Enhancement of solubility and dissolution rate of poorly water-soluble naproxen by complexation with 2-hydroxypropyl-β-cyclodextrin

The solubility and dissolution rate of naproxen (NPX) complexed with 2-hydroxypropyl-β-cyclodextrin (2-HPβCD) using coprecipitation, evaporation, freeze-drying and kneading method were investigated. Solubility of NPX linearly increased (correlation coefficient, 0.995) as 2-HP-βCD concentration increased, resulting in A_L type phase solubility curve. Inclusion complexes prepared by four different methods were compared by differential scanning calorimetry (DSC). The NPX showed sharp endothermic peak around 156°C but inclusion complexes by evaporation, freeze-drying and kneading method showed very broad peak without distinct phase transition temperature. In contrast, inclusion complex prepared by coprecipitation method resulted in detectable peak around 156°C which is similar to NPX, suggesting incomplete formation of inclusion complex. Dissolution rate of inclusion complexes prepared by evaporation, freeze-drying and kneading except coprecipitation method was largely enhanced in the simulated gastric and intestinal fluid when compared to NPX powder and commercial NAXEN^® tablet. However, about 65% of NPX in gastric fluid still remained unreleased but most of NPX dissolved within 5 min in intestinal fluid. In case of inclusion complex prepared by coprecipitation method, formation of inclusion complex appeared to be incomplete, resulting in no marked enhancement of dissolution rate. From these findings, inclusion complexes of poorly water-soluble NPX with 2-HPβCD were useful to increase solubility and dissolution rate, resulting in enhancement of bioavailability and minimization of gastrointestinal toxicity of drug upon oral administration of inclusion complex.     

红霉素在几种缓冲液中的溶解度

红霉素在水中溶解度同其解离度有一定关系，当ｐＨ＜６．０时红霉素以盐的形式存在，其溶解度随ｐＨ值降低而迅速增大。在酸性范围内，红霉素的溶解度随温度升高而增大，这与游离碱的反温度溶解特性不同，不同温度下的溶解度随ｐＨ变化曲线相交于ｐＫａ为８．６附近。     

Metastable Equilibrium Solubility Behavior of Carbonated Apatite in the Presence of Solution Strontium

The purpose of this study was to use the concept of metastable equilibrium solubility (MES) to describe the anomalous solubility behavior of carbonated apatite (CAP) in the presence of solution strontium. A CAP sample (4.8 wt% CO₃, synthesized at 70°C) was prepared by precipitation. Baseline MES distributions were determined in a series of 0.1 M acetate buffers containing only calcium and phosphate (no strontium) over a broad range of solution conditions. In order to assess the influence of strontium, MES profiles were then determined in a similar fashion with 20, 30, 40, 50, 60, 70, and 80% of the solution calcium being replaced on an equal molar basis by solution strontium. From the compositions of the equilibrating buffer solutions, ion activity products (IAPs) of the form Ca_10-nSr_n(PO₄)₆(OH)₂ (n = 0–10) were calculated in an attempt to determine the correct function governing the dissolution of the CAP preparation. The results demonstrate the following important findings: (a) at high solution strontium/calcium ratios (i.e., when 60% or more of the solution calcium was replaced by strontium), the MES profiles in all the experiments were found to be essentially superimposable when the solution IAPs were calculated using the stoichiometry of Ca₆Sr₄(PO₄)₆(OH)₂, and (b), at low solution strontium/calcium ratios (i.e., when 40% or less of the solution calcium was replaced by strontium), the stoichiometry yielding MES data superpositioning was found to be that of hydroxyapatite. When other stoichiometries were assumed, good superpositioning of the data was not possible.     

3种一步法自酸蚀粘接剂固化后的吸水性和溶解性

目的 比较3种市售的一步法自酸蚀粘接剂的吸水性及溶解性,为临床操作提供指导.方法 选择3种一步法自酸蚀粘接剂Adper Easy Bond (AEO)、Optibond All-in-one (OP)和BeautiBond (BB),各制备50个圆盘试件(直径为8.0mm,厚度为1.0mm),浸泡于去离子水中,并分组于不同浸泡时间段(1天、7天、30天、90天、180天),通过浸水前后质量变化测定其吸水值与溶解值.结果 在每个浸泡期,OP的吸水值、溶解值均为最高,AEO吸水值居中、溶解值最低,BB吸水值最低而溶解值居中,不同品牌粘接剂组间比较,差异均有统计学意义(P＜0.05);3种粘接剂的溶解值均随时间延长显著增加,不同浸泡时间组内比较,差异均有统计学意义(P＜0.05).结论 3种市售的一步法自酸蚀粘接剂固化后的吸水性和溶解性明显不同,可能与其组成有关.     

