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Journal ArticleDOI

The calculation of formation curves of metal complexes from pH titration curves in mixed solvents

01 Jan 1954-Journal of The Chemical Society (resumed) (The Royal Society of Chemistry)-pp 2904-2910
About: This article is published in Journal of The Chemical Society (resumed).The article was published on 1954-01-01. It has received 530 citations till now. The article focuses on the topics: Titration curve.
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Journal ArticleDOI
TL;DR: In this paper, the effect of unknown junction potentials on acid dissociation constants has been investigated, with particular references to nitrilotriacetic acid (NTA) and ethylenediaminetetric acid (EDTA).

1,197 citations

Journal ArticleDOI
TL;DR: This review will consider recent developments in physicochemical profiling used to identify candidate molecules with physical properties related to good oral absorption and 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).
Abstract: 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.

482 citations


Cites background or methods from "The calculation of formation curves..."

  • ...The most explored solvent systems are based on wateralcohol mixtures [95,135,137,152-181]....

    [...]

  • ...To reveal the other two pKas of M6G and to test for overlapping pKas, it is necessary to transform the titration curves into Bjerrum plots [88,92,94,125,134-136]....

    [...]

Book
Alex Avdeef1
21 Aug 2003
TL;DR: Partitioning Into Liposomes, Transport Model, and Some Simple Rules: A Model for Solubility and Permeability.
Abstract: Preface. Acknowledgments. Definitions. 1. Introduction. 2. Transport Model. 3. Charge State. 4. Partitioning Into Octanol. 5. Partitioning Into Liposomes. 6. Solubility. 7. Permeability. 8. Summary and Some Simple Rules. References. Index.

481 citations


Cites background or methods from "The calculation of formation curves..."

  • ...The most frequently explored solvent systems are based on water–alcohol mixtures [119,164,166,181–210]....

    [...]

  • ...To reveal the other two pKa values of M6G and to test for overlapping pKa values, it is necessary to transform the titration curves into Bjerrum plots [112,116,118,153,163–165]....

    [...]

Journal ArticleDOI
TL;DR: In this paper, a series of semiaqueous HCl solutions of known concentration, containing 0.1 M KNO 3 (as ionic strength adjuster) and 0-70 wt % methanol, was titrated at 21, 25, and 37 o C with standardized KOH, pH 2-12.
Abstract: A series of semiaqueous HCl solutions of known concentration, containing 0.1 M KNO 3 (as ionic strength adjuster) and 0-70 wt % methanol, was titrated at 21, 25, and 37 o C with standardized KOH, pH 2-12. The pH measuring circuit (Ross-type electrode) was calibrated with an aqueous pH buffer (Nernst slope assumed). The operational pH readings were related to p c H (=-log [H + ]) by the four-parameter equation: pH=α+Sp c H+j H [H + ]+j OH [OH - ]

241 citations

Journal ArticleDOI
TL;DR: A generalized, weighted, nonlinear least squares procedure is developed, based on pH titration data, for the refinement of octanol-water partition coefficients and ionization constants of multiprotic substances, which allows for CO2 corrections in instances where the base titrant may have CO2 as an impurity.

222 citations