What is Polymorphism?

The word polymorphism is a combination of two words- poly and morph. The word poly means various and morph means shape.

Polymorphism is defined as the phenomenon in which a substance exists in more than one crystalline form due to different atomic arrangements in a crystal. The various forms of a substance are termed polymorphs.

Need of Polymorphism

Following are the various importance that tells the need for polymorphism:

• To achieve a system with high physical stability because several polymorphs will have more stability than others.
• Stable polymorph represents the lowest energy state and least aqueous solubility.
• Metastable polymorphs represent the high energy state and high aqueous solubility.
• Metastable polymorphs can easily convert to stable polymorphs due to their higher energy state.
• The effect of polymorphism on biodiversity is the most important consequence for drug substances.

Properties of Polymorphism

Following are the various properties shown by polymorphs in the liquid or gaseous state:

• Melting and sublimation temperature
• Solubility and dissolution rate
• Stability
• Vapor pressure
• Crystal structure
• Heat capacity
• Solid-state reaction
• Optical and electrical property

Types of Polymorphism

Following are the various types of polymorphism based on the stability of solid crystal with respect to temperature and pressure:

• Monotropic polymorphism
• Enantiotropic polymorphism

Monotropic polymorph

In Monotropic polymorphism, a single polymorph is stable at all temperatures below the melting point, and other polymorphs are unstable. The metastable or unstable polymorphs changes to stable form at all temperature by the transition.

The reversible transition is not possible in monotropic polymorphism. Chloramphenicol palmitate and Mentolazone are examples of monotropic polymorph.

Enantiotropic polymorph

In enantiotropic polymorphism, one polymorphic form or polymorphism is stable over a specific range of temperature and pressure, while other forms or polymorphs are stable over different temperatures and pressures.

The one polymorphic form or polymorph can transform reversibly into a different form at a specific temperature. Sulfur and Carbamazepine are examples of enantiotropic polymorph.

Factors affecting polymorphism

Following are the various factors that affect the polymorphism:

• Temperature
• Humidity
• Photostability
• Effect of grinding
• Effect of solvent
• Effect of compression

Methods for polymorph preparation

Following are the various methods used for the preparation of polymorphs:

• Solvent evaporation method
• Slow cooling approach
• Solvent diffusion technique
• Vapor diffusion method
• Vacuum sublimation

Solvent evaporation method

The solvent evaporation method is also known as rota evaporation. In this method, the saturated drug solution is produced in a suitable solvent, and the solvent is later removed by rotatory evaporation. Air drying at various temperatures can also be used to achieve different potential polymorphs.

The diagrammatical representation of the solvent evaporation method is shown as:

Slow cooling approach

In the slow cooling approach, polymorphic forms of less soluble drugs in the solvent system of boiling range 30-90 degrees centigrade are produced. The solute is heated in the solvent just above the boiling point to produce the saturated solution in this process. The saturated solution is transferred to a stopped tube and connected to a flask containing water at a temperature just below the solvent's boiling point. The flask is left in such condition for the next several days. This method is improved to obtain more reliable crystal forms using various solvent mixtures of multiple polarities. The variation in the solvent composition may inhibit or promote the growth of particular crystal faces and can yield crystal of required morphology. This phenomenon is also termed as solution growth approach.

The diagrammatical representation for slow cooling approach is shown as:

Solvent diffusion technique

The solvent diffusion method is employed when the amount of drug available is less or sensitive to air or solvent. In this method, the solution is placed in a common tube, and the additional less dense solvent is also dropped down the slides of the tube using a pipette or other equipment to form discrete layer. The slow diffusion of the solvent results in crystallization at the interface.

The diagrammatical representation of solvent diffusion technique is shown as:

Vapor diffusion method

The vapor diffusion method is also applicable for fewer quantities of the sample. In this method, the concentrated drug solution is placed as a drop hanging on the underside of a microscope coverslip. The cover slip with the hanging drop is sealed with silicon oil over a solution carrying a high precipitant concentration.

The latter has less vapor pressure as compared to the drug solution due to precipitant concentration. It results in diffusion of the solvent from the drop towards the reservoir and subsequent crystallization within hours to weeks.

