Drugs, polymorphism

The primary method for demonstration of the existence of drug polymorphs, or solvate species, is that of powder x-ray diffraction (XRD). Such measurements represent a specification of the internal structure within a crystal, and an evaluation of its lattice type. Since dissolution and subsequent drying can sometimes yield an undesired structure, it is also important to confirm crystal structures at each formulation stage during the beginning of the development process. 

When drug polymorphs cannot interconvert as a result of being suspended in aqueous solution, a different bioavailability of the two forms usually results [126], For instance, the peak concentration of chloramphenicol in blood serum was found to be roughly proportional to the percentage of the B-polymorph of chloramphenicol palmitate present in a matrix of the A-polymorph [133]. The same concept has been found to apply to hydrate species, where the higher solubility and dissolution rate of the anhydrous phase relative to the trihydrate phase resulted in measurably higher blood levels when using the anhydrate as... 

Transporter Drug polymorphic effects Reference variabihty Reference... 

Can be used to detect polymorphs of drugs (polymorphs are different crystal forms of a molecule that have different physical properties such as solubility and melting point which may be important in the manufacturing process). 

CYP2C9 Phenytoin, warfarin, nonsteroidal antiinflammatory drugs Polymorphic... 

Literature Examples of Solubility Increases Using Drug Polymorphs... 

Singhal, D. 8t Curatolo, W., Drug polymorphism and dosage form design A practical perspective Adv. Drug Deliv. Rev. 2004, 56, 335-347. 

A second well-studied genetic drug polymorphism involves the stereoselective aromatic (4)-hydroxylation of the anticonvulsant mephenytoin, catalyzed by CYP2C19. This polymorphism, which is also inherited as an autosomal recessive trait, occurs in 3-5% of Caucasians and 18-23% of Japanese populations. It is genetically independent of the debrisoquin-sparteine polymorphism. 

Chongprasert, S., and Nail S. L. (1998), Influence of drug polymorphism on the physical chemistry of freeze-drying, Digital dissertations and theses, Purdue e-pubs, ETD Collection for Purdue University, available http //docs.lib.purdue.edu/dissertations/ AAI9939331/. 

Toscani, S. (1998) An up-to-date approach to drug polymorphism. Thermochim. Acta, 321, 73-9. [252]... 

When organic (drug) molecules crystallize from a solvent, the crystal structure is dependent upon the speed of crystallization, temperature, polarity of the solvent, concentration of the material, etc. Since the energy of the crystal affects the (physiological) rate of dissolution and thus the potency and activity of the drug, polymorphism is an important pharmaceutical concern [39]. The most common tool to determine crystal form is differential scanning calorimetry (DSC). Unfortunately, DSC uses small samples and may not represent the bulk of the material. X-ray diffraction is another excellent technique, but quite slow and sometimes difficult to interpret. 

Danesh A, Chen XY, Davies MC, et al. The discrimination of drug polymorphic forms from single crystals using atomic force microscopy. Pharm Res 2000 17(7) 887-890. 

Ghetti P, Ghedini A, Stradi R. Analytical potential of PT-IR microscopy. I. Applications to the drug polymorphism study. Boll Chin Parm 1994 133 689-697. 

The key issues in the study of drug polymorphism are the identification of different polymorphs (from a regulatory and patent viewpoint as much as from a formulation one), the determination of polymorph stability, and the assessment of processing conditions on polymorph generation. Whereas DSC is widely used as a means of routine screening for polymorphs, it is by no means universally effective as a means of identification. For example, several studies have indicated that DSC shows very similar traces for the various polymorphs of cimetidine (e.g., 15) hence, the generation of apparently identical peaks is not a guarantee of the absence of different crystal modifications. In other cases, however, the differentiation between polymorphs may be more obvious. 

JC Bellows, FP Chen, PN Prasad. Determination of drug polymorphs by laser Raman spectroscopy. I. AmpiciUin and griseofulvin. Drug Dev Ind Pharm 3 451-458,1977. 

Effects of Pharmaceutical Processing on Drug Polymorphs and Solvates... 

---