Polymorphism

Polymorphism in chemistry states that it is the condition in which a solid chemical substance can exist in more than one crystalline form. When a set of building blocks is given, you can make the various structures with the same blocks given to you.

Think of the blocks as molecules and the structures as crystals. A crystal of a solid is formed when the molecules are symmetrically arranged in a repeating pattern. However, looking for a combination of drugs, there can be more than one repeating pattern in which they can arrange themselves. This results in the condition are polymorphism in chemistry. Here the same chemical compound exists in different crystalline forms.

Introduction to Polymorphism

In materials science, polymorphism describes the existence of solid material in more than one form or in a crystal structure. Polymorphism is a form of isomerism. Any crystalline material can exhibit the phenomenon of polymorphism. Allotropy defines polymorphism for chemical elements. Polymorphism is of practical relevance to agrochemicals, dyestuffs, pharmaceuticals, foods, pigments, and explosives.

According to the International Union of Pure and Applied Chemistry, a polymorphic transition is a reversible transition. It is a reversible transition of a solid crystalline phase at a certain temperature and pressure to another phase of the same chemical composition with a different crystal structure. Any materials with two polymorphs are dimorphic, with three polymorphs are trimorphic, and so on.

Many compounds exhibit polymorphism. It has been claimed that “every compound has different polymorphic forms. In general, the number of forms for a given compound is proportional to the time and money spent in research on that compound.”

The various polymorphs of a compound possess distinct physical and sometimes chemical properties too. Although the solutions and vapours appear identical. Various polymorphs of a substance exhibit difference 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 very 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. Thus, one polymorph can be stable at a low-temperature range, one can be stable at a high-temperature range, and so on. The compounds acetazolamide and carbamazepine exhibit this type of polymorphism.

Relationship between Polymorphs and Solvates

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

• Thermodynamically the most stable anhydrous form ceases to be most stable. It converts into solvate in the presence of the right amount of the solvent.

• The thermodynamically most stable solvate do not necessarily associate with the lowest degree of a solvate.

• A particular solvate may have polymorphs. For example, Nedocromil Zinc.

Factors Affecting Polymorphism

According to Ostwald’s rule, less stable polymorphs crystallize before the stable form. The concept depends on the idea that unstable polymorphs more closely resemble the state in the solution. The fibrous vs rhombic benzamide illustrates the case. Another example is two polymorphs of titanium dioxide.

Polymorphs have disparate stabilities. Some convert rapidly at room or any temperature. Most polymorphs of organic molecules only differ in lattice energy by a few kJ/mol. Approximately 50% of known polymorph pairs differ by less than 2 kJ/mol and stability differences of more than 10 kJ/mol are rare.

Polymorphism affects the details of crystallisation. The solvent in all aspects affects the nature of the polymorph. Nature includes concentration. Other components of the solvent, i.e., species that inhibiting or promote certain growth patterns. An important factor is often the temperature of the solvent from which crystallisation is carried out.

Application of Polymorphism

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

Polymorphism in Pharmacy

• Paracetamol powder has very poor compression properties. It 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 manufactured from solvents with a high dielectric constant, For example, 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 the polymorphs was virtually inactive compared to the alternative polymorph. Later, the inactive polymorph transfigures the active polymorph into the inactive form upon contact. The reason behind it 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. The worthless inactive polymorph causes major production problems. These problems were finally solved by administering the medicine through gel caps and tablets instead of the original capsules.

FAQs on Polymorphism

Question 1: Which properties can differ due to Polymorphism?

Answer: The different types of polymorphs of a compound possess distinct physical and sometimes chemical properties, although the solutions and vapours appear identical. Different 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.

Question 2: Explain the importance of polymorphism in Pharmaceuticals?

Answer: Bioavailability and Solubility are the two most important aspects of drug delivery. Polymorphism affects both of them. Polymorphism in drugs affects various physicochemical properties like bioavailability, dissolution rate, solubility, and manufacturability. That’s the reason why the detection of polymorphs in the drug manufacturing process and drug discovery is extremely important for quality control and assurance.

Question 3: When Polymorphism occurs in elements, what is it called?

Answer: Polymorphism is the ability of the given chemical composition to crystallize in more than one form. It is the result of changes in temperature or pressure. In some cases, both the varied structures of such chemical substances are is polymorphs or polymorphic forms.

Question 4: What is the difference between Allotropy and Polymorphism?

Answer: The existence of different molecular structures of elements is allotropy. The existence of different crystalline forms of elements or compounds is polymorphism.