Drug polymorphism examples

The existence of various isoforms of many of the enzymes involved with phase I and phase II reactions has been noted above. Key enzymes are also subject to variation by genetic polymorphisms so there may be considerable difference in the metabolic efficiency between individuals and between different ethnic groups. Such genetic differences account for most the variability we see between individuals capacity to metabolise certain drugs. For example, refer to Section 6.4.3. 

Polymorphism also adds more variability to safety margins. Polymorphism of GYP enzymes is particularly important as it may have a profound effect on the pharmacokinetic features of a drug. For example, the benzodiazepine etizolam is almost exclusively metabolized by GYP2G19 and its deficiency could lead to toxicity [11]. 

Literature Examples of Solubility Increases Using Drug Polymorphs... 

Nature of the drug formulation Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, particle size, salt form, crystal polymorphism, and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption. 

There are no good predictors of the occurrence of dysrhythmias, but there are several susceptibility factors (26 7), including a history of sustained tachydysrhythmias, poor left ventricular function, and myocardial ischemia. Potassium depletion and prolongation of the QT interval are particularly important, and these particularly predispose to polymorphous ventricular dysrhythmias (for example torsade de pointes). Altered metabolism of antidysrhjdhmic drugs (for example liver disease, polymorphic acetylation or hydroxylation, and drug interactions) can also contribute. 

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. 

Table 1 lists theoretically possible polymorphs of chiral drugs and practical examples [13,21,28 35]. The most common are polymorphic enantiomers, polymorphic racemic compounds, and the existence of both a racemic conglomerate and a racemic compound of a chiral drug. Polymorphs may be discovered by crystallization from supersaturated solutions in various solvents, by solvent-mediated polymorphic transformation, by crystallization of amorphous solids under different conditions. 

More recent examples of the construction of energy-temperature diagrams for drug polymorphs include those published by Schmidt and co-workers for two local anaesthetics, hydroxyprocaine hydrochloride (HPCHC, Figure 9, 11) and salicaine hydrochloride (SLCHC, Figure 9,12) [49,50]. Comprehensive solid-state analysis of these compounds included HSM, DSC, TG, FUR and Raman spectroscopy, SSNMR, PXRD, single crystal XRD and vapour pressure sorption analysis. 

G6PD deficiency is discussed in Chapters 20 and 52 and malignant hyperthermia in Chapter 49. At least one gene other than that encoding the ryanodine receptor is involved in certain cases of malignant hypertension. Many other examples of drug reactions based on polymorphism or mutation are available. 

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