Noriaki Murase

Crystalline form information from multiwell plate salt screening by use of raman microscopy

PurposeThe purpose of this study was to establish a useful methodology, possibly providing information on the stoichiometry of pharmaceutical drug salts obtained from salt screening by using a multiwell plate and a Raman microscope.MethodsTamoxifen salt screening was conducted with monobasic and polybasic acids on 96-well quartz plates with a Raman microscope. Appearance and crystalline forms of salts prepared on 96-well plates were observed by polarizing light microscope and Raman microscope, respectively. Based on the results of the salt screening, tamoxifen citrate and fumarate salts were prepared on a large scale. The salts prepared were characterized by powder X-ray diffractometry (PXRD) and ion chromatography.ResultsThe results of the multiwell salt screening indicated that tamoxifen has a tendency toward the formation of mono salt as opposed to hemi salt with polybasic acid, and that most of tamoxifen salts gave several potential polymorphic forms. PXRD patterns of scaled-up tamoxifen citrate and fumarate salts suggested that the same crystalline form was obtained from the binary mixture regardless of molar ratios of 2:1 or 1:1 (tamoxifen/acid). The crystalline forms obtained were tamoxifen monocitrate and monofumarate salts as measured by ion chromatography.ConclusionsSalt screening on multiwell plates with a Raman microscope provided novel insight into the characteristics prediction of the stoichiometrical salts in addition to potential polymorph information. Based on the stoichiometrical information of salts, the amount of compound and time required for crystalline form selection of drug candidates would be significantly reduced.

In vitro phototoxicity of dihydropyridine derivatives: A photochemical and photobiological study

Some photosensitizing drugs can cause phototoxic skin responses even after systemic administration; therefore, avoidance of undesired side-effects is a key consideration in drug discovery and development. As a prediction tool for phototoxic risk, we previously proposed the monitoring of reactive oxygen species (ROS) generated from compounds irradiated with UVA/B, which can be effective for understanding photochemical/photobiological properties. In this investigation, we evaluated the photosensitizing properties of a novel dihydropyridine derivative, with bradykinin B(2) receptor antagonist activity (compound A) using our ROS assay and several analytical/biochemical techniques. Exposure of compound A, and several dihydropyridine-type calcium channel antagonists to simulated sunlight resulted in the significant production of singlet oxygen, superoxide, or both, which indicates their photosensitive/phototoxic potential. This is consistent with the observation that compound A under UVA/B light exposure caused significant photodegradation and even peroxidation of fatty acid, which could lead to phototoxic dermatitis. Interestingly, the addition of radical scavengers, especially GSH, MPG and BHA, could attenuate the lipid peroxidation, suggesting the involvement of ROS generation in the phototoxic pathways of compound A. In the 3T3 neutral red uptake phototoxicity test, compound A also showed a phototoxic effect on 3T3 mouse fibroblast cells. These findings also support the usefulness of the ROS assay for the risk assessment studies on the drug-induced phototoxicity even at the early stages of pharmaceutical development.

In vitro phototoxic potential and photochemical properties of imidazopyridine derivative: A novel 5-HT4 partial agonist

Drug-induced phototoxic skin responses have been recognized as undesirable side effects, and as we previously proposed the determination of reactive oxygen species (ROS) from photo-irradiated compounds can be effective for the prediction of phototoxic potential. In this investigation, we evaluated the photosensitizing properties of imidazopyridine derivative, a novel 5-HT(4) partial agonist, using ROS assay and several analytical/biochemical techniques. Exposure of the compound to simulated sunlight resulted in the significant production of singlet oxygen, which is indicative of its phototoxic potential. In practice, an imidazopyridine derivative under UVA/B light exposure also showed significant photodegradation and even photobiochemical events; peroxidation of fatty acid and genetic damage after DNA-binding, which are considered as causative agents for phototoxic dermatitis. Interestingly, both photodegradation and lipoperoxidation were dramatically attenuated by the addition of radical scavengers, especially singlet oxygen quenchers, suggesting the possible involvement of ROS generation in the phototoxic pathways. In the 3T3 neutral red uptake phototoxicity test, imidazopyridine derivative also showed the phototoxic effect on 3T3 mouse fibroblast cells. These results suggest the phototoxic risk of newly synthesized imidazopyridine derivative and also verify the usefulness of ROS assay for phototoxicity prediction.

Scalable Preparation of Benzimidazole Compounds

Abstract The preparation of benzimidazole compound 7, an ORL‐1 agonist, is described. The four‐step procedure gave the compound 7 in 29% overall yield.