关于单结合胆红素水溶性的研究

目的:进一步研究单结合胆红素(MCB)的水难溶特性及其在病理性胆汁中参与胆红素沉淀和色素性结石形成的作用机制.方法:应用胆红素高效液相色谱分析技术,先从人胆汁中获得结合胆红素,再经分离、制备及纯化得到纯MCB.然后观察其水溶解度并与其它型胆红素比较.结果:在pH7.9,温度37℃接近生理的条件下,MCB的溶解度(558.25±5.96μm)仅为双结合胆红素(DCB)的1/7,比不结合胆红素(UCB)高约44倍并随pH值改变而呈曲线变化.pH7.9时最大;pH4.5时为0;而当pH>9时,反而低于呈离于状态的UCB.结论:MCB虽作为结合型胆红素在胆道生理条件下的不溶性明显高于UCB,但比DCB要低得多;而在胆道病理条件下,其水溶性不但远低于DCB,甚至还不如离子化的UCB,这可能是MCB参与胆红素沉淀及胆色素结石形成的理化基础.     

Interpretation of gas-blood ratio inP O 2polarography

Summary The differences inP _{O 2}readings between gas and blood were studied with a Clark-type electrode in the range of 38.5 to 713 mm HgP _{O 2}.The tonometered blood samples were taken in two different ways. The results showed that the gas-blood ratior _b(equilibrating gasP _{O 2}reading/equilibrated bloodP _{O 2}reading) depended not only on the sampling method but also on theP _{O 2}range: it varied from 1.005 to 1.032 for aP _{O 2}of 96.5 mm Hg, and from 1.040 to 1.081 for aP _{O 2}of 713 mm Hg according to the sampling procedure.A theoretical analysis demonstrated that the variation ofr _bwith the bloodP _{O 2}can be attributed to the influence of the degree of oxygen saturation of the hemoglobin on theP _{O 2}gradient existing in the blood diffusion boundary layer adhering to the electrode membrane.This work was supported by grants from the High Authority of the European Coal and Steel Community and from the Fonds de la Recherche Scientifique Médicale, Belgium.     

Metastable Equilibrium Solubility Behavior of Bone Mineral

Previous studies have shown that carbonated apatites with a range of carbonate contents and crystallinities exhibit the phenomenon of metastable equilibrium solubility (MES) distributions. The purpose of the present study was to investigate the solubility behavior of bone mineral using the concepts of MES and MES distributions and, together with crystallinity and chemical composition data, examine the similarity of bone mineral to carbonated apatite (CAP). Bone samples were harvested from 1-, 5-, and 8-month-old rats. The organic components of the bone samples were removed by hydrazine deproteination. Carbonated apatite was synthesized by the hydrolysis of dicalcium phosphate dihydrate (DCPD) in a NaHCO₃-containing media at 50°C. The MES distributions of bone mineral and CAP were determined by equilibrating predetermined amounts of CAP or bone mineral in a series of 0.1 M acetate buffers containing calculated levels of calcium and phosphate and maintained at essentially constant pHs of 5.0, 5.3, 5.7, and 6.5. From the compositions of the equilibrating buffer solutions, ion activity products based upon the stoichiometries of octacalcium phosphate, hydroxyapatite, and carbonated apatite were calculated in an attempt to determine the function governing the dissolution of CAP and bone mineral. The results of this study demonstrated that the MES distribution phenomenon appeared to hold for bone mineral and that the changes in crystallinity of bone mineral with age correlated well with changes in the MES values. A CAP sample was prepared that was found to be an excellent synthetic prototype closely mimicking the physicochemical behavior of bone mineral from an 8-month-old rat. Another finding of this study was that the ion activity product function based upon the hydroxyapatite stoichiometry well described the MES results obtained with both CAP and bone mineral. The interpretation that a surface complex with hydroxyapatite stoichiometry governs the solubility behavior of bone mineral is, therefore, consistent with the experimental data. Other calcium phosphate stoichiometries for the surface complex showed systematic variations in the MES profiles when the pH of the equilibrating solution was varied. Received: 30 October 1997 / Accepted: 1 October 1998     

Bioreversible quaternary N-acyloxymethyl derivatives of the tertiary amines bupivacaine and lidocaine—synthesis, aqueous solubility and stability in buffer, human plasma and simulated intestinal fluid

