The prediction of mineral solubilities in natural waters: The Na-K-Mg-Ca-H-Cl-SO4-OH-HCO3-CO3-CO2-H2O system to high ionic strengths at 25°C

Thermodynamics of the carbon dioxide system in the oceans

Calculation of the thermodynamic and transport properties of aqueous species at high pressures and temperatures: Correlation algorithms for ionic species and equation of state predictions to 5 kb and 1000°C

The dissociation constants of carbonic acid in seawater at salinities 5 to 45 and temperatures 0 to 45°C

About 30% of drug candidate molecules are rejected due to pharmacokinetic-related failures. When poor pharmaceutical properties are discovered in development, the costs of bringing a potent but poorly absorbable molecule to a product stage by "formulation" can become very high. Fast and reliable in vitro prediction strategies are needed to filter out problematic molecules at the earliest stages of discovery. This review will consider recent developments in physicochemical profiling used to identify candidate molecules with physical properties related to good oral absorption. Poor solubility and poor permeability account for many PK failures. FDA's Biopharmaceutics Classification System (BCS) is an attempt to rationalize the critical components related to oral absorption. The core idea in the BCS is an in vitro transport model, centrally embracing permeability and solubility, with qualifications related to pH and dissolution. The objective of the BCS is to predict in vivo performance of drug products from in vitro measurements of permeability and solubility. In principle, the framework of the BCS could serve the interests of the earliest stages of discovery research. The BCS can be rationalized by considering Fick's first law, applied to membranes. When molecules are introduced on one side of a lipid membrane barrier (e.g., epithelial cell wall) and no such molecules are on the other side, passive diffusion will drive the molecules across the membrane. When certain simplifying assumptions are made, the flux equation in Fick's law reduces simply to a product of permeability and solubility. Many other measurable properties are closely related to permeability and solubility. Permeability (Pe) is a kinetic parameter related to lipophilicity (as indicated by the partition and distribution coefficients, log P and log D). Retention (R) of lipophilic molecules by the membrane (which is related to lipophilicity and may predict PK volumes of distribution) influences the characterization of permeability. Furthermore, strong drug interactions with serum proteins can influence permeability. The unstirred water layer on both sides of the membrane barrier can impose limits on permeability. Solubility (S) is a thermodynamic parameter, and is closely related to dissolution, a kinetic parameter. The unstirred water layer on the surfaces of suspended solids imposes limits on dissolution. Bile acids effect both solubility and dissolution, by a micellization effect. For ionizable molecules, pH plays a crucial role. The charge state that a molecule exhibits at a particular pH is characterized by the ionization constant (pKa) of the molecule. Buffers effect pH gradients in the unstirred water layers, which can dramatically affect both permeability and dissolution of ionizable molecules. In this review, we will focus on the emerging instrumental methods for the measurement of the physicochemical parameters Pe, S, pKa, R, log P, and log D (and their pH-profiles). These physicochemical profiles can be valuable tools for the medicinal chemists, aiding in the prediction of in vivo oral absorption.

Physicochemical Profiling (Solubility, Permeability and Charge State)

https://escholarship.org/content/qt0q17p49d/qt0q17p49d.pdf?t=p0t1ys

Thermodynamics of aqueous carbonate solutions including mixtures of sodium carbonate, bicarbonate and chloride

Electromotive-force measurements have been made on HCl−MgCl2−H2O mixtures at 5, 15, 25, 35 and 45°C at eleven different ionic strengths from 0.1–5.0 mol-kg
 −1
 . The results are interpreted in terms of the simple Harned's equations, as well as the more complicated Pitzer ion-component treatment of multicomponent electrolyte mixtures. Activity coefficients for HCl in the salt mixtures obey Harned's rule up to and including I=5.0. For the salt in the acid mixtures, Harned's rule holds true up to and including I=0.5. The contribution of higher-order electrostatic terms (Eθ and E'θ) in the Pitzer equations is important for accurate evaluations of unlike cation-cation interactions (θH,Mg), and cation-anion-cation interactions (ΨH,Mg,Cl). The values ofSθH,Mg and ΨH,Mg,Cl (determined with Eθ and E'θ), θH,Mg and ΨH,Mg,Cl (determined without Eθ and E'θ), as well as the trace activity coefficients of HCl, γ
 tr
 A
 , in solutions of MgCl2 (where ionic strength fraction of the salt,y
B = 1) at all the experimental temperatures and ionic strengths, are reported. Results of this study are compared with those for similar systems. At I=0.1 and 25°C, the results of the Bronsted-Guggenheim specific interaction theory are discussed briefly.

Activity coefficients for ternary systems: VI. The system HCl + MgCl2 + H2O at different temperatures; application of Pitzer's equations

Activity coefficients of hydrochloric acid in mixed solutions with calcium chloride have been measured at total ionic strengths of 0.1, 0.25, 0.5, 1.0, 1.5 and 2.0 mol kg–1 at nine different temperatures from 278.15 to 318.15 K at intervals of 5 K, and at total ionic strengths of 2.5, 3.0, 3.5, 4.0, 4.5 and 5.0 mol kg–1 from 278.15 to 318.15 K at intervals of 10 K, using e.m.f. cells of the type Pt, H2(g, 1 atm)|HCl(mA), CaCl2(mB)|AgCl|Ag. The results have been interpreted in terms of Pitzer's equations, from which the calculations of the activity coefficients of calcium chloride in the mixtures have been made. The values of SθMN and ψMNX(including higher-order electrostatic effects) and θMN and ψMNX(excluding higher-order effects) were determined based on Pitzer's treatment. The trace activity coefficients of HCl, γtrA(when yB, the ionic strength fraction of CaCl2 in the mixture, equals 1), are also reported. Within the experimental error, Harned's rule is obeyed for hydrochloric acid at all experimental temperatures and over the entire range of ionic strengths studied. In the case of calcium chloride, Harned's rule is a good description only for I= 0.1, 0.25 and 0.5 mol kg–1, over the range of temperatures examined.

Activity coefficients for the system HCl + CaCl2+ H2O at various temperatures. Applications of pitzer's equations

The potential for the cell Pt,H/sub 2/,CO/sub 2/exclamationM(HCO/sub 3/)/sub 2/,MCI/sub 2/,CO/sub 2/(aq)exclamationAgCl,Ag with M = Mg and Ca was measured over a wide range of molalities at 298.15 K. The data were interpreted by the mixed-electrolyte equations of Pitzer and Kim to yield the ion-interaction parameters for Mg/sup 2 +/, HCO/sub 3//sup -/, and for Ca/sup 2 +/, HCO/sub 3//sup -/. The trace activity coefficients of M(HCO/sub 3/)/sub 2/ in MCI/sub 2/ and in NaCl are calculated.

James J. Gibbons

Papers

Thermodynamics of aqueous carbonate solutions including mixtures of sodium carbonate, bicarbonate and chloride

Activity coefficients for ternary systems: VI. The system HCl + MgCl2 + H2O at different temperatures; application of Pitzer's equations

Activity coefficients for the system HCl + CaCl2+ H2O at various temperatures. Applications of pitzer's equations

Thermodynamics of aqueous magnesium and calcium bicarbonates and mixtures with chloride

Thermodynamics of the unsymmetrical mixed electrolyte hydrogen chloride-lanthanum chloride