高效液相色谱法测定去氧氟尿苷在不同介质中的平衡溶解度和表观油水分配系数

目的测定去氧氟尿苷在不同介质中的平衡溶解度以及在正辛醇-水和正辛醇-缓冲液体系中的表观油水分配系数。方法采用HPLC法测定去氧氟尿苷的浓度,采用摇瓶法测定去氧氟尿苷的表观油水分配系数。结果37℃,pH=7时去氧氟尿苷在水中的平衡溶解度为2.570 1 g.L-1,在pH〈5磷酸盐缓冲液中的平衡溶解度较低;去氧氟尿苷在正辛醇和水相中表观油水分配系数Papp为0.97;当pH〈7时,受pH影响不显著,表现为亲水性。结论去氧氟尿苷在水中的平衡溶解度及油水分配系数与介质的pH值有关,可以通过改变pH值,增加该药物新剂型的稳定性。     

Solubility of molecular crystals: polymorphism in the light of solubility theory

The thermodynamic theory of solubility of molecular crystals in solvents is reviewed with an emphasis on solutes showing polymorphism as in case of many pharmaceuticals. The relation between solubility and binary phase diagrams of the solute solvent system is treated. The astonishing variety of possible solubility curves as a function of temperature is explained using simple models for the solution thermodynamics assuming no mixing between the solvent and solute in the solid phase, though including the case of solvates or pseudo polymorphs. In passing a new method is introduced that allows to estimate the transition temperature of enantiotropically related polymorphs from melting temperatures and enthalpies of the polymorphs.     

Correlation between the transdermal permeation of ketoprofen and its solubility in mixtures of a pH 6.5 phosphate buffer and various solvents

The passage of a drug through the skin is directly proportional to the concentration of the drug in the donor phase and to the permeability coefficient constant Kp. Kp is determined essentially by two factors: the dissolution of the drug in the stratum corneum (measured by the partition coefficient P) and the diffusion in the same stratum (measured by the diffusion constant D). In our study, several saturated solutions of ketoprofen in mixtures of a pH 6.5 phosphate buffer and various co-solvents were studied to find correlations between the solubility of the ketoprofen in the mixtures and its permeation parameters in in vitro permeation studies with Franz cells. The results show that D does not change in the different mixtures; the diffusion of the drug into the stratum corneum is not influenced by the presence of the co-solvents, whereas the partition coefficient is strongly influenced. In particular, Kp and P were found to be inversely proportional to solubility, meaning that when the co-solvent increases the solubility, the partition of the drug and consequently Kp decrease. These findings were confirmed in some developed gels, and the developed gels were found to enhance the ketoprofen permeation with respect to the formulation in a commercial Fastum gel.     

Solubility of drugs in aqueous solutions. Part 4. Drug solubility by the dilute approximation

As in our previous publications in this journal [Int. J. Pharm. 258 (2003a) 193; Int. J. Pharm. 260 (2003b) 283; Int. J. Pharm. 267 (2003c) 121], this paper is concerned with the solubility of poorly soluble drugs in aqueous mixed solvents. In the previous publications, the solubilities of drugs were assumed to be low enough for the so-called infinite dilution approximation to be applicable. In contrast, in the present paper, the solubilities are considered to be finite and the dilute solution approximation is employed. As before, the fluctuation theory of solutions is used to express the derivatives of the activity coefficient of a solute in a ternary solution (dilute solute concentrations in a binary solvent) with respect to the concentrations of the solvent and cosolvent. The expressions obtained are combined with a theoretical equation for the activity coefficient of the solute. As a result, the activity coefficient of the solute was expressed through the activity coefficients of the solute at infinite dilution, solute mole fraction, some properties of the binary solvent (composition, molar volume and activity coefficients of the components) and parameters reflecting the nonidealities of binary species. The expression thus obtained was used to derive an equation for the solubility of poorly soluble drugs in aqueous binary solvents which was applied in two different ways. First, the nonideality parameters were considered as adjustable parameters, determined from experimental solubility data. Second, the obtained equation was used to correct the solubilities of drugs calculated via the infinite dilution approximation. It was shown that both procedures provide accurate correlations for the drug solubility.     

