Polymorphism drugs influenced

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

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... 

Polymorphism can influence every aspect of the solid state properties of a drug. Many of the examples given in preceding chapters on the preparation of different crystal modifications, on analytical methods to determine the existence of polymorphs and to characterize them and to study structure/property relations, were taken from the pharmaceutical industry, in part because there is a vast and growing body of literature to provide examples. One of the important aspects of polymorphism in pharmaceuticals is the possibility of interconversion among polymorphic forms, whether by design or happenstance. This topic has also been recently reviewed (Byrn et al. 1999, especially Chapter 13) and will not be covered here. Rather, in this section, we will present some additional examples of the variation of properties relevant to the use, efficacy, stability, etc. of pharmaceutically important compounds that have been shown to vary among different crystal modifications. 

The activity (induction or inhibition) of various CYP enzymes is influenced by a variety of factors that have been identified to date. For example, genetic polymorphisms are most significant in CYP families lA, 2A6, 2C9, 2C19, 2D6, and 2E1. Nutrition effects have been documented in families lAl, 1A2, IBl, 2A6,2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 (10, 11) smoking influences families lAl, 1A2, and 2E1 (12) alcohol influences family 2E1 (13) drugs influence families lAl, 1A2, 2A6,2B6,2C, 2D6, 3A3, and 3A4,5 and environmental xe nobio tics such as polycyclic aromatic hydrocarbons. 

Once again, it would not be feasible to review all the examples in the biomedical literature of polymorphisms influencing disease severity or progression. However, Table 12.7 summarizes many of these polymorphisms that influence disease severity and associated drug response. We will discuss a few of these disease states in detail. 

A large proportion of drug substances, whether neutral molecules, free adds, free bases or salts, are capable of exhibiting polymorphism or pseudopolymorphism (hydrate or solvate formation). It has been reported that 70% of barbiturates, 60% of sulfonamides and 23% of steroids exhibit polymorphism." Polymorphism often influences a range of physicochemical properties such as solubility, dissolution rate, stability and powder properties as well as bioavailability. Usually, it is possible to determine the most stable polymorph and discover recrystallization solvents that uniquely produce this form and improve the physicochemical and physicome-chanical properties and chemical stability of the drug. 

A key issue in pharmaceutical manufacturing is the reproducibility of solid-state attributes of the crystalline product. Batch-to-batch variation in the crystal size, habit, polymorphism, or chemical purity could be caused when certain impurities—usually, reaction by-products from the upstream processes—are present in the crystallizing solution. The resulting modification of crystal properties can affect downstream processing and formulation of the final product. Sometimes tailor-made and polymeric additives are used to tune the crystallization process and, hence, crystal properties at the molecular level. For instance, a good crystal habit can facilitate better filtration and separation. A stable (or metastable) polymorph can influence the stability and formulation behavior of the drug product. 

Ethnic differences have been shown to influence response to psychotropic medications. Much of the focus on the explanation for such differences has been on drug-metabolizing (CYP) enzymes of the liver and their sway over pharmacokinetic factors. It is now well recognized that differences in the distribution of polymorphic variants of CYP enzymes exist between different ethnic groups. However, within ethnic groups there are considerable inter-individual variations in drug kinetics, which may not be accounted for solely by genetic variation. Responses to pharmacotherapy are multifaceted and involve the interaction of environmental and... 

Selection of the most suitable chemical form of the active principle for a tablet, while not strictly within our terms of reference here, must be considered. For example, some chloramphenicol esters produce little clinical response [13], There is also a significant difference in the bioavailability of anhydrous and hydrated forms of ampicillin [14], Furthermore, different polymorphic forms, and even crystal habits, may have a pronounced influence on the bioavailability of some drugs due to the different dissolution rates they exhibit. Such changes can also give rise to manufacturing problems. Polymorphism is, of course, not restricted to active ingredients, as shown, for example, in an evaluation of the tableting characteristics of five forms or sorbitol [15]. 

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