Nanosuspensions for the formulation of poorly soluble drugs: I. Preparation by a size-reduction technique

A basic problem of poorly soluble drugs is often an insufficient bioavailability. To allow the i.v. injection of these drugs, they were formulated as nanosuspensions by high pressure homogenization. The effect of the production parameters pressure and cycle number on the mean particle size and on the polydispersity of the nanosuspension was investigated with special attention to contamination by microparticles — the limiting factor for i.v. injection. Properties of the nanosuspensions are increased saturation solubility C_s and dissolution rate dc/dt. These phenomena are explained using the Prandtl and the Ostwald–Freundlich equations. These properties promote the dissolution of the nanosuspensions in the blood after i.v. injection. The size distribution obtained and the use of an APV Gaulin homogenizer (FDA approved for parenterals) lead to a pharmaceutical product considered acceptable by the regulatory authorities.     

Inclusion complexation of glibenclamide with 2-hydroxypropyl-β-cyclodextrin in solution and in solid state

Phase solubility diagrams have been used to investigate complexation between 2-hydroxypropyl-β-cyclodextrin (HPBCD) and glibenclamide (GM) in aqueous medium. More stable GM-HPBCD complexes were formed in alkaline medium (in which the drug is in ionized form) than in acid medium (in which the drug is in non-ionized form). The formation of solid GM-HPBCD inclusion complexes has been evaluated by using kneading, spray-drying and freeze-drying methods. Characterization of the resulting mixtures by X-ray diffraction, infrared spectroscopy and differential scanning calorimetry indicated that inclusion complexes can be obtained by spray drying and freeze drying but not by kneading. According to the phase solubility results, drug solubility in alkaline medium was greatly improved by inclusion with HPBCD, whereas in acid medium inclusion with HPBCD had no appreciable effect. Cyclodextrin complexation of ionized drug molecules in alkaline medium resulted in greater total solubilization, i.e., solubilization of the drug due to both cyclodextrin complexation and ionization.     

巴比妥在乙醇—水混合溶剂中的溶解度研究

本研究提出一个新的溶解度方程，用以预测巴比妥在乙醇－水混合溶剂中的溶解度。结果表明，大多数的情况准确性较高，最大误差为１０．６％。     

Human blood platelets as cellular models for investigation of membrane active drugs: Beta-adrenergic blocking agents

Summary Beta-adrenergic blocking agents inhibit serotonin uptake by human blood platelets; in addition they induce release of the previously accumulated amine in vitro. Propranolol was the most active drug, followed by alprenolol, Kl 255, Kö 592, INPEA, oxprenolol, pindolol, Kö 1366, practolol, and sotalol. Kinetic analysis revealed a mixed type of inhibition of serotonin uptake. A significant correlation between these parameters and the lipid solubilities of the respective drugs was found. In contrast to the active serotonin uptake labelled -sympatholytics were accumulated by the platelets passively, i. e. independently of temperature and of time of incubation. The degree of accumulation by human blood platelets and human erythrocyte ghosts was again correlated with the hydrophobicity of the compounds. Therefore, it is concluded that these effects of -adrenergic blocking agents are mainly unspecific in nature, depending on the lipid solubility of the drugs, and leading to conformational changes within the membranes. This assumption is supported by the electron microscopical findings in human platelets, indicating ultrastructural changes and cell lysis.Supported by a grant of the Deutsche Forschungsgemeinschaft.Part of this work has been presented at the 2^nd Int. Symp. on Metabolism and Membrane Permeability of Erythrocytes, Thrombocytes and Leucocytes, Vienna 1972 (Lemmer et al., 1972).     

Aspects of the influence of magnesium ions on the formation of calcium oxalate

Summary The influence of magnesium ions on the solubility and formation of calcium oxalate was studied. Both calcium oxalate mineral constituents of urinary calculi (whewellite and weddellite) were prepated in the presence of Mg²⁺-ions. For preparation, a gel growth technique and precipitation in aqueous solutions were used. The metastable weddellite formed only when Mg²⁺ concentration, reaction, temperature and precipitation velocity (see text) were combined in the proper way. It is concluded that Mg²⁺ions may induce an increase of solubility of calcium oxalate but in contrast also broaden the Ostwald-Miers range, thus favouring the formation of larger crystals.