Cutaneous cryptococcosis in a patient affected by chronic lymphocytic leukaemia: a case report

Cryptococcosis is an opportunistic infection, the incidence of which is increased in the immunocompromised patients. Cryptococcus neoformans is an encapsulated fungus that mainly infects the lungs and the central nervous system, possibly involving different organs. Cutaneous cryptococcosis is classified into localized infection, usually occurring after traumatic inoculation (primary cutaneous cryptococcosis) and cutaneous manifestation due to hematogenous dissemination (secondary cutaneous cryptococcosis), mostly in patients with underlying immunosuppression. We report a case of cutaneous cryptococcosis in a patient affected by chronic lymphocytic leukaemia.     

Solubility prediction in water-ethanol mixtures based on the excess free energy approach using a minimum number of experimental data

The solubility of nalidixic acid in water-ethanol mixtures has been determined at 25 degrees C. The generated solubility data sets have been used to assess the accuracy of different numerical analyses for the excess free energy model and a new numerical method for solubility prediction in water-ethanol mixtures based on four experimental determinations is proposed. The accuracy of a previously presented numerical method to fit all data points is compared with that of a proposed analysis using average percentage deviation (APD). The APD obtained are 14.6 (+/- 8.0) and 8.4 (+/- 4.1), respectively for previous and proposed methods. A minimum number of three and four data points employed to train the original forms of the excess free energy model and the solubility at other solvent compositions were predicted. The APDs obtained were 61.4 and 23.0%, respectively. The APD produced for the proposed numerical method was 16.1%.     

Solubility at the Molecular Level: Development of a Critical Aggregation Concentration (CAC) Assay for Estimating Compound Monomer Solubility

Purpose

In drug discovery research the formation of soluble compound aggregates is a major cause of false positives, false negatives, and distorted values in High-Throughput Screening assays that measure either binding or functional activity. These aggregation-based artifacts lead to serious distortions in the SAR which are critical to successful lead optimization. In this work we introduce a new approach by which the ??critical aggregation concentration?? (CAC) is determined, thereby overcoming limitations inherent to traditional solubility methods and enabling estimation of small molecule monomer solubility.

Methods

The theoretical and experimental basis of a new confocal Static Light Scattering plate reader assay is presented.

Results

Tests conducted with model systems, commercial compounds, and Abbott library compounds show that the CAC assay can measure aqueous monomer solubilities reproducibly and reliably, achieving a sensitivity of ~0.2???m, which is an improvement of approximately two orders of magnitude over nephelometry.

Conclusions

Determination of compound monomer solubilities in a screening format is possible for the first time with the cSLS-CAC methodology. It is currently in routine use in Abbott??s drug discovery program, and has enabled identification of many compound induced artifacts in binding or activity assays that are missed by traditional kinetic solubility measurements.     

Switch to icatibant in a patient affected by hereditary angioedema with high disease activity: a case report

Icatibant, an antagonist of the bradykinin B2 receptor, was approved for the treatment of acute attacks of hereditary angioedema in the EU in 2008. This paper presents the case of a 65-year-old woman affected by frequent acute attacks of hereditary angioedema who benefitted from a change of therapy to icatibant, following years of treatment with C1-inhibitor.     

Mathematical representation of solubility of amino acids in binary aqueous-organic solvent mixtures at various temperatures using the Jouyban-Acree model

Applicability of a solution model for calculating solubility of amino acids in binary aqueous-organic solvent mixtures at various temperatures was shown. The accuracy of the proposed model was evaluated by computing mean percentage deviation (MPD) employing available solubility data of amino acids in binary solvents at various temperatures from the literature. The overall MPD (+/- SD) for correlation of solubility data was 16.5 +/- 8.8%. In addition, the equations calculating solubility of amino acids in binary solvent mixtures at a fixed temperature was revisited.     

