Equilibrium versus kinetic measurements of aqueous solubility, and the ability of compounds to supersaturate in solution—a validation study (original) (raw)
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European Journal of Pharmaceutical Sciences, 2020
The solubility of three drugs (glimepiride, pioglitazone, sibutramine) with different acid/base properties and expected supersaturation behavior was examined in detail using the shake-flask (SF) and potentiometric (CheqSol) methods. Both uncharged (free) species and hydrochloride salts were used as starting materials. On the one hand, the SF method provided information about the thermodynamic solubility at any pH value, including the counterion-dependent solubility of ionic species. Additionally, this method easily allowed the identification of the solid phase in equilibrated solutions by powder X-ray diffraction, and the detection and quantification of aggregation and complexation reactions. On the other hand, CheqSol method permitted the measurement of the equilibrium solubility of neutral species, the observation of changes in solid forms, and the extent and duration of supersaturation (kinetic solubility) for "chaser" compounds. The combined information from both methods gave an accurate picture of the solubility behavior of the studied drugs.
Journal of Pharmaceutical Sciences, 2016
ABT-072 is a candidate drug evaluated for treatment of hepatitis C virus. It is an acidic compound with extremely low intrinsic aqueous solubility. An in vitro dissolution-partition system, referred as biphasic test method, was used to characterize ABT-072 prototype formulations. This test used 2 aqueous dissolution media of pH 2 and 6.5 in a sequential manner to simulate the transition of drug in gastrointestinal tract. The biphasic test used in this work effectively differentiated various ABT-072 formulations derived from conventional and enabling technologies. In vitro profiles of these formulations indicate a complex interplay among the 3 competitive kinetic processes including dissolution, precipitation, and partition in the aqueous media. The relative amount of drug partitioned into the organic phase (i.e., octanol) from different formulations was found to be directly related to their in vivo exposures observed in both dogs and human subjects, respectively. An in vitro-in vivo relationship was obtained between ABT-072 concentrations in octanol at t ¼ 2 h from these formulations and the relative bioavailabilities in dogs and human subjects. This work revealed the significance of polymeric precipitation inhibition by sustaining a supersaturated state of ABT-072 and its impact on in vivo exposure in human subjects.
Solubility: it's not just for physical chemists
Drug Discovery Today, 2006
Solubility data are used to make crucial decisions from the earliest stages of drug discovery throughout the development process, but often the decision-maker is far removed, in terms of both organization and scientific background, from the scientist who generates the data. Here we provide a reference point for consumers of solubility who are presented with increasingly sophisticated strategies to measure sooner, faster or more accurately. We discuss the fundamental forces that govern solubility, the role of physicalchemical parameters such as pH and pK a , and the principles involved in different solubility measurements. Our ultimate goal is to enable a decision-maker, when presented with solubility data, to have in hand the tools to evaluate not just the magnitude but also the context and appropriateness of those measurements to the drug in question.
Journal of Pharmaceutical Innovation, 2019
Purpose Delaying precipitation of weakly basic drugs in supersaturated state following their transition from the acidic gastric environment to the near-neutral proximal small intestinal fluid is emerging as a promising tactic for achieving higher transitional solubility and improving bioavailability of such drugs. The aim of this study was to assess the effect of supersaturation on drug dissolution and permeation in vitro, and to evaluate the in vitro-in vivo correlation of the supersaturation effect for the poorly soluble basic drug ketoconazole. Method We monitored dissolution of drugs in simulated gastric fluid followed by drug dissolution in simulated intestinal fluid and simultaneous permeation across Caco-2 cell monolayers using the IDAS2 experimental procedure. The pH shift from pH 1.6 to pH 6.5 (mimicking in vivo gastric to intestinal transition) was used to induce transient in vitro supersaturation of the tested weakly basic poorly soluble drugs. Polymeric precipitation inhibitor, hydroxypropyl methylcellulose acetate succinate (HPMCAS), was added to dissolution medium in order to increase the amplitude and duration of the pH-driven supersaturation of the weakly basic drug ketoconazole in the in vitro IDAS2 setting. The effect of HPMCAS on oral bioavailability of ketoconazole was demonstrated in the rat pharmacokinetic model. Results Drug supersaturation induced by pH shift was assessed in vitro by comparing drug dissolution and permeation under the 2-stage (pH shift from gastric pH 1.6 to intestinal pH 6.5) conditions vs. 1-stage (constant intestinal pH 6.5) conditions. Compared to the 1-stage conditions, 2-stage procedure increased in vitro dissolution AUC (area under the concentration-time curve) of the weakly basic drugs dipyridamole, ketoconazole, and itraconazole by 393%, 161%, and 71%, respectively, accompanied by corresponding 543%, 264%, and 46% increase in in vitro permeation. In contrast, the BCS 2 acidic drug warfarin exhibited 9% decrease in dissolution under 2-stage conditions, which was associated with a 21% decrease in permeation. None of the tested BCS 1 drugs (minoxidil and metoprolol) exhibited supersaturation after the gastric to intestinal pH shift; consistent with the absence of supersaturation, and the permeation of these drugs was not affected by the transition from simulated gastric to simulated intestinal environments. The polymeric precipitation inhibitor, HPMCAS, increased the in vitro dissolution and permeation AUC values of ketoconazole by 187% and 119%, respectively, and ketoconazole plasma AUC 0-24h and C max by 54% and 49% following oral administration in rats. Conclusion This study has shown that the novel in vitro dissolution-absorption methodology simulating the in vivo gastrointestinal environments that influence drug release and absorption of orally administered drugs constitutes a sensitive and physiologically relevant approach for investigating the potential utility of formulation excipients for exploiting supersaturation as a means to improve systemic drug absorption.
