Water solubility, of drugs

SCHEME 11.30 Nitrogen- and oxygen-linked glucLironide formation markedly enhances the polarity and water solubility of drugs. 

Poor water solubility of drugs and new chemical entities presents major challenges in the development of clinically useful formulations. Of the various approaches used for enhancing the solubility of poorly soluble drugs, polymeric delivery systems have been used effectively. Paclitaxel has been used as a model hydrophobic drug to show the effectiveness of solubility-enhancing properties of various polymeric delivery systems. Recently, hydrotropic polymers were developed based... 

Conjugation to poly(ethylene glycol) (PEG), or PEGylation, is a well-established approach in protein stabilization (which is described in Section 8.2.3). PEGylation can also be used to increase the water solubility of drugs. For example, conjugation to PEG increases the aqueous solubility of paclitaxel and its derivatives [4] (Table 8.2 and Figme 8.2). The increase in solubility is... 

One of the major problems encountered with dispersed systems appears during their preparation, and often results from poor water solubility of drugs leading to either a low yield in drug loading or a slow or incomplete release of the drug. In order to overcome these drawbacks, several authors have proposed the use of cyclodextrins (CyDs) in the formulation of these systems. Alternatively, CyDs themselves can be employed as raw materials for particle preparation, instead of polymers and lipids. 

Fig. 3 Use of phosphates to enhance water solubility of drugs Table 1 Prodrug variations based upon ester linkages...

Cq water solubility of drug. c. solubility in O.IM solution of the respective CD (molarity of CDPS relates to the actual CD content of the polymer). in ySCD solutions the maximally obtained solubility. 

Drug metabolism Metabolism increases the water solubility of drugs by enzymatically introducing polar functional groups so that they can be excreted what is the chemistry of the drag How fast is it inactivated Is it converted into more active or even toxic components ... 

It is poorly soluble in acetone, 2-butanone, ethyl acetate, acetonitrile, and DMF, and insoluble in alcohols, petroleum ether, and diethyl ether. The partition coefficients of a number of solutes between PCL and water have been measured and correlated with octanol-water partition coefficients (Fig. 9) (58,59). The linear correlation (Eq. 2) when combined with the water solubility of the solutes serves as a method of estimating the solubility of drugs in PCL from first principles. ... 

Anderson, B. D., Conradi, R. A., Predictive relationships in the water solubility of salts of a nonsteroidal anti-inflammatory drug, J. Pharm. Sci. 74, 815-820 (1985). 

McFarland, J. W. Du, C. M. Avdeef, A., Factors influencing the water solubility of crystalline drugs, in van de Waterbeemd, H. Lennemas, H. Artursson, P. (eds.), Drug Bioavailability. Estimation of Solubility, Permeability, Absorption and Bioavailability, Wiley-VCH, Weinheim, 2003 (in press). 

Faller and Wohnsland [18, 19] developed the PAMPA assay using phospholipid-free hexadecane, supported on 10 pm-thick polycarbonate filters, and were able to demonstrate interesting predictions. Their PAMPA method appeared to be a satisfactory substitute for obtaining alkane/water partition coefficients, which are usually very difficult to measure directly, due to the poor solubility of drug molecules in alkanes. Apparently, membrane retention was not measured. 

Factors Influencing the Water Solubilities of Crystalline Drugs... 

The measurement of the solubility of drugs in polar and non-polar media is very important in the pharmaceutical field. One method proposed to describe this solubility is the partition coefficient between octanol and water. The mathematical calculation of an octanol-water partition coefficient from values for functional groups was first proposed by Hansch et al. as Hansch s n constants,1 and was later developed by Rekker as hydrophobic fragmental constants (logP).2 This method was further improved by the use of molecular connectivities.17 The prediction of logP values can be performed by either a computer program or by manual calculation. For example, approximate partition coefficients (log P) have been calculated by Rekker s method ... 

Wohnsland and Faller ([175] performed measurements using a thin (9-10 //in) supported, phospholipid-free hexadecane layer. To validate their model, they used 32 well-characterized chemically diverse compounds. The permeability values obtained with their model could be correlated with known human absorption values if the maximum permeability obtained at different pH was taken into account. However, several disadvantages are related to this method. For hydrophilic drugs, hexadecane by itself has an increased barrier function in comparison with membranes. In addition, the hexadecane layers are not very stable, which makes this assay difficult to apply as a routine screening method. The advantage of this PAMPA setup is that it appears to be a satisfactory substitute for obtaining alkane-water partition coefficients, which are usually very difficult to measure directly, due to the poor solubility of drug molecules in alkanes. 

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