Correlating the solubility of indomethacin in 1,4-dioxane + water mixtures by means of the Jouyban-Acree model

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Abstract

In this work the validity of the Jouyban-Acree and Yalkowsky-Roseman models is evaluated to correlate the solubility of indomethacin in 1,4-dioxane + water cosol- vent mixtures. The solubility correlation is studied as a function of temperature and cosolvent composition. Both models require only the experimental solubility values in the pure solvents at all the temperatures evaluated. The solubility calculated values by using both models deviate notoriously from experimental values in several cases

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Rational design of a combination medication for the treatment of obesity.

Kishore Gadde, Patrick Mahlen O'Neil, Maria Guttadauria … (2008)

Existing obesity therapies are limited by safety concerns and modest efficacy reflecting a weight loss plateau. Here, we explore combination therapy with bupropion (BUP), a putative stimulator of melanocortin pathways, and an opioid antagonist, naltrexone (NAL), to antagonize an inhibitory feedback loop that limits sustained weight reduction. In vitro electrophysiologic experiments were conducted to determine the extent to which BUP+NAL stimulated hypothalamic pro-opiomelanocortin (POMC) neurons in mouse brain. A subsequent study further characterized the effect of combination BUP+NAL treatment on food intake in lean and obese mice. Finally, a randomized, blinded, placebo-controlled trial in obese adult subjects was conducted. Randomization included: BUP (300 mg) + NAL (50 mg), BUP (300 mg) + placebo (P), NAL (50 mg) + P or P+P for up to 24 weeks. BUP+NAL stimulated murine POMC neurons in vitro and caused a greater reduction in acute food intake than either monotherapy, an effect consistent with synergism. Combined BUP+NAL provided sustained weight loss without evidence of an efficacy plateau through 24 weeks of treatment. BUP+NAL completers diverged from NAL+P (P < 0.01) and P+P (P < 0.001) at week 16 and from BUP+P by week 24 (P < 0.05). The combination was also well tolerated. Translational studies indicated that BUP+NAL therapy produced synergistic weight loss which exceeded either BUP or NAL alone. These results supported the hypothesis that NAL, through blockade of beta-endorphin mediated POMC autoinhibition, prevents the classic weight loss plateau observed with monotherapies such as BUP. This novel treatment approach (BUP+NAL) holds promise for the treatment of obesity.\

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Review of the cosolvency models for predicting solubility of drugs in water-cosolvent mixtures.

Abolghasem Jouyban (2008)

The cosolvency models presented from 1960 to 2007 were reviewed and their accuracies for correlating and/or predicting the solubility of drugs in water-cosolvent mixtures were discussed. The cosolvency models could be divided into theoretical, semi-empirical and empirical models, the first group of models provide basic information from the solution, while the last group of models are good suitable for solubility correlation studies. The simplest cosolvency model, i.e. the log-linear model of Yalkowsky, provides an estimate of drug solubility in water-cosolvent mixtures using aqueous solubility of the drug, whereas the Jouyban-Acree model predicts the solubility with an acceptable error with the cost of one more data point (the solubility in neat cosolvent) which is required as input value in the prediction process. A number of error terms used in the literature was also discussed with a brief comments on the acceptable prediction error for pharmaceutical applications.