changes in compound distribution in .NET framework

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changes in compound distribution
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pounds will be isolated in amorphous or thermodynamically unstable polymorphic form have profound implications for in vitro assays in traditional biology laboratories. This author anticipates an increase in the noise level of traditional biology in vitro assays, in particular, as compounds are increasingly distributed as DMSO stock solutions, and anticipates a resultant very negative reaction from traditional biology personnel. The reason for the increased noise level is the increased degree of uncertainty as to the actual concentration of a compound being screened when compounds are distributed as DMSO stock solutions. The purely technical considerations relating to compound physical form and resultant precipitation from DMSO stocks are similar in HTS assays and traditional biology in vitro assays, but the people considerations are very different. Personnel involved in HTS assays have long been tolerant of the problems attendant to HTS screens. They do not get upset if active compounds are missed in an HTS screen because of poor aqueous or DMSO solubility. To people familiar with HTS assays, it is just part of the cost of doing business, an inevitable trade-off between the greatly enhanced screening capacity of HTS versus an inevitable loss of accuracy. This type of mindset is very different from that likely to be encountered among traditional biologists. Traditional biologists place a premium on in vitro screen accuracy and take pride in assay reproducibility. Uncertainty as to compound concentration is minimized when stock solutions are freshly prepared from a neat amorphous material or a freshly prepared DMSO stock. In essence with respect to compound distribution, a traditional biology lab works within the one working-day scenario. However, all this changes if the method of compound distribution changes toward an automated dispensing of drug in DMSO stocks. Compound concentration in an in vitro assay becomes an important noise factor if the compound has precipitated from DMSO as part of the compound storage process. The biologist may interpret assay results as re ective of compound aqueous insolubility. However, the problem may have occurred at an even earlier stage in that precipitation actually occurred from the DMSO stock solution. In addition compound loss from DMSO may be interpreted as a chemical instability (degradation) problem. Considerable semantic confusion can result from the term instability. To the biologist it may mean compound loss from solution. The chemist may interpret instability as a change in chemical structure, namely as a chemical degradation problem. These differences are meaningful because different strategies may be chosen to deal with compound loss from a DMSO stock depending on whether the problem is precipitation or chemical degradation.
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solubility in the design of combinatorial libraries Implications for In Vivo Assays
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Process changes in chemistry that increase the probability that new compounds will be isolated in amorphous or thermodynamically unstable polymorphic form enhance the probability that in vivo activity will be detected if the compound aqueous solubilization is performed fairly rapidly. Likely the biologist or drug metabolism person will want to ensure oral exposure of a solution to an animal fairly quickly so that dosing occurs before the compound precipitates. Alternately, dosing might be performed with neat amorphous solid materials as a suspension. In either of these scenarios the oral dosing with amorphous solid will appear more ef cacious than if the oral dosing started with a suspension of the less soluble, thermodynamically more stable crystalline product form. The oral activity improvement attendant to the amorphous form of the compound may not be detected until a serious attempt is made to obtain crystalline material. This could come as late as the clinical candidate nomination stage. What should be avoided at all costs is the choice of the best orally active compound by a comparison of the oral bioavailability of poorly characterized solid forms. The oral absorption component of oral bioavailability (but not the metabolism factor) is extremely dependent on crystalline form. Making a choice using poorly characterized solid forms risks choosing a nonoptimum compound. In fact this error may not even be noticed if only the clinical candidate has been crystallized. Critical to these arguments is the presumption that most in vivo assays will not be conducted with stored compound in DMSO stock solutions.
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