The diagrammatical representation of the vapor diffusion method is shown as:

Vacuum sublimation

The vacuum sublimation method is used for purifying solid samples by heating them under vacuum conditions. The sample sublimes and the vapor condenses as a purified compound on a cooled surface, while impurities are deposited behind.

The diagrammatical representation of the vacuum sublimation is shown as:

Methods to identify polymorphism

Following are the various methods used to identify polymorphism:

• X-ray diffraction method
• Optical crystallography
• Differential thermal analysis
• Thermo gravimetric analysis
• Differential scanning calorimeter
• Hot stage microscopy

X-ray diffraction method

The X-ray diffraction method is based on the scattering of x-rays by crystal surface or object. It provides complete information about the crystal. It identifies the unit cell dimension, establishes the crystalline lattice system, and provides a distinct difference between crystalline forms of the compound.

In this process, a crystal is mounted on a goniometer and slowly rotated and bombarded with x-rays; it will generate a diffraction pattern of evenly spaced spots termed as reflections. It is a time taking process, so its use is limited to specific applications only.

Optical crystallography

Optical crystallography is used for the identification of polymorph crystals existing in isotropic and anisotropic forms. The optically isotropic crystal exhibit one index of refraction for the light of each color, while the anisotropic crystal exhibits multiple refractions and multiple refractive indices for the light of each color.

Differential thermal analysis

Differential thermal analysis is the analytical method in which the temperature difference between the sample and reference material is monitored when the two substances are subjected to an identical heating program.

Thermogravimetric analysis

Thermogravimetric analysis is testing performed on the sample to obtain a change in weight concerning the temperature change. In thermogravimetric analysis, a high degree of precision in measuring weight and change in temperature is required. The weight loss curve requires transformation before results are interpreted because of common weight loss in various samples or objects.

Differential scanning calorimeter

The differential scanning calorimeter is defined as a thermal analytical method in which the difference in the thermal energy is needed to increase the temperature of a sample, and reference is identified as a function of temperature in a specified atmosphere. It quantitatively measures heat absorbed or released by a material undergoing a chemical or physical change. It derives information on glass transform, transition temperature, and others.

Hot stage microscopy

Hot stage microscopy is defined as a process in which fluid stage transformation of an object occurs and is observed as a function of temperature. The silicon oil stage microscopy is adopted for the estimation of pseudopolymorph.

Common Mistakes

Following are the common mistakes performed by students:

• Sometimes, students get confused between allotropy and polymorphism.
• Sometimes, students forget the concept of properties of polymorphism.
• Sometimes, students get confused about which type of polymorph is stable.
• Sometimes, students get confused about the factors affecting polymorphism.

Context and Application

The topic polymorphism is significant in various courses and professional exams of undergraduate, graduate, postgraduate, doctorate levels. For example:

• Bachelor of Technology in Mechanical Engineering
• Bachelor of Science in Chemistry
• Master of Technology in Production Engineering
• Doctorate of Philosophy in Chemistry

Related Concept

• Crystal Structure in objects
• Allotropy
• Object property and strength
• Type of isomerism
• Atomic structure

Practice Problems

Q1. The reversible transition is not possible in which type of polymorphism?

1. Monotropic polymorphism
2. Enantiotropic polymorphism
3. Monotropic and Enantiotropic polymorphism
4. None of these

Correct option- (a)

Q2. Which of the following factor will not affect the polymorphism?

1. Temperature
2. Humidity
3. Photostability
4. Density

Correct option- (d)

Q3. In which type of polymorphism preparation method has solution growth approach?

1. Solvent evaporation method
2. Slow cooling approach
3. Solvent diffusion technique
4. Vapor diffusion method

Correct option- (b)

Q4. The method of identifying polymorphism or polymorph object based on scattering is _____?

1. X-ray diffraction method
2. Optical crystallography
3. Differential thermal analysis
4. Thermo gravimetric analysis

Correct option- (a)

Q5. In optical crystallography, which type of crystal exhibits multiple refractions?

1. Isotropic crystal
2. Anisotropic crystal
3. Both isotropic and anisotropic crystal
4. None of these

Correct option- (b)