POLYMORPHISM

POLYMORPHISM

Polymorphism (Greek word, Polus = many and morph = shape) is the phenomenon in whicha substance exists in more than one crystalline forms. This can be happened under different conditions of temperature and pressure. Different crystalline forms are called Polymorphic.

For example; Mercuric iodide (Hgl) and calcium carbonate (CaCO3) exist in two types of crystal forms like (a) Orthorhombic and (b) Trigonal. Polymorphous substances have similar chemical properties but different physical properties.

It essentially means that in different polymorphs, the same molecule exists in different ways.

If this difference is because of packing, it is termed as packing polymorphism and if it is due to difference in conformation, it is called conformational polymorphism. As a result of polymorphism, molecules have different arrangements in the unit cell of its crystal and thus display different physical properties.

These include different packing properties, thermodynamic properties such as solubility, free energy, melting point, etc., spectroscopic properties, kinetic properties such as dissolution rate, stability, and mechanical properties such as hardness, compatibility, tensile strength, etc.

In Pharmaceutical field, polymorphism is very important because full characterization of a material has an essential role in determining its ultimate use.

In polymorphism, chemical identity of the material is not changed from one polymorph to another, so that a direct correlation between activity and solid state structure may be established.

For example, paracetamol exists in different ways in solid state because of their free energy difference. The free energy difference may be from 0.5 to a maximum of about 8 kcal / mol.

Based on this, some forms of compounds are slightly unstable compared to others and we can have a functional classification based on this factor.

TYPES OF POLYMORPHISMS

Polymorphs are categorized into two types depending upon their stability with respect to the range of temperatures and pressure.

Polymorphs which are stable at all temperatures below the melting point are called Monotropes.

When one of the polymorphs is stable (having lower free energy and solubility) over a certain temperature range and pressure, while the other polymorph is stable over a different temperature range and pressure, then the two polymorphs are said to be Enantiotropes.

Generally, it is possible to distinguish between monotropes and enantiotropes from their heats of fusion. An endothermic polymorphic transition indicates enantiotropes whereas an exothermic one indicates monotropes. Other than Differential Scanning Calorimetric (DSC) analysis, there are a number of efficient ways to characterize polymorphs.

CHARACTERIZATION OF POLYMORPHS

Many methods have been employed for characterizing polymorphs in pharmaceutical solids. Two methods; Polarizing optical microscopy and thermo-microscopy have proven to be useful tools. Thermal analysis procedures, such as differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), can be used to obtain additional information, including phase changes, and to deduce whether each isolated form is a solvate or anhydrate. These thermal methodologies are employed to distinguish between enantiotropic and monotropic systems. For an enantiotropic system, the relative stability of a pair of solid forms inverts at some transition temperature beneath the melting point while a single form is always more stable beneath the melting point in a monotropic system.

 POLYMORPHISM IN PHARMACEUTICAL COMPOUNDS

The property of self-organization of drug molecules in a several ways in solid state with nearly same lattice energies and the conformational flexibility of the molecule is the cause ifor the existence of crystal polymorphism in active pharmaceutical ingredients (APIs).

Thus the study of polymorphism in pharmaceutical field becomes very essential in drug and the excipient molecule. This study can be helpful in the drug development programme and can avoid future problems in manufacturing and also in the final performance of the drug delivery systems.

Many pharmaceutical molecules show the property of polymorphism which is essentially be studied at large about the changes in the physical and biological properties.

Thus, it is very important to select the proper polymorphic form of the API for getting desired effect and stability throughout its shelf life.

Usually the form that is most stable is preferred in market formulation as the metastable form may transform to other stable forms. But it is a universally accepted rule that the metastable form has higher solubility than the stable form and this form converts into the stable form as a result of spontaneous change but the reverse never happens. Thus, whenever possible, metastable forms having high solubility that can survive for years without changing to the stable form are selected for formulation. This means that, forms that have considerable activation barrier in moving from metastable state to stable state would be selected. That is, careful evaluation of both thermodynamic parameters (tendency toward formation of more stable polymorphs) and kinetic parameters (which lead to formation of metastable polymorphs) is of high importance in crystallization process of such compounds.