Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

Strategies to Address Low Drug Solubility in Discovery and Development

COSMO-RS: a novel and efficient method for the a priori prediction of thermophysical data of liquids

https://www.umsl.edu/~chickosj/JSCPUBS/dsccal.pdf

Reference materials for calorimetry and differential thermal analysis

In the alkoxy-derived sol-gel system, various macroporous morphologies can be obtained by inducing the phase separation parallel to the sol-gel transition. This principle of macroporous morphology control can be best applied to pure silica and silica-based multicomponent oxide systems. The earlier the phase separation takes place than the sol-gel transition, the larger the characteristic sizes of pores and gel skeletons become. The time resolved light scattering measurements revealed that the morphology formation process exhibits the features of spinodal decomposition and that the final gel morphology is determined by the competitive kinetics between the domain coarsening and the structure freezing by sol-gel transition. The mesopore structure of such macroporous gel skeletons could be easily tailored by the solvent exchange procedures. Silica gels with controlled macropores and mesopores were successfully applied as a material for the continuous rod type column for high performance liquid chromatography.

Pore Structure Control of Silica Gels Based on Phase Separation

Blood compatibility of polyethylene oxide surfaces

Speeds of sound, isentropic and isothermal compressibilities, and isochoric heat capacities of {xc-C6H12+(1−x)C6H6}, x{CCl4+(1−x)C6H6}, and x{C7H16+(1−x)C6H6} at 298.15 K

Determination of the excess volumes of (cyclohexane + benzene) between 293.15 and 303.15 K by use of a vibrating densimeter

Calorimetric measurements of the heat of mixing have been made at 25.0±0.01°C for binary mixtures of n-butanol with polar liquids (acetonitrile, acetone, n-butyl ether, and n-butyl amine), and for binary mixtures of polar liquids with n-hexane. The calorimeter for measuring the heats of mixing was of twin type, and a thermomodule, HTM 0516 type (Sharp Electric Co., Ltd., Osaka) was used as the temperature-sensing device. By plotting the values of the heat of mixing, ΔHx1M, against the mole fraction of component 1, x1, and by extrapolating the curve to an infinite dilution (x1→0) for each system, the heats of mixing per mole of component 1 at an infinite dilution (\undersetx1→0limΔHx1M) were obtained graphically. By using the values of \undersetx1→0limΔHx1M obtained for these systems and by using the same treatment as that described in a previous paper [S. Murakami, K. Amaya and R. Fujishiro, This Bulltein, 37, 1776(1964)], the intermolecular hydrogen bond energies between alcohol and polar molecules were ...

The Heats of Mixing for Binary Mixtures. III. The Intermolecular Energy of Hydrogen Bonding between Alcohol and Several Other Polar Molecules

Heat capacities of {xCnH2n+1OH + (1 − x)C7H16} for n = 1 to 6 at 298.15 K

Excess enthalpy, excess isobaric heat capacity, density, and speed of sound in mixtures of heavy water (D2O) + dimethylsulfoxide (DMSO), and D2O + dimethylformamide (DMF) were measured at 25‡C. The same properties of the mixtures of normal water + DMSO, and H2O + DMF were also measured to estimate isotope effects on the thermodynamic excess functions. Both DMSO and DMF are proton acceptors and thus form hydrogen bonds with water. Large negative excess enthalpies and volumes of mixing and excess isentropic compressibilities show that the hydrogen bonding structures of DMSO and DMF with water are stronger and more compact than those in pure water. The excess heat capacity of DMSO-containing mixtures changes sign from negative to positive with increasing water content. The deviations of the excess properties of D2O systems from those of H2O systems indicate that the hydrogen bonding structure with D2O is stronger and more compact.

Sachio Murakami

Papers

Speeds of sound, isentropic and isothermal compressibilities, and isochoric heat capacities of {xc-C6H12+(1−x)C6H6}, x{CCl4+(1−x)C6H6}, and x{C7H16+(1−x)C6H6} at 298.15 K

Determination of the excess volumes of (cyclohexane + benzene) between 293.15 and 303.15 K by use of a vibrating densimeter

The Heats of Mixing for Binary Mixtures. III. The Intermolecular Energy of Hydrogen Bonding between Alcohol and Several Other Polar Molecules

Heat capacities of {xCnH2n+1OH + (1 − x)C7H16} for n = 1 to 6 at 298.15 K

Isotope effects on thermodynamic properties in four binary systems: Water (or heavy water) + dimethylsulfoxide (or N,N-Dimethylformamide) at 25‡C