Stabilization of the maleate salt of a basic drug by adjustment of microenvironmental pH in solid dosage form

Tablet formulations of the maleate salt of a basic drug (I) showed a major loss in potency and a lack of mass balance upon storage under accelerated stability testing conditions. No such stability issues were observed in capsules that were compositionally similar, and even the tablet was stable when it was encapsulated in capsule shell. It was identified that the salt converts to its free base form in the microenvironment of the tablet formulation. Studies using radiolabeled drug substance showed that the free base formed in the tablet volatilized under test conditions used and was absorbed in the wall of plastic container. No mass loss was observed with encapsulated tablets since the capsule shell either protected the drug substance from volatilization or trapped any drug substance that volatilized. The conversion of the salt to free base could be related to the pH-solubility profile of the compound where the pH(max) (pH of maximum solubility) was 3.3-3.6, above which the salt would convert to base while no such conversion would occur below this pH. The microenvironmental pH of the tablet was found to be 4.3, favoring the salt-to-base conversion. A stable tablet formulation with shelf-life >3 years was successfully developed by lowering the microenvironemental pH of tablet from 4.3 to <3.0 by adding citric acid to the formulation.     

Pyrene toxicity is affected by the nutrient status of a marine sediment community: Implications for risk assessment

Risk assessment of toxicants often disregards that environmental conditions, like changing nutrient status, may affect ecosystem response to a toxicant even within an ecosystem. We investigated if effects of pyrene on shallow-water sediments depended on nutrient status of the sediment during 58 days of incubation. Natural undisturbed sediment cores were pre-exposed to two concentrations of inorganic nutrients (nitrogen and phosphorous) for 14 days. After terminating nutrient additions, pyrene was applied once to half the Nu_high and half the Nu_low cores in a concentration of 2 mg/kg DW, normalized to 1% TOC. Pyrene affected the sediment systems in both Nu_high and Nu_low, but effects of pyrene differed between nutrient regimes. In the Nu_low system, effects of pyrene were mainly seen on the sediment community structure, such as meiofauna community structure. On the contrary, effects of pyrene in Nu_high were mainly seen on community functions, such as changes in inorganic nutrient fluxes. Direct and indirect effects of pyrene were observed in both nutrient regimes, but they operated on different timescales depending on the variable in focus. This study shows the need to include environmental factors such as nutrient status in risk assessment of toxicants.     

Determination of the binding parameter constants of Renagel capsules and tablets utilizing the Langmuir approximation at various pH by ion chromatography

Sevelamer hydrochloride is a cross-linked polymeric amine; it is the active ingredient in Renagel capsules and tablets. Sevelamer hydrochloride is indicated for the control of hyperphosphatemia in patients with end-stage renal disease. The binding parameter constants of sevelamer hydrochloride were determined using the Langmuir approximation for three different dosage forms at pH 4.0, 5.5 and 7.0. The three dosage forms were Renagel 403 mg capsules, Renagel 400 mg tablets and Renagel 800 mg tablets. The results demonstrate the equivalency of all three dosage forms at each pH. The results also demonstrate a shift in the binding mechanism from pH 4.0 to 7.0.     

Estimation of intragastric drug solubility in the fed state: comparison of various media with data in aspirates

The suitability of various media to forecast the solubility of ketoconazole and dipyridamole in the fed stomach at various periods after meal administration was evaluated. Solubilities were measured with the shake‐flask method in gastric fluids aspirated 30, 60 and 120 min after administration of 500 ml Ensure plus^® to healthy fasted adults, in three sets of simulated gastric fluids based on milk, and in simple aqueous buffered media. Simple aqueous buffered media vastly underestimated the intragastric solubility of model compounds in the fed state. When using undigested milk‐based media, the solubilities of model compounds in aspirates were also underestimated by a factor of 2.5–27. Solubility in milk digested with pepsin was useful for estimating the intragastric solubility of ketoconazole (within 20%) but overestimated the intragastric values of dipyridamole by a factor of 2–19. For both drugs, the solubility in milk digested with pepsin and lipase predicted the solubility in aspirates collected 60 min after meal administration, whereas at other times it overestimated the intragastric solubility (by a factor of <5). Both the use of biorelevant media and simulation of intragastric digestion are necessary for the prediction of drug solubility in the fed stomach. Milk digested with pepsin and lipase enabled the estimation of the intragastric solubility of dipyridamole and ketoconazole at 1 h after meal intake. Simulation of vesicle/micellar structures seems to be key for the prediction of intragastric solubility in the fed stomach. Copyright © 2009 John Wiley & Sons, Ltd.