Crystalline form information from multiwell plate salt screening by use of Raman microscopy.
OBJECTIVE
The 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.


METHODS
Tamoxifen 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.


RESULTS
The 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.


CONCLUSIONS
Salt 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.
Department of Pharmaceutical Technology, Kobe Pharmaceutical University, Higashi-Nada, Kobe, 658-8558, Japan. takashi.kojima@pfizer.com
Takashi
T
Kojima
Satomi
S
Onoue
Noriaki
N
Murase
Fumie
F
Katoh
Takashi
T
Mano
Yoshihisa
Y
Matsuda
D002852:Chromatography, Ion Exchange; D002951:Citrates / Q000737:chemistry; D003460:Crystallization; D005650:Fumarates; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012492:Salts / Q000737:chemistry; D013059:Spectrum Analysis, Raman / Q000379:methods*; D013629:Tamoxifen / Q000737:chemistry; D014961:X-Ray Diffraction
D002951:Citrates; D005650:Fumarates; D004364:Pharmaceutical Preparations; D012492:Salts; D013629:Tamoxifen