Appendix I F. Polymorphism

Polymorphism (or crystal polymorphism) is a phenomenon related to the solid state; it is the ability of a compound in the solid state to exist in different crystalline forms having the same chemical composition. Substances that exist in a non-crystalline solid state are said to be amorphous.

When this phenomenon is observed for a chemical element (for example, sulfur), the term allotropy is used instead of polymorphism.

The term pseudopolymorphism is used to describe solvates (including hydrates), where a solvent is present in the crystal matrix in stoichiometric proportions; the term may also be extended to include compounds where the solvent is trapped in the matrix in variable proportions. However the term pseudopolymorphism is ambiguous because of its use in different circumstances. It is therefore preferable to use only the terms "solvates" and "hydrates".

Where a monograph indicates that a substance shows polymorphism, this may be true crystal polymorphism, occurence of solvates, allotropy or occurrence of the amorphous form.

The identity of chemical composition implies that all crystalline and amorphous forms of a given species have the same chemical behaviour in solution or as a melt; in contrast, their physico-chemical and physical characteristics (solubility, hardness, compressibility, density, melting point, etc.), and therefore their reactivity and bioavailability may be different at the solid state.

When a compound shows polymorphism, the form for which the free enthalpy is lowest at a given temperature and pressure is the most thermodynamically stable. The other forms are said to be in a metastable state. At normal temperature and pressure, a metastable form may remain unchanged or may change to a thermodynamically more stable form.

If there are several crystalline forms, one form is thermodynamically more stable at a given temperature and pressure. A given crystalline form may constitute a phase that can reach equilibrium with other solid phases and with the liquid and gas phases.

If each crystalline form is the more stable within a given temperature range, the change from one form to another is reversible and is said to be enantiotropic. The change from one phase to another is a univariate equilibrium, so that at a given pressure this state is characterised by a transition temperature. However, if only one of the forms is stable over the entire temperature range, the change is irreversible or monotropic.

Different crystalline forms or solvates may be produced by varying the crystallisation conditions (temperature, pressure, solvent, concentration, rate of crystallisation, seeding of the crystallisation medium, presence and concentration of impurities, etc.).

The following techniques may be used to study polymorphism:

• — X-ray diffraction of powders,

• — X-ray diffraction of single crystals,

• — thermal analysis (2.2.34) (differential scanning calorimetry, thermogravimetry, thermomicroscopy),

• — microcalorimetry,

• — moisture absorption analysis,

• — optical and electronic microscopy,

• — solid-state nuclear magnetic resonance,

• — infrared absorption spectrophotometry (2.2.24),

• — Raman spectrometry (2.2.48),

• — measurement of solubility and intrinsic dissolution rate,

• — density measurement.

These techniques are often complementary and it is indispensable to use several of them.

Pressure/temperature and energy/temperature diagrams based on analytical data are valuable tools for fully understanding the energetic relationship (enantiotropism, monotropism) and the thermodynamic stability of the individual modifications of a polymorphic compound.

For solvates, differential scanning calorimetry and thermogravimetry are preferable, combined with measurements of solubility, intrinsic dissolution rate and X-ray diffraction.

For hydrates, water sorption/desorption isotherms are determined to demonstrate the zones of relative stability.

In general, hydrates are less soluble in water than anhydrous forms, and likewise solvates are less soluble in their solvent than unsolvated forms.