Aqueous solubility and

Taxol s journey to the clinic was slow and arduous. Initial difficulties with aqueous solubility and lack of knowledge regarding its mechanism, of action delayed its development until 1979 when, in another seminal paper in the field, S.B.Horwitz and her collaborators disclosed their findings on the interaction of taxol with microtubules.4 Taxol s unique biological action, which includes promotion of microtubule formation and microtubule stabilization, stimulated a renewed interest in taxol as a potential drug candidate. The problem of procuring adequate supplies of taxol became even... 

You are given samples of 1-propanol, pentane, and ethanoic acid. Describe how you would use chemical tests, such as aqueous solubility and acid—base indicators, to distinguish among the three compounds. 

Despite the work of Overton and Meyer, it was to be many years before structure-activity relationships were explored further. In 1939 Ferguson [10] postulated that the toxic dose of a chemical is a constant fraction of its aqueous solubility hence toxicity should increase as aqueous solubility decreases. Because aqueous solubility and oil-water partition coefficient are inversely related, it follows that toxicity should increase with partition coefficient. Although this has been found to be true up to a point, it does not continue ad infinitum. Toxicity (and indeed, any biological response) generally increases initially with partition coefficient, but then tends to fall again. This can be explained simply as a reluctance of very hydrophobic chemicals to leave a lipid phase and enter the next aqueous biophase [11]. An example of this is shown by a QSAR that models toxicity of barbiturates to the mouse [12] ... 

Tewari YB, Miller MM, Wasik SP, et al. 1982. Aqueous solubility and octanol/water partition coefficient of organic compounds at 25.0°C. J Chem Eng Data 27 451-454. 

In this study, complexation of A9-THC and cannabidiol (prepared by freeze drying) with randomly methylated b-cyclodextrin and hydroxypropyl-b-cyclodextrin (HP-fi-CD) was studied by the phase-solubiHty method. The aqueous solubility of CBD and THC increased as a function of CD concentration, and the dissolution increased for THC and CBD cyclodextrin complexes significantly in contrast to plain THC and CBD. These results demonstrate that cyclodextrins increased both the aqueous solubility and dissolution rate... 

Livingstone, D. J., Ford, M. G., Huuskonen, J. J., Salt, D. W. Simultaneous prediction of aqueous solubility and octanol/water partition coefficient based on descriptors derived from molecular structure. J. Comput.-Aided Mol. Des. 2001, 15, 741-752. 

In the current era many medicinal chemists are unaware of the very important role of compound soUd state properties on aqueous solubility and therefore to oral absorption. In many organizations compound purification by crystallization has disappeared being replaced by automated reverse-phase HPLC purification. If medicinal chemists isolate a compound as a white powder from evaporation of... 

Johnson, S. R Zheng, W. Recent progress in the computational predicaion of aqueous solubility and absorption. AAPS J. 2006, 8, 27 - 40. 

The determination of log Poa is far from being trivial whether potentiometric, shake-flask, chromatographic or other techniques are used and, often, this value is derived from the back-calculation discussed above, using logDj and pKj, which of course has to be known. This is often done in shake-flask determinations so that there is appreciable aqueous solubility (and thus partition) in the aqueous phase for highly Hpophilic drugs and it may also be accompanied by a variahon of the phase ratio, in favor of the phase where the compound is expected to be less soluble, to avoid saturation phenomena. 

Class IV drugs have low aqueous solubility and poor membrane permeability and as such are often considered as poor drug candidates for oral administration. Other routes of administration may need to be considered. For example, neomycin falls into this category, and its oral use is to achieve sterilization of the gut. There is too little information about these compounds and the effect of food to offer general observations. 

During the past 30 years, there have been significant developments of parenteral disperse formulations. The use of parenteral emulsions can overcome the problems of low aqueous solubility and water hydrolysis of many drugs [184, 185]. Such formulations can avoid the use of conventional co-solvent systems and the undesirable effects caused by precipitation of drugs at the injection site. Recent developments of parenteral disperse formulations have the potential to provide sustained release and targeting of drugs [186-189],... 

These esters of p-hydroxybenzoic acid have been used primarily to prevent growth of molds but in higher concentrations possess some weak antibacterial activity. Their effective use is limited by low aqueous solubility and by reports of stinging and burning sensations related to their use in the eye. They bind to a number of nonionic surfactants and polymers, thereby reducing their bioactivity. They are used in combination, with the methyl ester at 0.03-0.1% and the propyl ester at 0.01-0.02%. Parabens have also been shown to promote corneal absorption [140]. 

Certain surface-active compounds [499], when dissolved in water under conditions of saturation, form self-associated aggregates [39,486-488] or micelles [39,485], which can interfere with the determination of the true aqueous solubility and the pKa of the compound. When the compounds are very sparingly soluble in water, additives can be used to enhance the rate of dissolution [494,495], One can consider DMSO used in this sense. However, the presence of these solvents can in some cases interfere with the determination of the true aqueous solubility. If measurements are done in the presence of simple surfactants [500], bile salts [501], complexing agents such as cyclodextrins [489 191,493], or ion-pair-forming counterions [492], extensive considerations need to be applied in attempting to extract the true aqueous solubility from the data. Such corrective measures are described below. 

Changes in the method of compound distribution for biological assays and therefore changes in apparent aqueous solubility and compound concentration. 

Katritzky, A. R., Wang, Y., Sild, S., Tamm, T., QSPR studies on vapor pressure, aqueous solubility, and the prediction of water-air partition coefficients, J. Chem. Inf. Comput. Sci. 1998, 38, 720-725. 

QMPRPlus was used to generate in silico estimates of log P, aqueous solubility, and human jejunal permeability from 3D molecular structures. The predictive... 

Abramowitz, R., Yalkowsky, S. H. (1990) Estimation of aqueous solubility and melting point of PCB congeners. Chemosphere 21, 1221-1229. 

Amidon, G. L., Anik, S. T. (1981) Application of the surface area approach to the correlation and estimation of aqueous solubility and vapor pressure. Alkyl aromatic hydrocarbons. J. Chem. Eng. Data 26, 28-33. 

Bruggeman, W. A., van der Steen, J., Hutzinger, O. (1982) Reversed-phase thin-layer chromatography of polynuclear aromatic hydrocarbons and chlorinated biphenyls. Relationship with hydrophobicity as measured by aqueous solubility and octanol-water partition coefficient. J. Chromatogr. 238, 335-346. 

Dunnivant, F. M., Elzerman, A. W., Jurs, P. C., Hansen, M. N. (1992) Quantitative structure-property relationships for aqueous solubilities and Henry s law constants of polychlorinated biphenyls. Environ. Sci. Technol. 26, 1567-1573. 

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