Design of water-soluble prodrugs may constitute a means to improve the oral bioavailability of drugs suffering from dissolution rate-limited absorption. The model drug bupivacaine containing a tertiary amine function has been converted into bioreversible quaternary N-acyloxymethyl derivatives. The pH-independent solubility of the N-butanoyloxymethyl derivate exceeded 1000 mg ml⁻¹ corresponding approximately to a 10,000-fold increase in water solubility compared to that of bupivacaine base. The kinetics of hydrolysis of the prodrugs was studied in the pH range 0.1–9.8 (37 °C). Decomposition was found to follow first-order kinetics and U-shaped pH-rate profiles were constructed. The observed differences between the hydrolytic lability of the derivatives might most likely be ascribed to steric effects. In most cases, the prodrugs were quantitatively converted into bupivacaine. However, for the hydrolysis of the N-butanoyloxymethyl derivative at neutral to slightly alkaline pH parallel formation of bupivacaine (80%) and an unknown compound X (20%) was observed. LC–MS analysis of the latter compound suggests that an aromatic imide structure has been formed from an intramolecular acyl transfer reaction involving a nucleophilic attack of the amide nitrogen atom on the ester carbonyl carbon atom. Whereas the derivatives were poor substrates for plasma enzymes; they were hydrolyzed rapidly to parent bupivacaine in the presence of pancreatic enzymes (simulated intestinal fluid) at 37 °C. The data indicate that such prodrugs possess sufficient stability in the acidic environment of the stomach to reach the small intestine in intact form where they can be cleaved efficiently by action of pancreatic enzymes prior to drug absorption. Thus, the N-acyloxymethyl approach might be of potential utility to enhance oral bioavailability of tertiary amines exhibiting pK_a values below approximately 6 and intrinsic solubilities in the low μM range.     

The fitting of scheffé-type models for estimating solubilities of multisolvent systems

In pharmaceutical studies it is often necessary to dissolve a slightly polar drug in a mixture of water and one or more cosolvents, such as ethanol, glycerol, and propylene glycol, to increase the drug's solubility. It is also of interest to knowwhether a maximum in the solubility profile of the drug exists in the mixture of solvents and if so, where.

Scheffé-type models are particular forms of polynomial equations that can be used with variables that are expressed as proportions of the total mixture. These models are simple in form, yet are extremely versatile in terms of modeling the linear and nonlinear blending properties of the constituents in the mixtures. Several data sets are presented to illustratethe fitting of the Scheffé-type models for modeling the solubility of multisolvent systems.     

Mechanical and physical properties of silorane and methacrylate-based composites

ObjectivesThis study measured the degree of conversion (DC), sorption, solubility and microhardness of methacrylate (Filtek Z250 and Filtek Z350XT) and silorane-based composites (Filtek P90).MethodsDC was measured using near infrared spectroscopy immediately and 24 h after the photoactivation. Sorption and solubility measurements were performed after 24 h, 4 weeks and 12 weeks of storage in water. Knoop microhardness was measured after 24 h and after thermal cycling. The data were statistically analyzed using ANOVA followed by Tukey's, Tamhane or paired t-tests (α = 0.05).ResultsThe DC for P90 (37.22 ± 1.46) was significantly lower than the Z250 (71.44 ± 1.66) and Z350 (71.76 ± 2.84). Water sorption was highest in the Z250 and lowest in the P90. All the tested composites exhibited similar values after 24 h of immersion, and no significant differences were observed. No significant differences were observed between the solubilities of the P90 composite (12 weeks) and the Z250 or Z350 composites (4 weeks). KHN values were less elevated for the P90 composite and similar for the Z250 and Z350 composites. An effect of thermal cycling on KHN values was observed for all the composites (p < 0.001).ConclusionsSilorane produced the lowest DC and KHN values and exhibited lower water sorption and solubility compared to methacrylate-based composites. These differences suggest that silorane composites exhibit better hydrolytic stability after 3 months of water immersion compared to conventional methacrylate-based composites.Clinical significanceSilorane had higher hydrolytic stability after 3 months of water immersion than the methacrylate-based resins, despite the lower values of DC and KHN recorded.     

