Miniaturized assay for solubility and residual solid screening (SORESOS) in early drug development.
OBJECTIVE
The aim was to develop a miniaturized method for solubility and residual solid screening of drug compounds in aqueous and non-aqueous vehicles in early drug development.


METHODS
Different crystal modifications of caffeine, carbamazepine, and piroxicam were added into 96-well filter plates and solubility was determined in 100 microl of 17 pharmaceutical vehicles. After filtration, drug concentration was determined by Ultra Performance Liquid Chromatography (UPLC). Residual solid drug in the filter plates was analyzed by high-throughput (HT) transmission X-ray Powder Diffraction (XRPD).


RESULTS
HT XRPD analysis revealed solid form conversions of all compounds during solubility determination, e.g., formation of hydrates in aqueous vehicles (caffeine, carbamazepine, piroxicam) or conversion of a metastable crystal form to the stable form (caffeine). Drug solubility was strongly dependent on the crystal modifications formed during the solubility assay.


CONCLUSIONS
The new assay allows the simultaneous, small scale screening of drug solubility in various pharmaceutical vehicles and identification of changes in solid form. It is useful for the identification of formulations and formulation options in non-clinical and clinical development.
Wyttenbach
Nicole
N
Department of Preclinical Research, Pharma Division, F. Hoffmann-La Roche Ltd., Bldg. 093/724, CH-4070, Basle, Switzerland. nicole.wyttenbach@roche.com
Alsenz
Jochem
J
Grassmann
Olaf
O
D002110:Caffeine / Q000032:analysis / Q000737:chemistry; D002220:Carbamazepine / Q000032:analysis / Q000737:chemistry; D002853:Chromatography, Liquid / Q000379:methods; D003460:Crystallization; D015195:Drug Design; D006863:Hydrogen-Ion Concentration; D008832:Microchemistry / Q000379:methods*; D004364:Pharmaceutical Preparations / Q000032:analysis* / Q000737:chemistry; D010894:Piroxicam / Q000032:analysis / Q000737:chemistry; D033362:Powder Diffraction / Q000379:methods; D015203:Reproducibility of Results; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods* / Q000639:trends; D013696:Temperature; D014961:X-Ray Diffraction / Q000379:methods
D004364:Pharmaceutical Preparations; D012997:Solvents; D010894:Piroxicam; D002220:Carbamazepine; D002110:Caffeine