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organic compound stability in large, diverse pharmaceutical
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and sample integrity. However, these technologies are not uniformly used throughout the drug discovery industry and therefore are not included in this discussion. A few recent studies have considered compound stability and integrity for each of the aforementioned storage formats. For example, Kozikowski et al.20 evaluated the stability of approximately 1500 compounds maintained in a dry lm format and stored for various lengths of time from one to four years. DMSO solutions of the compounds were analyzed by ow-injection analysis mass spectrometry (FIA-MS) prior to evaporation of the DMSO and dry lm storage. Among the 1194 compounds that were detected in the initial analysis, 1055 (88%) were observed to be stable and present once reconstituted in DMSO following two years of storage in a dry lm format.20 Additionally Yan et al. conducted a stability study on 1% of the compounds in their collection of more than 300,000 compounds stored in a dry lm format at -78 C. Similar to the results presented by Kozikowski, the authors reported that most of the compounds demonstrated good stability after two years of storage as a dry lm.21 Darvas et al. investigated the stability of 3000 compounds selected from approximately 300 diverse combinatorial libraries by LC/MS analysis and observed that 96% of the compounds had a projected shelf life of two years or longer with less than 10% compound loss, while 80% of the collection had a shelf life of greater than ve years when stored at 25 C in solid state storage. These stability studies were conducted, however, at 75 C for eight days, and the shelf life at 25 C was extrapolated from the data at 75 C and kinetic parameters obtained at elevated temperature for selected compounds in the test set.7,8 Similarly Savchuk et al. conducted a stability study of 2212 selected compounds stored as frozen DMSO solutions at 4 C and 20% relative humidity. They observed 98% retention of the compounds following a single year of storage.26 These data con rm that storage in a solid state, either as a dry lm or as a dry powder, will generally allow one to maintain the integrity of a large and diverse compound collection for a number of years (5 years or longer) when stored at or below room temperature with proper humidity control. Compound storage as frozen DMSO solutions is also suitable as long as the temperature is well below the melting temperature of the sample solution (see earlier discussions on temperature effect). On the other hand, compounds stored in DMSO at room temperature are much less stable than those stored in solid-state formats, and therefore current compound storage systems must be designed to minimize the exposure and length of time compounds are stored or processed at ambient atmospheric conditions prior to biological screening. There have been numerous studies designed
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compound stability under different storage conditions
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to evaluate the shelf life of diverse compound collections stored as room temperature DMSO solutions. In a recent study Kozikowski et al.11 evaluated the stability of a broad diversity of compound classes representative of a typical pharmaceutical screening collection over a time period of one year in order to develop a predictive model representative of the stability behavior of their entire repository. The approximately 7000 compounds included in the study were a chemically diverse as a set and representative of the diversity of the chemical repository at Procter and Gamble Pharmaceuticals as determined by principal component analysis and comparison against the P&GP repository collection; that is, a total of 67% of variance in the original chemical descriptor space is accounted for by the rst three principal components. Samples were prepared as 10 mM solutions in DMSO and stored at ambient atmospheric conditions in 96-well microtiter plates with tted covers. The large sample number included in the study dictated that a high-throughput analytical method such as FIA-MS be used instead of quantitative method such as high pressure liquid chromatography mass spectrometry (HPLC-MS). Therefore this study de nes compound fate as sample purity or concentration were not determined. Samples were analyzed at three time points: at the t = 0 or the starting point of the study, and t = 12 months or the end point of the study, and at an intermediate time between 1 and 11 months. As expected, sample loss occurred with prolonged storage. After one month of storage at room temperature the probability of observing the compound was 95.3%, the probability of observing the compound after six months was approximately 80%, and after one year in DMSO the probability had been reduced to 52% (Figure 13.7). More generally, by these results and subsequent independent studies by other research groups, the shelf life de ned as the time after which 20% or more of the compounds show substantial degradation (e.g., >50% degradation versus t = 0; Figure 13.6) for large and diverse screening collections stored as room temperature DMSO solutions is between 6 to 12 months.15,16 Further these studies indicate that 50% of the compounds will undergo substantial degradation after four years of storage in DMSO at room temperature. Nevertheless, it should be recognized that results may vary for the various compound classes, sample concentrations, and other noncontrolled environmental conditions.15,19,20 13.2.3. Sample Container Material Plastic or Glass
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Besides environmental conditions, sample storage container materials can affect compound stability and recovery because of the potential for the
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100 Probability of Observing a Compound (%)
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