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.  

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 with respect to temperature and pressure, we can classify polymorphism into two broad categories. 

  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. 

  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. 

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 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 actually 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.

FAQ (Frequently Asked Questions)

1. Explain the Importance of Polymorphism in Pharmaceuticals?

Solubility and bioavailability are two important aspects of drug delivery. Polymorphism affects both of them. Polymorphism in drugs affects various physicochemical properties like solubility, bioavailability, dissolution rate, and manufacturability. This is the reason that detection of polymorphs in the drug manufacturing process and drug discovery is extremely crucial for quality control and assurance. 

2. When Polymorphism Occurs in Elements, What is it Called?

Polymorphism is essentially the ability of specified chemical composition to crystallize in more than one form. This process is the result of changes in temperature or pressure, or in some cases both. The varied structures of such chemical substances are called polymorphs or polymorphic forms. 

3. What is the Difference Between Allotropy and Polymorphism?

The existence of different molecular structures of elements is called allotropy. The existence of different crystalline forms of elements or compounds is called polymorphism. The differences are listed clearly in the table below. 

4. How Do We Identify the Distant Polymorphs? How Can We Ensure the Formation of a Particular Polymorph When Manufacturing a Compound in a Lab?

  • Laboratory studies are absolutely crucial to assess the potential of a compound to form various polymorphs, identify the conditions in which specific polymorphs are formed, the physical properties of each polymorph, and the stability of each polymorph. 

  • The primary analysis technique used to identify the polymorphs is x-ray diffraction. Solid State NMR, Raman and NIR spectroscopy, and thermal methods like DSC and TGA are some other techniques that can be used.

  • In order to facilitate the formation of the desired polymorph, we use seeding methodology.