Pharmaceutical implications of polymorphism

We have already considered the problems in tahleting and injection which may result from 

Modified from R. Bouche and M. Draguet-Brughman Tertiary butyl acetate (tebutate). Trimethyl acetate. J. Pham. Belg., 32, 347 (1977) with additions.  

The transformation between polymorphic forms can lead to formulation problems. Phase transformations can cause changes in crystal size in suspensions and their eventual caking. Crystal growth in creams as a result of phase transformation can cause the cream to become gritty. Similarly, changes in polymorphic forms of vehicles, such as theobroma oil used to make suppositories, could cause products with different and unacceptable melting characteristics. 

For analytical work it is sometimes necessary to establish conditions whereby different forms of a substance, where they exist, might be converted to a single form to eliminate differences in the solid-state infrared spectra which result from the different internal stmc-tures of the crystal forms. As different crystal forms arise through different arrangements of the molecules or ions in a three-dimensional array, this implies different interaction 

The most important consequence of polymorphism is the possible difference in the bioavailability of different polymorphic forms of a dmg particularly when the dmg is poorly soluble. The rate of absorption of such a dmg is often dependent upon its rate of dissolution. The most stable polymorph usually has the lowest solubility and often the slowest dissolution rate. Fortunately, the difference in the bioavailability of different polymorphic forms of a dmg is usually insignificant. It has been proposed that when the free energy differences between the polymorphs are small there may be no significant differences in their biopharmaceutical behaviour as measured by the blood levels they achieve. Only when the differences are large may they affect the extent of absorption. For example, for 

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A large number of compounds of pharmaceutical interest are capable of being crystallized in either more than one crystal lattice structure (polymorphs), with solvent molecules included in the crystal lattice (solvates), or in crystal lattices that combine the two characteristics (polymorphic solvates) [122,123]. A wide variety of structural explanations can account for the range of observed phenomena, as has been discussed in detail [124,125]. The pharmaceutical implications of polymorphism and solvate formation have been recognized for some time, with solubility, melting point, density, hardness, crystal shape, optical and electrical properties, vapor pressure, and virtually all the thermodynamic properties being known to vary with the differences in physical form [126]. 

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