polymorphism can be seen in the drugs acetazolamide and carbamazepine.

Relationship Between Polymorphs and Solvates

A solvate is an aggregate constituting a solute ion or a molecule along with one or more solvent molecules.

• Thermodynamically, when the most stable anhydrous polymorph ceases to be the most stable, it converts into a solvate in the presence of the right amount of solvent. 

• The thermodynamically most stable solvate is not necessarily the lowest level of a solvate. 

• A particular solvent can have polymorphs, for example, Nedocromil Zinc 

Application of Polymorphism 

Polymorphism is mainly useful in the pharmaceutical field for drug development. The structure of the solid crystal is essential to determine the effectiveness of the drug and the effects it can have on the body. Owing to variations in the solubility of polymorphs, one polymorph can be more therapeutically successful than another polymorph of the same product. In many cases, a particular drug receives regulatory approval for only one of its polymorphs. 

Polymorphism is extremely useful in the pharmaceutical industry for drug development. The structure of the solid crystal is critical in determining the drug's effectiveness and potential side effects. Due to differences in polymorph solubility, one polymorph of the same substance and use can be more therapeutically successful than another. In many circumstances, a drug's regulatory approval is limited to just one of its polymorphs.

Polymorphism in Pharmacy

• Paracetamol powder has poor compression properties; this poses difficulties in making tablets, so a new, more compressible polymorph of paracetamol has been found. 

• Cortisone acetate is found in at least five separate polymorphs, four of which are soluble in water and transform to a stable shape. 

• Carbamazepine beta-polymorph was produced from solvents with a high dielectric constant ex aliphatic alcohol, while alpha polymorphic solvents such as carbon tetrachloride were crystallized from low dielectric constants. 

The Peculiar Case of Ritonavir

Ritonavir is an antiviral drug. One of its polymorphs was virtually inactive compared to the alternative polymorph. Later, it was discovered that the inactive polymorph transformed the active polymorph into the inactive form upon contact. This was because of its lower energy and greater stability making spontaneous rearrangement energetically desirable. Just a few particles of the lower energy polymorph could convert massive amounts of ritonavir into the clinically worthless inactive polymorph, causing major production problems that were finally solved by administering the medicine through gel caps and tablets instead of the original capsules.

Ritonavir is a type of antiviral medication. In comparison to the alternate polymorph, one of the polymorphs was virtually inert. When the active polymorph comes into contact with the inactive polymorph, the active polymorph transforms into the inactive form. It was chosen because of its lower energy and greater stability, making spontaneous rearrangement attractive from an energetic standpoint. Massive amounts of ritonavir could be converted into the therapeutically useless inactive polymorph with just a few particles of the lower energy polymorph. The useless inactive polymorph wreaks havoc on production. These issues were finally resolved by using gel caps and tablets instead of capsules to dispense the medication.