Aqueous solubility: Simple predictive methods (in silico,in vitro and bio-relevant approaches)

Aqueous solubility is a key physicochemical attribute required for the characterisation of an active pharmaceutical ingredient (API) during drug discovery and beyond. Furthermore, aqueous solubility is highly important for formulation selection and subsequent development processes. This review provides a summary of simple predictive methods used to assess aqueous solubility as well as an assessment of the more complex in silico methodologies and a review of the recent solubility challenge. In addition, a summary of experimental methods to determine solubility is included, with a discussion of some potential pitfalls.     

Solubility Properties of Racemic Praziquantel and Its Enantiomers

ABSTRACT

The purpose of this study was to characterize the solubility and thermodynamic properties of the optical isomers of the anti-schistosomal drug, praziquantel (PZQ) and to compare these properties to those of the racemic product used in commercial preparations (Biltricide®, generic drugs), The crystalline enantiomers of PZQ exhibited different thermal properties than the racemic drug. The melting points and the enthalpies of fusion obtained from the differential scanning calorimetry (DSC) scans were nearly identical between the isomers and were substantially lower than those of racemic PZQ [(±)-PZQ]. The DSC results indicate that (±)-PZQ is a racemic compound and not a racemic mixture. This was confirmed by powder x-ray diffraction analysis and the IR spectra. The 30° decrease in the melting point was reflected in increased solubility of the enantiomers, which amounted to twice that of the racemic PZQ. The behavior of the isomers in the presence of β-cyclodextrin (β-CD) was studied in water at 37°C. The solubility data (phase solubility diagrams) were linear for up to the highest concentration of added β-CD investigated. The apparent stability constants determined from the phase solubility diagrams showed that both the (+) and (-) enantiomers as well as (&[±)-PZQ exhibited moderate affinity to form a 1:1 complex in solution with β-CD. The findings of this study may be of importance when efforts are considered to improve pharmaceutical formulation of this anti-schistosomal drug.     

Nobiletin and its derivatives overcome multidrug resistance (MDR) in cancer: total synthesis and discovery of potent MDR reversal agents

Our recent studies demonstrated that the natural product nobiletin (NOB) served as a promising multidrug resistance (MDR) reversal agent and improved the effectiveness of cancer chemotherapy in vitro. However, low aqueous solubility and difficulty in total synthesis limited its application as a therapeutic agent. To tackle these challenges, NOB was synthesized in a high yield by a concise route of six steps and fourteen derivatives were synthesized with remarkable solubility and efficacy. All the compounds showed improved sensitivity to paclitaxel (PTX) in P-glycoprotein (P-gp) overexpressing MDR cancer cells. Among them, compound 29d exhibited water solubility 280-fold higher than NOB. A drug-resistance A549/T xenograft model showed that 29d, at a dose of 50 mg/kg co-administered with PTX (15 mg/kg), inhibited tumor growth more effective than NOB and remarkably increased PTX concentration in the tumors via P-gp inhibition. Moreover, Western blot experiments revealed that 29d inhibited expression of NRF2, phosphorylated ERK and AKT in MDR cancer cells, thus implying 29d of multiple mechanisms to reverse MDR in lung cancer.     

About consistency of Solid's solubility data in supercritical CO2 and some thermodynamic properties estimation

In chemical industry, usual solvents are being replaced by supercritical fluids. Last few years, extraction by these environmentally benign solvents has had much attention and now is considered as the newest separation technology. However, developing new applications and improving existing ones is based on a set of thermodynamic and physical properties of pure solutes related to phase equilibrium for which experimental values cannot be found and consequently, there is an increase need for accurate estimates of these properties. This paper is interested firstly to a thermodynamic property which is the Krichevskii parameter and secondly to a thermophysical one which is the sublimation pressure. First parameter is considered as a governor of thermodynamic properties in binary dilute mixtures near the solvent's critical point and can be calculated from some rigorous relationships and in this paper a review and a new way for its estimation are presented based on consistency of solid's solubility data in supercritical fluids and dilute solution theory. Second parameter is considered as the predominant influencer on solubility in supercritical fluids and unavailability of its experimental values presents an obstacle to thermodynamic modeling of solubility data. For this reason and as a second step, in this paper we present a new manner for its estimation. Obtained results are relevant, very promising for each considered property and the methodology can be applied for other solutes with more complex structures as Pharmaceuticals (antibiotics, drugs, anti-inflammatories …), polycyclic aromatic hydrocarbons (PAHC) and dyestuffs.