Determination of solution aggregation using solubility, conductivity, calorimetry, and pH measurements

Streng, William H.

doi:10.1016/0378-5173(95)04317-9

Cited by 25 publications

(14 citation statements)

References 3 publications

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“…6c). Also, we see aggregates at 25-C, but these are less apparent in the 37-C data of Glomme et al, consistent with previous observations that aggregation is temperature sensitive (14,15,21). The dipyridamole example at 23-C (Fig.…”

Section: Summary Of Solubility-excipient Trendssupporting

confidence: 92%

“…Zhu and Streng (15) found that the self-association of dolasetron to form cationic dimers and trimers (Case 2b below) was enthalpy-driven (H-bond and/or pY Y Yp interactions), not by hydrophobic/electrostatic interactions, with the aggregation constants, log K 2j3 , ranging from 0.6 to 1.7 (M j j1 scale, cf., BTHEORETICAL SECTION^). Decamers with log K 10 =12.1 were observed for MDL201346A by Streng et al (14). Such aggregates were found to have unusually high solubility and/or solubility very sensitive to temperature.…”

Section: Introductionmentioning

confidence: 89%

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Solubility-Excipient Classification Gradient Maps

et al. 2007

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This study assessed the effect of excipients (sodium taurocholate, 2-hydroxypropyl-f-cyclodextrin, potassium chloride, propylene glycol, 1-methyl-2-pyrrolidone, and polyethylene glycol 400) on the apparent intrinsic solubility properties of eight sparingly soluble drugs (four bases, two neutrals, and two acids): astemizole, butacaine, clotrimazole, dipyridamole, griseofulvin, progesterone, glibenclamide, and mefenemic acid. Over 1,200 UV-based solubility measurements (pH 3-10) were made with a high-throughput instrument. New equations, based on the "shift-in-pKa" method, were derived to interpret the complicated solubility-pH dependence observed, and poorly predicted by the Henderson-Hasselbalch equation. An intrinsic solubility-excipient classification gradient map visualization tool was developed to rank order the compounds and the excipients. In excipient-free solutions, all of the ionizable compounds formed either uncharged or mixed-charge aggregates. Mefenamic acid formed anionic dimers and trimers. Glibenclamide displayed a tendency to form monoanionic dimers. Dipyridamole and butacaine tended to form uncharged aggregates. With strong excipients, the tendency to form aggregates diminished, except in the case of glibenclamide. We conclude that a low-cost, compound-sparing, and reasonably accurate high-throughput assay which can be used in early screening to prioritize candidate molecules by their eventual developability via the excipient route is possible with the aid of the "self-organized" intrinsic solubility-excipient classification gradient maps.

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Section: Summary Of Solubility-excipient Trendssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 89%

Solubility-Excipient Classification Gradient Maps

et al. 2007

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“…4 from (14) is applied to the apparent P ABL , the excipient-free solutions (0% NaTC, Table III) appear to indicate aqueous diffusion of monomers in the case of astemizole, clotrimazole, and dipyridamole, since the ratio of the apparent molecular weight, MW*(based on the assumption of 40 mm ABL) to the true molecular weight, MW*/MW, is close to 1. In the same buffer solutions, aggregates of the order of 4Y7 seem to be indicated for some of the other low-solubility drugs (27). In 3 mM sodium taurocholate solutions, only dipyridamole appears to behave as a monomer (Table III), with the other molecules appearing as aggregates of order 3Y5.…”

Section: Pampa Measurements With Excipientsmentioning

confidence: 96%

PAMPA–Excipient Classification Gradient Map

et al. 2006

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The effect of excipients on the artificial membrane permeability (Double-Sink PAMPA) properties of eight sparingly soluble drugs was studied. Quantities of excipient were selected to match the concentrations expected in the gastrointestinal fluid under clinically relevant conditions. Over 1,200 measurements were performed. To correct for the effects of the aqueous boundary layer and determine the intrinsic permeability, precisely measured ionization constants were used. The intrinsic permeability of weak acids was enhanced (up to 100 fold) but that of weak bases depressed (up to 270 fold) by the excipients: mefenamic acid > glybenclamide > progesterone > griseofulvin > clotrimazole > astemizole > dipyridamole > butacaine. Excipient enhancement ranked: 3 mM NaTC > 0.24% PEG400 > 0.2 M KCl > 0.24% NMP > 5% PEG400 > 0.24% PG > 1% PEG400 > 0.1M KCl > 1% PG > 1% NMP > 5% PG > 0.24% HP-beta-CD > 1% HP-beta-CD > 15 mM NaTC. The study clearly indicates that the method is suitable for use in preclinical development to assess the effect of excipients on the permeability of sparingly soluble drug candidates. The method is quick, cost-effective, and reasonably accurate. The self-rank-ordered PAMPA-Mapping may be a helpful visualization tool for delivery screening.

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“…We have performed the data analysis of the observed molar conductivity following the procedure described in detail by Streng et al [10]. …”

Section: Methodsmentioning

confidence: 99%

Investigation on the self-association of an inorganic coordination compound with biological activity (Casiopeína III-ia) in aqueous solution

Marín-Medina

García‐Ramos

Ruíz-Azuara

et al. 2016

Chemistry Central Journal

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From studies using different experimental techniques employed to determine the presence of aggregates e.g. isothermal titration calorimetry, surface tension, electrical conductivity, UV–Vis spectrophotometry, dynamic and static light scattering, it is clearly demonstrated that the compound [Cu(4, 4′-dimethyl-2, 2′-bipyridine)(acetylacetonato)H2O]NO3 (Casiopeína III-ia), promising member of a family of new generation compounds for cancer treatment, is able to auto associate in aqueous media. Physicochemical properties associated with the formation of the aggregates were determined in pure water and in phosphate buffer media in order to simulate physiological conditions. From isothermal titration calorimetry and electrical conductivity measurements we calculated the dissociation constant of the aggregates, K D. For pure water the values obtained in both techniques are 2.73 × 10−4 and 5.93 × 10−4 M respectively while for the buffer media we obtained 4.61 × 10−4 and 1.57 × 10−3 M. The enthalpy of dissociation, ∆H D, calculated from the calorimetric data shows that the presence of the phosphate ions has an energetic effect on the aggregate stability since in pure water a value of 18.79 kJ mol−1 was obtained in comparison with the buffer media where a value 4 times bigger was found (70.48 kJ mol−1). With the data collected from these techniques the number of monomers calculated which participate in the formation of the aggregates is around two. From our surface tension, electrical conductivity and UV–Vis spectrophotometry measurements the critical aggregate concentration, cac, was determined. For each technique specific concentration ranges were obtained but we can summarize that the cac in pure water is between 3 and 3.5 mM and for the buffer media is between 3.5 and 4 mM. Dynamic light scattering measurements provide us with the hydrodynamic diameter of the aggregates and from static light scattering measurements we determined the molecular weight of the Casiopeína III-ia aggregates to be of 1000.015 g mol−1 which is two times the molecular weight of the Casiopeína III-ia molecule. This value is in agreement with the number of monomers which participate in the formation of the aggregates obtained from isothermal titration calorimetry and electrical conductivity data analysis.

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Determination of solution aggregation using solubility, conductivity, calorimetry, and pH measurements

Cited by 25 publications

References 3 publications

Solubility-Excipient Classification Gradient Maps

Solubility-Excipient Classification Gradient Maps

PAMPA–Excipient Classification Gradient Map

Investigation on the self-association of an inorganic coordination compound with biological activity (Casiopeína III-ia) in aqueous solution

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