DMSO solubility prediction

Japertas P, Verheij H, and Petrauskas A. DMSO Solubility Prediction. LogP 2004, Zurich, Switzerland, 2004. 

I. V. In silica approaches to prediction of aqueous and DMSO solubility of druglike compounds trends, problems and solutions. Curr. Med. Chem. 2006, 13, 223-241. 

In silico approaches to prediction of aqueous and DMSO solubility of drug-like compounds trends, problems and solutions. Current Medicinal Chemistry, 13 (2), 223-241 Meltzer, P.S., Kallioniemi, A. and Trent, J.M. (2002) Chromosome alterations in human solid tumors, in The Genetic Basis of Human Cancer (eds B. Vogelstein and K.W. Kinzler), McGraw-Hill, New York, pp. 93-113. 

Solubility in DMSO is less intuitive than aqueous solubility, based on examination of the chemical structure. Chemists can usually differentiate between compounds that are soluble or insoluble in water, but it is much harder to predict compounds that are soluble or insoluble in DMSO (Balakin, 2003). Solubility in DMSO is determined by a subtle balance of oppositely-directed inter- and intramolecular forces. Computational models have been developed to predict DMSO solubility with greater than a 90% success rate (Balakin, 2003 Balakin et al., 2004 Japertas et al., 2004 Lu and Bakken, 2004 Delaney, 2005). Software can be used to provide an alert to a compound with a low DMSO solubility... 

Here, we briefly describe the automated Caco-2 assay used at the research site in AstraZeneca R D Molndal. The solubility of the test compounds is measured (or theoretically predicted) before they are run in the Caco-2 assay. In order to be able to make correct determinations of the permeability coefficient, the substance must be dissolved when added to cell monolayer in the transport experiment. Compounds with insufficient solubility are therefore not tested. We generally apply a test concentration of 10 pM, but in specific projects or under certain circumstances a concentration of only 1 pM is applied. The test compounds are first prepared in DM SO solution (1 mM) on a parent plate and are then diluted in transport buffer to give a final drug concentration of 10 pM (solution containing 1% DMSO) when added to the cell monolayers. 

Having seen that structural predictions are very difficult, we will now turn to the choice of transition metal. We have already seen the dependence of the coordination mode in square planar complexes on various factors and noticed the preference for polymeric chains with the silver(I) complexes owing to the linearly coordinated silver centre. Chiu et al. [325] reported on a series of arylmethylene and methyl wingtipped bis-carbene complexes of silver(I) (polymeric bridging) and palladium(II) (monomeric chelating). Carbene transfer to palladium was achieved in DMSO since solubility in CHjCfj was very poor. 

During the drug discovery process the solubility in a mixture of water with another cosolvent like DM SO is commonly measured. The compounds are usually dissolved first in DMSO and then diluted in water and/or buffer solution. Therefore, a classification model has been successfully derived to predict the solubility in this solvent mixture using the VolSurf type of descriptors (Fig. 10.9(b)) for a set of 150 compounds with two latent variables (Table 10.2). 

Table 10.2 Percentage of the compounds predicted by the discriminative models for solubility in a mixture of 2% DMSO in water. (High soluble compound, high-medium intermediate to high solubility compounds, medium-low intermediate to low solubility compounds, low considered as insoluble compounds.)...

Figure 10.9. Prediction vs. Experimental, (a) Intrinsic solubility (b) solubility in a 2% DMSO solution. PLS coefficients (c) intrinsic solubility and (d) solubility.

Although DMS is only moderately soluble in rainwater, there has been some interest in the oxidation in the liquid phase, where modeling suggests that the multiphase reactions can be important. Ozone seems to be the most important oxidant, where there is a predicted lifetime for DMS of a few days in clouds. The oxidation reactions offer the potential for these heterogeneous processes to yield more soluble oxidized sulfur compounds such as DMSO and DMSO2 (Betterton, 1992 Campolongo e/u/., 1999). 

Biomimetic artificiai membranes-factors Effects of pH and co-solvents on the BAMPA were investigated to determine the optimal conditions for the prediction of oral absorption. The permeability (Pam) of 33 structurally diverse drugs to the PC/PE/ PS/PI/CHO/1,7-octadiene membrane system [bio-mimetic lipid (BML) membrane] was measured at pH 5.5,6.5, and 7.4. The pH dependence of Pam was in accordance with the pH partition theory. The better prediction of oral absorption (fraction of a dose absorbed) was shown under the pH 5.5 condition for determining the permeability of poorly soluble compounds were examined. Dimethysulfoxide (DMSO), ethanol (EtOH) and polyoxyethyleneglycol 400 (PEG 400) were added up to 30% to the transport medium as solubilizers. DMSO, EtOH and PEG 400 decreased Pam of hydrocortisone and propranolol. For example, DMSO (30%) decreased Pam of hydrocortisone and propanol by 60 and 70%2, respectively. DMSO and PEG 400 also decreased Pam of ketoprofen. In contrast, EtOH produced an opposite effect on permeability, that is, an increased Pam of ketoprofen. Therefore, the high concentration of these co-solvents could lead to the under- or overestimation of drug permeability. 

Now let s examine the miscibility situation of supercritical CO2 with the same liquids at 400 bar and 40°C the solubility parameter of CO2 is about 7.3. Carbon dioxide at 400 bar is miscible with hexane, so again we might be pleased with the fact that 82- 81 = 1 predicts miscibility behavior. But CO2 is also miscible with methanol, DMF, NMP, and DMSO, and the solubility parameters for the respective four liquids are clearly different by more than 1 H. How do we explain that CO2 is miscible with the liquids Although CO2 is strictly a nondipolar molecule, i.e., its dipole moment is zero, it has strong bond dipoles or, equivalently, a large quadrupole, which can interact with other polar molecules. 

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