Research ArticlesDevelopment of a partially automated solubility screening (PASS) assay for early drug development
Section snippets
INTRODUCTION
Drug solubility is a crucial factor for absorption in the gastrointestinal tract, and compounds with too low aqueous solubility often have inappropriate pharmacokinetic properties and carry a higher risk to fail during early or late development. Therefore, phase appropriate solubility measurements are performed along the drug discovery and development process, the assays and their focus varying with the phase.
In drug discovery, in silico prediction and high‐throughput screening (HTS) of aqueous
Materials
Sodium dihydrogen phosphate, ethanol, sodium dodecyl sulfate (SDS), polyethylene glycol 400 (PEG 400), propylene glycol, Cremophor EL®, Tween 80®, olive oil, Danazol, ketoconazol, and sodium taurocholate were obtained from Sigma‐Aldrich Chemie GmbH (Deissenhofen, Germany). Digoxin was purchased from Fluka (Buchs, Switzerland). Mefenamic acid was kindly provided by Amphray Laboratories (Mumbai, India). L‐alpha‐egg lecithin as Lipoid EPC 98% pure was obtained from Lipoid (Ludwigshafen, Germany).
Compound Distribution into 96‐Well Microtiter Plates
A low‐tech, manual method was established for rapid and flexible distribution of compounds into 96‐well plates (Fig. 1). In a typical experiment, crystalline compound was dispersed in heptane at a concentration of 25 mg/mL and, while constantly stirring, 20–160 µL volumes were transferred into 96‐well plates using Gilson positive air‐displacement pipettes. Alternatively, amorphous compound was dissolved in organic solvent or suspended in heptane. Solvent or heptane was removed by evaporation in
DISCUSSION
The described PASS assay is adapted to the needs of a modern drug discovery–development interface setting with respect to compound consumption, volume, speed, and throughput. Compound is distributed into individual wells as suspension in heptane and heptane is rapidly removed by evaporation. This approach is cheap, fast, flexible, and avoids the time‐ and labor‐intensive process of weighing of hundreds of samples at submilligram quantities into 96‐well plates, if an automated weighing station
Acknowledgements
We gratefully acknowledge R. Raso for performing the solubility studies.
REFERENCES (54)
- et al.
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
Adv Drug Deliv Rev
(2001) - et al.
Impact of solid state properties on developability assessment of drug candidates
Adv Drug Deliv Rev
(2004) - et al.
Pharmaceutical profiling in drug discovery
DDT
(2003) - et al.
Thermodynamics of paracetamol solubility in sugar‐water cosolvent systems
Int J Pharm
(1990) - et al.
Comparison of a miniaturized shake‐flask solubility method with automated potentiometric acid/base titrations and calculated properties
J Pharm Sci
(2005) - et al.
Prediction of drug solubility from structure
Adv Drug Deliv Rev
(2002) - et al.
Trends in solubility of polymorphs
J Pharm Sci
(2005) - et al.
Accuracy of calculated pH‐dependent aqueous drug solubility
Eur J Pharm Sci
(2004) - et al.
Analysis of the solubilization od steroids by bile salt micelles
J Pharm Sci
(1997) - et al.
The effect of solubilization on the oral bioavailability of three benzimidazole carbamate drugs
Int J Pharm
(2004)
Rapid, small‐scale determination of organic solvent solubility using a thermogravimetric analyzer
Int J Pharm Biomed Anal
Development of an automated in‐line microfiltration system coupled to an HPLC for the determination of solubility
J Pharm Biomed Anal
Crystallization of hydrocortisone acetate: Influence of polymers
Int J Pharm
Prediction of solubility of sulfonamides in water and organic solvents based on the extended regular solution theory
Int J Pharm
Solubility behavior of polymorphs I and II of mefenamic acid in solvent mixtures
Int J Pharm
In vivo in vitro correlations for a poorly soluble drug, danazol, using the flow‐through dissolution method with biorelevant dissolution media
Eur J Pharm Sci
Optimized conditions for MDCK permeability and turbidimetric solubility studies using compounds representative of BCS classes I–IV
Eur J Pharm Sci
Peak seeker: An algorithm for rapid determination of solubility
JALA
Effect of cholic and deoxycholic acid conjugates on solubility and dissolution of indomethacin and phenylbutazone
Int J Pharm
Evaluation of cyclodextrin solubilization of drugs
Int J Pharm
A high‐throughput screening method for the determination of aqueous drug solubility using laser nephelometry in microtiter plates
Anal Chem
Revisiting the solubility concept of pharmaceutical compounds
Monatshefte für Chemie
pH‐metric solubility: Correlation between the acid‐base titration and the saturation shake‐flask solubility‐pH methods
Pharm Res
Solubility measurement using differential scanning calorimetry
Ind Eng Chem Res
Impact of the amount of excess solids on apparent solubility
Pharm Res
New media discriminate dissolution of poorly soluble drugs
Pharm Res
Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs
Pharm Res
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Eva Meister's present address is Department of Pharmaceutics, University of Erlangen‐Nuremberg, 91058 Erlangen, Germany.