Polymorphs significance

Osteoporosis is a prevalent disease that typically reduces bone strength and predisposes to fractures. It is a multifactorial disorder resulting from the interaction of genetic and acquired factors. Candidate gene studies and, more recently, genome-wide studies have identified a number of polymorphisms significantly associated with bone mass and fractures. Anti-resorptive drugs, which inhibit the differentiation and activity of osteoclasts, are frequently used to treat patients with osteoporosis. 

The most common crystalline forms are polymorphs, hydrates, and solvates (pseudopolymorphs). Polymorphs are formed when a substance crystallizes in two or more crystal structures. Polymorphism significantly impacts on physicochemical properties of materials, such as stability, density, melting point, solubility, bioavailability, and so on. Hence the characterization of all possible polymorphs, identifying the stable (thermodynamic) polymorph, and design of reliable processes for consistent production are critical in modem day drug development. 

CYP2B6516G>T polymorphisms significantly affect the metabolism of efavirenz. In 63 HIV-infected children, median age 12 (range 3-19) years, who took efavirenz for at least 4 weeks, CYP2B6516 G/G, G/T, and T/T genotypes were found in 48%, 41%, and 11% respectively [148 ]. The516G>T allele frequency was 32%. The mean concentrations of efavirenz for children with the G/G, G/T, and T/T genotypes were 1604, 2635, and 11 582 ng/ml respectively. There was a correlation between efavirenz concentrations over 4000 ng/ml and psychiatric adverse effects, but no association with rashes, hepatotoxic-ity, or central nervous system disturbances. 

Many molecules are obtained and used in a crystalline form, the nature of which can have e significant impact on their properties and behaviour. Moreover, it is sometimes possible foi a given material to exist in more than one crystalline form, depending upon the conditions under which it was prepared. This is the phenomenon of polymorphism. This can be important because the various polymorphs may themselves have different properties. It is Iberefore of interest to be able to predict the three-dimensional atomic structure(s) that a gi en molecule may adopt, for those cases where it is difficult to obtain experimental data and also where one might wish to prioritise molecules not yet synthesised. 

A significant advantage of the PLM is in the differentiation and recognition of various forms of the same chemical substance polymorphic forms, eg, brookite, mtile, and anatase, three forms of titanium dioxide calcite, aragonite and vaterite, all forms of calcium carbonate Eorms I, II, III, and IV of HMX (a high explosive), etc. This is an important appHcation because most elements and compounds possess different crystal forms with very different physical properties. PLM is the only instmment mandated by the U.S. Environmental Protection Agency (EPA) for the detection and identification of the six forms of asbestos (qv) and other fibers in bulk samples. 

The ideas developed in this chapter are descriptive of shock waves in fluids. Solids have many significant features that distinguish them from liquids and gases, such as shear strength, polymorphic phase transformations, heterogeneous structure, anisotropy, and viscoplastic behavior. The influences of these special properties of solids on shock compression are the topics of several of the other chapters, and for the most part are ignored in this introduction to the basic principles of shock compression. 

Fig. 2.12. If solids undergo a shock-induced polymorphic transformation, the volume change at the transformation causes significant changes in the wave profile produced by shock loading. In the figure, is the applied pressure, Pj is the pressure of the phase transition, and HEL is the Hugoniot elastic limit.

Moreover, there exist polymorphic MOP variants. An Asn40Asp polymorphism has been found with a high abundance in the Caucasian and Asian population. This receptor variant is less expressed in the brain and carrier of this polymorphism appears to need more opioids for analgesic treatment. There are many additional MOP polymorphisms with unknown functional significance. In spite of many studies there appears to exist no significant association of polymorphisms in the MOP gene and drug addiction [5]. 

There are only very few genes which do not carry any polymorphisms. And there exists even a significant number of polymorphic genes that are not expressed at all in part of the population due to genetic polymorphisms. Table 1 summarizes a few selected polymorphisms with their functional and medical impact. 

It is also well known that different polymorphic forms can present largely different crystallite moduli along the chain axis (both observed and calculated). These differences can be large if large variations in the chain conformations are involved, and can have a significant influence on the bulk properties... 

Langlois MR, Delanghe JR Biological and clinical significance of haptoglobin polymorphism in humans. Clin Chem 1996 2 1589. 

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