Suggested Improvements for Measurement of Equilibrium Solubility-pH of Ionizable Drugs

Avdeef, Alex

doi:10.5599/admet.3.2.193

Cited by 42 publications

(52 citation statements)

References 61 publications

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“…9 The creation of standard experimental datasets for solubility prediction is on-going. 25 There are methods which apply physically motivated fitted equations 12 or full calculations from first principles 11,26 to solubility prediction. The fitted equation approach has shown good accuracy, but is limited by requirements for additional experimental input, although promising attempts have been made to predict some of these quantities.…”

Section: Introductionmentioning

confidence: 99%

Are the Sublimation Thermodynamics of Organic Molecules Predictable?

McDonagh

Palmer

Mourik

et al. 2016

J. Chem. Inf. Model.

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We compare a range of computational methods for the prediction of sublimation thermodynamics (enthalpy, entropy and free energy of sublimation). These include a model from theoretical chemistry that utilizes crystal lattice energy minimization (with the DMACRYS program) and QSPR models generated by both machine learning (Random Forest and Support Vector Machines) and regression (Partial Least Squares) methods. Using these methods we investigate the predictability of the enthalpy, entropy and free energy of sublimation, with consideration of whether such a method may be able to improve solubility prediction schemes. Previous work has suggested that the major source of error in solubility prediction schemes involving a thermodynamic cycle via the solid state is in the modeling of the free energy change away from the solid state. Yet contrary to this conclusion other work has found that the inclusion of terms such as the enthalpy of sublimation in QSPR methods 2 does not improve the predictions of solubility. We suggest the use of theoretical chemistry terms, detailed explicitly in the methods section, as descriptors for the prediction of the enthalpy and free energy of sublimation. A dataset of 158 molecules with experimental sublimation thermodynamics values and some CSD refcodes has been collected from the literature and is provided with their original source references.

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Section: Introductionmentioning

confidence: 99%

Are the Sublimation Thermodynamics of Organic Molecules Predictable?

McDonagh

Palmer

Mourik

et al. 2016

J. Chem. Inf. Model.

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“…A recent survey of 4557 equilibrium solubility measurements ("4557" set) of druglike (mostly ionizable) molecules in aqueous media suggested a two-step procedure to reduce the interlaboratory variance in solubility data mining [3]. First, data from ionizable molecules can be adjusted for pH effects by calculating the intrinsic solubility, S 0 , based on the ionization constant, pK a , and the reported water solubility, S w .…”

Section: Introductionmentioning

confidence: 99%

“…Second, data can be normalized for temperature effects, by transforming solubility measurements performed at various temperatures (e.g., 10 -50 °C) to those at a benchmark value of 25 °C. With these two steps, it was thought to be possible to reduce the often cited interlaboratory reproducibility of 0.5 -0.7 log unit (or even higher) [4][5][6][7] down to near 0.15 [3]. Such improvements in data mining are expected to yield more reliable in silico prediction models of solubility for use in drug discovery.…”

Section: Introductionmentioning

confidence: 99%

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Solubility Temperature Dependence Predicted from 2D Structure

Avdeef

2015

ADMET DMPK

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“…The mathematical approach in pDISOL-X has been described by Völgyi et al (2013), and the program has been applied in several other recent studies (Avdeef, 2014a, b;Butcher et al, 2015;Avdeef, 2015a). Briefly, the novel data analysis method uses solubility as a function of pH, log S-pH, as measured input data from any analytical technique (along with standard deviations, SD(log S)).…”

Section: Refinement Of Intrinsic Salt Solubility and Aggregation Conmentioning

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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Suggested Improvements for Measurement of Equilibrium Solubility-pH of Ionizable Drugs

Abstract: Abstract

Cited by 42 publications

References 61 publications

Are the Sublimation Thermodynamics of Organic Molecules Predictable?

Are the Sublimation Thermodynamics of Organic Molecules Predictable?

Solubility Temperature Dependence Predicted from 2D Structure

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

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