Candidate drug selection, preferred

For parenteral IV formulations, a sterile solution of the compound is required. A terminal sterilization method is preferred, rather than aseptic filtration, because there is a greater assurance of achieving sterility. As noted by Moldenhauer (1998), the FDA requires a written justification to explain why a product is not terminally sterilized. Therefore, it is mandatory to assess whether the candidate drug is stable to autoclaving as part of any preformulation selection process. Autoclaving (usually 15 min at 121°C) at various pHs is undertaken, after which the solutions should be evaluated for impurities, colour, pH and degradation products. Clearly, if one compound shows superior stability after autoclaving, then this will be the one to choose. 

An alternative approach to normalizing rates of drug metabolism by recombinant CYP enzymes is the application of a relative activity factor (RAF), in which the correction is not based on specific content but on specific activity, which requires a comparison of the rate of metabolism of a selective marker substrate by each recombinant CYP enzyme and human liver microsomes (75,194). The RAF is then multiplied by the observed rates of drug metabolism by each recombinant CYP enzyme before assessing the relative contribution of each enzyme to the metabolism of the drug. This approach has not been well validated. For example, it is not known whether the relative activity factor remains constant for several marker substrate reactions catalyzed by the same CYP enzyme. If the relative activity factor varies in a substrate-dependent manner, it would be difficult to know which RAF value to apply to the drug candidate under investigation. Another limitation of this approach is that the relative activity factor must be empirically determined for each lot of recombinant CYP enzyme (and preferably each batch of pooled human liver microsomes). 

Several types of multiple-unit containers have been developed by the pharmaceutical industry. In general, multiple-imit containers are preferred over their singleunit coimterparts on the basis of economic effectiveness, but only drugs that can be sufficiently protected in this type of packaging can be viable candidates for multiple-unit packaging. The selection of mrJtiple-unit containers primarily depends on the dosage form. 

At this point, the lead is chemically modified to improve potency, selectivity, bioavailability, and its pharmacokinetic profile. This means a drug candidate should be potent enough to bind properly to the target. It needs to bind specifically to the target or else it will generate potential side effects. It needs to have proper absorption (preferably orally) and distribution throughout the body, and it should be metabolized without generating any toxic substances. Lastly, it should be easily eliminated from the body. 

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