Investigation of drug self-association in aqueous solution using calorimetry, conductivity, and osmometry

Zhu, Chengyue; Streng, William H.

doi:10.1016/0378-5173(95)04220-2

Cited by 20 publications

(14 citation statements)

References 4 publications

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“…Up to three different solids could be tested in a single calculation. The presence of particular species was suggested by the slope characteristics of the log S -pH curve [1,5,[7][8][9][10][11].…”

Section: Refinement Of Intrinsic and Salt Solubility And Aggregation mentioning

confidence: 99%

“…Such aggregates were found to have unusually high solubility, sensitively dependent on temperature. Zhu and Streng [9] found that the self-association of dolasetron to form cationic dimers and trimers was enthalpy driven (H-bond/aromatic ring rather than hydrophobic/electrostatic interactions), with the aggregation constants, K 2-3 , ranging from 4 to 50 M -1 at 25 °C. Many nonsteroidal antiinflammatory drugs [10], such as indomethacin, diclofenac, ibuprofen, ketoprofen, naproxen, and sulindac, can self-associate by forming mixed-charge micelle or micelle-like structures.…”

Section: Introductionmentioning

confidence: 99%

“…There are numerous reports of aggregation forming systems [1,[5][6][7][8][9][10][11][12]. For example, doxycycline [8], with intrinsic solubility S 0 0.72 mg•mL -1 , at 25 °C in 1 M NaCl/HCl acidic solutions, forms dimers with K 2 = 24 M -1 .…”

Section: Introductionmentioning

confidence: 99%

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Phosphate Precipitates and Water-Soluble Aggregates in Re-analyzed Solubility-pH Data of Twenty-five Basic Drugs

Avdeef

2014

ADMET DMPK

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Section: Refinement Of Intrinsic and Salt Solubility And Aggregation mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phosphate Precipitates and Water-Soluble Aggregates in Re-analyzed Solubility-pH Data of Twenty-five Basic Drugs

Avdeef

2014

ADMET DMPK

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“…There are only a handful of other examples of sub-micellar aggregation (Higuchi et al, 1953;Bogardus and Blackwood, 1979;Serajuddin and Rosoff, 1984;Serajuddin and Jarowski, 1985;Fini et al, 1995;Zhu and Streng, 1996;Ledwidge and Corrigan, 1998;Jinno et al, 2000). In the above examples, the stoichiometries of aggregation were estimated from the re-analysis of published solubility-pH data (Avdeef 2007(Avdeef , 2012; Völgyi et al, 2013;Avdeef, 2014a,b;Butcher et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Phenothiazines solution complexity – Determination of pKa and solubility-pH profiles exhibiting sub-micellar aggregation at 25 and 37°C

Pobudkowska

Ràfols

Subirats

et al. 2016

European Journal of Pharmaceutical Sciences

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The ionization constants (pK a ) and the pH-dependent solubility (log S-pH) of six phenothiazine derivatives (promazine hydrochloride, chlorpromazine hydrochloride, triflupromazine hydrochloride, fluphenazine dihydrochloride, perphenazine free base, and trifluoperazine dihydrochloride) were determined at 25 and 37 o C. The pK a values of these low-soluble surface active molecules were determined by the cosolvent method (n-propanol/water at 37 o C and methanol/water at 25 o C). The log S-pH profiles were measured at 24 h incubation time in 0.15 M phosphate buffers. The log S-pH "shape-template" method, which critically depends on accurate pK a values (determined independently of solubility data), was used to propose speciation models, which were subsequently refined by rigorous mass-action weighted regression procedure described recently. Differential scanning calorimetry (DSC), UV-visible spectrophotometry, potentiometric, and high performance liquid chromatography (HPLC) measurements were used to characterize the compounds. The intrinsic solubility (S 0 ) values of the three least-soluble drugs (chlorpromazine·HCl, triflupromazine·HCl, and trifluoperazine·2HCl) at 25 o C were 0.5, 1.1, and 2.7 μg/mL (resp.). These values increased to 5.5, 9.2, and 8.7 μg/mL (resp.) at the physiological temperature. The enthalpies of solution for the latter compounds were exceptionally high positive (endothermic) values (99-152 kJ·mol -1 ).Cationic sub-micellar aggregates were evident (from the distortions in the log S-pH profiles) for chlorpromazine, fluphenazine, perphenazine, and trifluoperazine at 25 o C. The effects persisted at 37 o C for chlorpromazine and trifluoperazine. The solids in suspension were apparently amorphous in cases where the drugs were introduced as the chloride salts.3

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“…There are many reports of such systems [1][2][3][4][5][6]. For example, doxycycline [3], with intrinsic solubility S 0 = 0.72 mg/mL, at 25 o C in 1 M NaCl/HCl solutions (pH 0 to 6), forms dimers with K 2 = 24 M -1…”

Section: Introductionmentioning

confidence: 99%

Anomalous Solubility Behavior of Several Acidic Drugs

Avdeef

2014

ADMET DMPK

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Investigation of drug self-association in aqueous solution using calorimetry, conductivity, and osmometry

Cited by 20 publications

References 4 publications

Phosphate Precipitates and Water-Soluble Aggregates in Re-analyzed Solubility-pH Data of Twenty-five Basic Drugs

Phosphate Precipitates and Water-Soluble Aggregates in Re-analyzed Solubility-pH Data of Twenty-five Basic Drugs

Phenothiazines solution complexity – Determination of pKa and solubility-pH profiles exhibiting sub-micellar aggregation at 25 and 37°C

Anomalous Solubility Behavior of Several Acidic Drugs

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