A quantitative approach to probe the dependence and correlation of food-effect with aqueous solubility, dose/solubility ratio, and partition coefficient (Log P) for orally active drugs administered as immediate-release formulations

Authors

  • Brahma N. Singh

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    1. Department of Pharmacy and Administrative Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York
    • Department of Pharmaceutics R & D, Emisphere Technologies, Inc., 765 Old Saw Mill River Road, Tarrytown, NY 10591
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Abstract

The purpose of the present review was to systematically evaluate if aqueous solubility, dose/solubility ratio, and partition coefficient (Log P) could be used as useful parameters to quantitatively probe the dependence and correlation of in vivo food effects with these physicochemical properties of orally active drugs administered as immediate-release (IR) formulations. Mean AUC data obtained under fasted and fed states of over 100 structurally diverse orally active drugs with different physicochemical properties were obtained from the primary literature. Correlations of AUC ratio (Fed/Fasted) with aqueous solubility, dose/solubility ratio, and Log P were derived and statistically evaluated by Pearson's correlation test (two-tailed). A negative correlation was obtained between the logarithm of the aqueous solubility and the AUC ratio (r=−0.5982, N=93), whereas a positive correlation existed between AUC ratio and Log P (r=0.5147, N=110) and between AUC ratio and dose/solubility ratio (r=0.5511, N=87). All these correlations were significant (P<0.0001). Based on this study, the estimated range within which a drug is not expected to be significantly affected by food falls between 0.148–89.39 mg/ml for aqueous solubility and between 0.23–624 ml for the dose:solubility ratio. The corresponding range of Log P for expecting a lack of food-effect lies between −1.13 and 2.98. Quantitatively, the effect of food was most pronounced for lipophilic, poorly water-soluble drugs (with only a few exceptions), irrespective of whether the drug is acidic, basic, or neutral. It is concluded that aqueous solubility, dose/solubility ratio, and partition coefficient can be used as useful parameters to probe the dependence and correlation of food-effect with these physicochemical parameters for immediate-release formulations. Drug Dev. Res. 65:55–75, 2005. © 2005 Wiley-Liss, Inc.

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