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Miniaturized Assay for Solubility and Residual Solid Screening (SORESOS) in Early Drug Development

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Purpose

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 μl 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.

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Abbreviations

CAF:

caffeine

CBZ:

carbamazepine

DSC:

differential scanning calorimetry

FaSSIF:

fasted state simulated intestinal fluid

FeSSIF:

fed state simulated intestinal fluid

FT-IR:

Fourier Transform IR spectroscopy

Mixed micelles (200 mM G/L):

aqueous vehicle containing 200 mM glycocholic acid and 200 mM lecithin

PCTE:

polycarbonate, track-edged

PXM:

piroxicam

SGF:

simulated gastric fluid

SORESOS:

solubility and residual solid screening

TGA:

thermo gravimetric analysis

UPLC:

Ultra Performance Liquid Chromatography™

XRPD:

X-ray Powder Diffraction

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Acknowledgments

The authors wish to thank Annunziato Raso for UPLC measurements, Dorothea Held and Sabine Schwarz for standard XRPD analyses, and André Bubendorf for IR spectroscopy studies.

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Authors and Affiliations

  1. Department of Preclinical Research, Pharma Division, F. Hoffmann-La Roche Ltd., Bldg. 093/724, CH-4070, Basle, Switzerland

    Nicole Wyttenbach & Jochem Alsenz

  2. Molecular Structure Research, Pharma Division, F. Hoffmann-La Roche Ltd., CH-4070, Basle, Switzerland

    Olaf Grassmann

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  1. Nicole Wyttenbach
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  2. Jochem Alsenz
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Correspondence to Nicole Wyttenbach.

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Wyttenbach, N., Alsenz, J. & Grassmann, O. Miniaturized Assay for Solubility and Residual Solid Screening (SORESOS) in Early Drug Development. Pharm Res 24, 888–898 (2007). https://doi.org/10.1007/s11095-006-9205-0

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