Methods of estimating the water activity of supersaturated aqueous solutions
Canadian Journal of Chemical Engineering, 1974
Empirical and semi-empirical methods of estimating the water activity of supersaturated aqueous solutions at up to twice the saturation molality are compared for CaCl2 and Na2SO4 at °0C and K2SO4, KH2PO4, NaCl, KCl, RbCl, CsCl, KNO3 and mannitol at 25°. An empirical method, applicable to both electrolytes and non-electrolytes, is described.Des méthodes empiriques et semi-empiriques d'estimation de l'activité de l'eau de solution aqueuses sursaturées sont comparées pour divers solutés jusqu'à deux fois la moralité de saturation. Les solutés comprennent le CaCl2 et Na2SO4 à 0°C et le K2SO4, KH2PO4, NaCl, KCl, RbCl, CsCl, KNO3 et le mannitol à 25°C. Une méthode complètement empirique a été développée qui peut être appliquée aux solutés électrolytes et non-électrolytes.
Study of pH-dependent solubility of organic bases. Revisit of Henderson-Hasselbalch relationship
Analytica Chimica Acta, 2010
In this paper the pH-equilibrium solubility profiles of six organic drugs are presented. The equilibrium solubility values were determined using the saturation shake-flask and the Chasing Equilibrium Solubility (CheqSol) methods. Results obtained by the two methods are in good agreement. The aim of the present work was to study the validity of the Henderson-Hasselbalch (HH) relationship in the case of structurally diverse weak bases. The significance of pH control and the effect of the salt form (e.g., fumarate) was also investigated. In the case of monoprotic bases, namely papaverine, promethazine, propafenone and ticlopidine the experimental solubility data precisely follow the HH equation until the limit of salt solubility. The common ion effect on salt solubility was found to be significant at low pHs. Deviation from the HH equation in the case of dibasic quetiapine hydrogen fumarate and the ampholyte desvenlafaxine hydrogen fumarate can be easily interpreted with the formation of different salt compositions. It was concluded that precise pH control is essential in shake-flask solubility measurements. It is also critical that the pK a value and the intrinsic solubility are accurately determined when the HH relationship is used to predict the pH-dependent aqueous solubility of drugs.
ADMET and DMPK, 2016
This commentary addresses data quality in equilibrium solubility measurement in aqueous solution. Broadly discussed is the "gold standard" shake-flask (SF) method used to measure equilibrium solubility of ionizable drug-like molecules as a function of pH. Many factors affecting the quality of the measurement are recognized. Case studies illustrating the analysis of both solution and solid state aspects of solubility measurement are presented. Coverage includes drug aggregation in solution (sub-micellar, micellar, complexation), use of mass spectrometry to assess aggregation in saturated solutions, solid state characterization (salts, polymorphs, cocrystals, polymorph creation by potentiometric method), solubility type (water, buffer, intrinsic), temperature, ionic strength, pH measurement, buffer issues, critical knowledge of the pK a , equilibration time (stirring and sedimentation), separating solid from saturated solution, solution handling and adsorption to untreated surfaces, solubility units, and tabulation/graphic presentation of reported data. The goal is to present cohesive recommendations that could lead to better assay design, to result in improved quality of measurements, and to impart a deeper understanding of the underlying solution chemistry in suspensions of drug solids.
Analytica Chimica Acta, 2007
In this paper the validation of pK a determination in MDM-water mixtures is presented. The MDM-water mixture is a new multicomponent cosolvent mixture (consisting of equal volumes of methanol, dioxane and acetonitrile, as organic solvents) that dissolves a wide range of poorly watersoluble compounds. The cosolvent dissociation constants (p s K a ) of 50 chemically diverse compounds (acids, bases and ampholytes) were measured in 15-56 wt% MDM-water mixtures by potentiometric or spectrophotometric titration and the aqueous pK a values obtained by extrapolation. Three different extrapolation procedures were compared in order to choose the best extrapolation in MDM-water mixture using a sub-set of 30 watersoluble compounds. The extrapolated results are in good agreement with pK a values measured in aqueous medium. No significant difference was found among these extrapolation procedures thus the widely used Yasuda-Shedlovsky plot was proposed for MDM cosolvent also. Further we also present that the single point estimation based on measurement in 20%/v MDM-mixture using a general calibration equation may be suitable for rapid pK a determination in the early phase of drug research.