Stability Screening

Advances in techniques for chemical synthesis allow medicinal chemists to synthesize hundreds to thousands of compounds per month. Metabolic stability screening in liver microsomes is used extensively in early discovery to select the analogs or compounds most likely to have favorable pharmacokinetic parameters. This provides information on the relation of structure to stability, thus guiding synthesis strategies. 

Xu, R. et al. 2002. Application of parallel liquid chromatography/mass spectrometry for high throughput microsomal stability screening of compound libraries. J. Am. Soc. Mass Spectrom. 13 155. 

The first aim of a thermal stability screening test (e.g., DSC/DTA) is to obtain data on the potential for exothermic decomposition and on the enthalpy of decomposition (AHd). These data, together with the initial theoretical hazard evaluation, are used in reviewing the energetic properties of the substance (Box 4) and the detonation and deflagration hazards of the substance (Boxes 7 and 8). The screening tests also provide data on the thermal stability of the substance or mixture, on the runaway potential, on the oxidation properties, and to a lesser extent, on the kinetics of the reaction (Box 10). 

Gustin, J. L., "Thermal Stability Screening and Reaction Calorimetry—Application to Runaway Hazard Assessment and Process Safety Management," /. Loss Prev. Proc. Ind., 6,275 (1993). 

In-vitro Microsomal Stability Screen Caco-2 Absorption Screen P450 Enzyme Inhibition Screen Rapid Rat" (CARRS) PO/PK Screen... 

Di, L. Kerns, E. H. Hong, Y. Kleintop, T. A. McConnell, O. J. et al. Optimization of a higher throughput microsomal stability screening assay for profiling drug discovery candidates. J Biomol Screen 2003, 8, 453-462. 

The compatibility of sorbitol in various solid [49,50] and solution [45-47] formulations has been investigated. In a study conducted using DSC as a stability screening tool, sorbitol was found to be incompatible with salbutanol sulfate [49] and cephalexin [50]. Sorbitol has been found to be... 

Thermal stability Screen size (mm) of screws (single/dual)... 

Figure 6.8 Schematic representation of the chloroacetaldehyde (ClAA) stability screening assay. With each screening round the ClAA concentration was increased by 0.1 M.

As depicted in Figure 6.8 the stability screening was based on DERA activity assay, the retro-aldol reaction of 2-deoxy-D-ribose 5-phosphate to acetaldehyde and D-glyceraldehyde 3-phosphate. D-glyceraldehyde 3-phosphate is further converted by the auxiliary enzymes triose phosphate isomerase and glycerol phosphate dehydrogenase. As the latter reaction consumes NADH it can be measured spectro-pho to metrically by the decrease in absorbance at 340 nm. 

Gustin, J.L. (1993) Thermal stability screening and reaction calorimetry. Application to runaway reaction hazard... 

Ackermann, B. L. Ruterbories, K. J. Hanssen, B. R. Lindstrom,T. D. 1998. Increasing the throughput of microsomal stability screening using fast gradient elution LC/MS. Proc. 46th ASMS Conf. Mass Spectrom. and Allied Topics (Orlando, Florida), 16. 

Stability screening using nuclear magnetic resonance shows that solutions of eugenol in dimethyl sulfoxide are stable for at least 24 hours [4]. 

Di D, Kerns EH, Hong Y, Kleintop TA, McConnell OJ, Huryn DM (2003) Optimization of a Higher Throughput Microsomal Stability Screening Assay for Profiling Drug Discovery Candidates. J Biomolecular Screening 8 453 162... 

Until very recently, metabolic stability screening and metabolite identification (metabolite ID) have been sequential processes that is, the metabolic stability assays are typically performed hrst to identify rapidly metabolized compounds and a follow-up metabolite ID study is performed next, typically at a 10-fold higher substrate concentration to ensure generation of sufficiently high-quality MS/MS information to support structure elucidation. 

Halladay JS, Wong S, Jaffer SM, Sinhababu AK, Khojasteh-Bakht SC. Metabolic stability screen for drug discovery using cassette analysis and column switching. Drug Metabol. Lett. 2007 1 67-72. 

Das, B. Sethi, R.K. Chopra, S.L. Sorption and desorption of water vapour on starch. Isr. J. Chem. 1972,10, 963-965. El-Shattawy, H.H. Kildsig, S.O. Peck, G.E. Cephalexin-direct compression excipients performulation stability screening using differential scanning calorimetry. Drug. Dev. Ind. Pharm. 1982, 8 (6), 897-909. 

Fig. 15 Stability screening. Example of DSC purity results obtained for a drug substance sensitive to moisture. From the top to the bottom Initial sample (purity 99.9%), sample stored under humid conditions at 50°C (purity 99.7%), sample stored under humid conditions at 80°C (purity 99.1%).

El-Shattawy HE, Peck GE, Kildsig DO. Aspartame-direct compression excipients preformulation stability screening using differential scanning calorimetry. Drug Dev Ind Pharm 1981 7 605-619. 

---