Introduction to 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.
FAQs on Polymorphism
1. What is polymorphism in chemistry, with an example?
In chemistry, polymorphism is the ability of a solid compound to exist in two or more crystalline forms that have different atomic arrangements in their crystal lattice. These different forms are called polymorphs. For example, calcium carbonate (CaCO₃) is a polymorphic compound that exists as two different minerals: calcite and aragonite, each with a unique crystal structure and physical properties.
2. How is polymorphism different from allotropy?
The key difference lies in what substance they describe. Polymorphism refers to the existence of multiple crystalline forms for a compound (like zinc sulfide). In contrast, allotropy is a specific term used to describe this same phenomenon when it occurs in an element. For instance, carbon exists in allotropic forms like diamond and graphite, while sulphur exists as rhombic and monoclinic allotropes.
3. Why is understanding polymorphism important in the pharmaceutical industry?
Polymorphism is critical in pharmaceuticals because different crystal forms of the same drug can have vastly different physical and chemical properties. This directly impacts:
- Solubility: One polymorph might dissolve faster than another, affecting how quickly the drug works.
- Bioavailability: The rate and extent to which the drug is absorbed by the body can change with each form.
- Stability: Some polymorphs are more stable than others, which is crucial for determining a drug's shelf life.
Controlling which polymorph is produced is essential for ensuring a drug is safe, effective, and consistent.
4. What conditions cause a single compound to form different polymorphs?
The formation of a specific polymorph is governed by both thermodynamic and kinetic factors during crystallisation. Key conditions include temperature, pressure, and the solvent used for crystallisation. For example, a compound might form one polymorph when cooled slowly from a specific solvent, but a different, less stable (metastable) polymorph when cooled rapidly or from a different solvent. The presence of impurities can also influence which crystal structure is formed.
5. How are different polymorphs identified and their formation controlled in a laboratory?
Different polymorphs are primarily identified using analytical techniques that can detect variations in crystal structure. The most definitive method is X-ray Diffraction (XRD). Other common methods include Differential Scanning Calorimetry (DSC), which measures heat flow differences, and Raman or IR spectroscopy. To control the formation of a desired polymorph, chemists often use a technique called seeding, where a tiny crystal of the desired form is added to a solution to encourage the growth of that specific polymorph.
6. What is the difference between enantiotropic and monotropic polymorphism?
The difference relates to the stability of the polymorphs with respect to temperature. In enantiotropic polymorphism, there is a clear transition temperature at which two forms can reversibly convert into one another; one form is more stable below this temperature, and the other is more stable above it. In monotropic polymorphism, one polymorph is always the most stable form at all temperatures, and any other polymorphs are metastable and will irreversibly convert to the stable form over time.
7. Is chemical polymorphism related to genetic polymorphism found in DNA?
No, they are entirely different concepts that happen to share a name. Chemical polymorphism refers to the different crystal structures of a solid compound. In contrast, genetic polymorphism refers to the existence of multiple different versions (alleles) of a gene or DNA sequence within a population. One is a concept from physical chemistry and materials science, while the other is fundamental to genetics and biology.
