Polymorphic drugs

Cashman, J. R. etal. (2001). Population distribution ofhuman flavin-containing monooxygenase form 3 gene polymorphisms. Drug Metab. Dispos., 29, 1629-37. 

For a polymorphic drug, the polymorph obtained depends on the physical conditions, such as temperature, pressure, solvent, and the rate of desupersaturation. For a solvated drug, in addition to these conditions, the thermodynamic activity of the solvating solvent may also determine the solvate obtained. However, kinetic factors may sufficiently retard the crystallization of a stable form or the solid-state transition to the stable form that an unstable form may be rendered metastable. 

In pharmaceuticals, NIR is used for, of course, moisture, polymorphic (drug) forms, percent crystallinity, isomer purity, tablet/capsule assay, coating levels, evaluation of dissolution times, and numerous process tests. It is a rapid means for the Food and Drug Administration to check for counterfeit drugs, and for the Drug Enforcement Agency to ascertain what type of materials are impounded in drug raids. ... 

Grunenberg, A., Flenck, J-O., Siesler, FI.W., 1996, Theoretical Derivation and practical Application of Energy / Temperature Diagrams as an Instmment in Preformulation Studies of Polymorphic Drug Substances, International Journal of Pharmaceutics, 129, 147-158. 

Nozawa, T., Minami, H., Sugiura, S., Tsuji, A., and Tamai, 1. (2005) Role of organic anion transporter OATPIBI (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin in vitro evidence and effect of single nucleotide polymorphisms. Drug Metab. Dispos. 33, 434—439. 

Rae, J. M., Cordero, K. E., Scheys, J. O., Lippman, M. E., Flockhart, D. A., and Johnson, M. D. (2003) Genotyping for polymorphic drug metabolizing enzymes from paraffin-embedded and immunohistochemically stained tumor samples. Pharmacogenetics. 13, 501-507. 

Santoso B. Genetic and environmental influences on polymorphic drug acetylation. PhD Thesis. University of Newcastle Upon-Tyne, Newcastle, UK, 1983. 

Alvan G. Clinical consequences of polymorphic drug oxidation. Fund Clin Pharmacol 1991 5 209. Alvan G. Genetic polymorphisms in drug metabolism. J Internal Med 1992 231 571. 

Narurkar, A., Purkaystha, A., Sheen, R, and Augustine, M. (1988). Hygroscopicity of celiprol hydrochloride polymorphs,Drug Dev. Ind. Pharm., 14 465-474. 

Bertilson, L. and Dahl, M. L. Polymorphic drug oxidation relevance to the treatment of psychiatric disorders. CNS Drugs 5 (1996) 200-212. 

Table 1 Some Examples of Firmly Established Polymorphic Drug Metabolizing Enzymes and Substrate Drugs ...

Lee JT, Kroemer HK, Silberstein DJ, Funck-Brentano C, Lineberry MD, Wood AJ, Roden DM, Woosley RL. The role of genetically determined polymorphic drug metabolism in the beta-blockade produced by propafenone. N Engl J Med 1990 322 1764-1768. 

Court MH, Krishnaswamy S, Hao Q, Duan SX, Patten CJ, Von Moltke LL, Greenblatt DJ (2003) Evaluation of 3 -azido-3 -deoxythymidine, morphine, and codeine as probe substrates for UDP-glucuronosyltransferase 2B7 (UGT2B7) in human liver microsomes specificity and influence of the UGT2B7 2 polymorphism. Drug Metab Dispos 31 1125-1133... 

Bertilsson L. Geographical/interracial differences in polymorphic drug oxidation. Cbn Pharmacokinet 1995 29 192-209. 

Jackson PR, Tucker GT, Lennard MS, et al. Polymorphic drug oxidation pharmacokinetic basis and comparison of experimental indices. Br J Clin Pharmacol 1986 22 541-550. 

Yokoi T, Sawada M, Kamataki T. Polymorphic drug metabolism studies with recombinant Chinese hamster cells and analyses in human populations. Pharmacogenetics 1995 5 S65-S69. 

Daly AK. Molecular basis of polymorphic drug metabolism. J Mol Med 1995 73 539-553. 

Grunenberg A, Henck JO, Siesler HW. 1996. Theoretical derivation and practical application of energy/temperature diagrams as an instrument in preformulation studies of polymorphic drug substances. Int. J. Pharm. 129 147-158. 

Griesser, U. J. and Burger, A. (1993). The polymorphic drug substances of the European Pharmacopoeia. Part 8. Thermal analytical and FTIR-microscopic investigations of etofylline crystal forms. J. Pharm. ScL, 61, 133 3. [128]... 

Rustichelli, C., Gamberini, G., Ferioli, V., Gamberini, M. C., Ficarra, R. and Tommasini, S. (2000). Solid state study of polymorphic drugs carbamazepine. J. Pharm. Biomed. Anal, 23,41-54. [148, 250]... 

Figure 4 Polymorphic drug oxidations by cytochrome P450. A, substrates subject to debrisoquine/sparteine polymorphism. R(+)-bufuralol is I -hydroxyl-ated by P450-IID6 the S(—)-enantiomer undergoes hydroxylation at the 2- and 4-positions debrisoquine is hydroxylated at the prochiral C4-atom to S(+)-hydroxy-debrisoquine sparteine metabolism by P450-IID6 consists of N-oxidation. B, substrates subject to hydantoin polymorphism (4 -hydroxylation). Extensive metabolizers convert S(+)-mephenytoin and -nirvanol to the 4 -hydroxy derivative (indicated by the arrow). Similarly, EMs metabolize the prochiral drug phenytoin to R(+)-4 -hydroxyphenytoin. = chiral center.

Solid-state NMR has emerged as a powerful tool in the analysis of polymorphic drug forms. CP-MAS spectroscopy can be used to identify the number of crystallographically inequivalent sites in a unit cell and to understand the molecular structure on the basis of the chemical shifts. Fig. 14 shows the solid-state spectra of two forms of lamivudine. Form II shows a relatively simple spectrum in which there is only one molecule in the crystallographic asymmetric unit. 

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