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Chemicals that exist in more than one solid‐state form are termed polymorphs; the classic example is carbon that can exist as diamond or graphite. Alternative polymorphic forms of a drug substance will have different crystalline forms which can affect their hydration and the time‐frame to reach equilibrium solubility. A change in polymorph can affect oral bioavailability due to the change in solubility as well as dissolution from the drug product.

The crystal structure determines the free energy within the solid and this can influence the rate of solvation. In early preclinical phases drug is often already in solution for evaluation of the potency and other key factors so polymorphism is irrelevant as this only affects solid materials. However, once the drug is produced and administered as a solid it is essential to understand the polymorphic form and relative stability of each form. Polymorphic screening is undertaken by dissolving the drug into a range of solvents and evaporating the solvents to characterise the crystalline or amorphous material formed.

Drug substances are manufactured as solids; a polymorph screen will be undertaken to identify the polymorphs present. This screen is usually undertaken early during drug development to identify and characterise the range of polymorphs.

It is important to not only recognise and characterise all polymorphs (for patenting purposes amongst others) but also to control the form of polymorph present upon manufacture and throughout the shelf‐life of the product. Solubility and dissolution can be used as surrogate measures of change in polymorph due to the measured difference in solubility and dissolution rate.

This phenomenon was significant for ritonavir in 1998 where the continued supply of the HIV drug was threatened due to the change in polymorph to a more stable and less soluble crystalline form. The original formulation contained ritonavir as an oral liquid or within semi‐solid capsules such that the drug was solubilised in an ethanol/water mix. A solubilised drug does not have a crystal structure thus no polymorphic control was required. However, it was noted that several batches of the semi‐solid capsules failed dissolution and upon investigation a second polymorph was identified which had much reduced solubility and subsequently reduced bioavailability which would limit exposure. As a result, a reformulation was required for both products [5].