Extended hildebrand solubility approach: satranidazole in mixtures of dioxane and water

The extended Hildebrand solubility parameter approach is used to estimate the solubility of satranidazole in binary solvent systems. The solubility of satranidazole in various dioxane-water mixtures was analyzed in terms of solute-solvent interactions using a modified version of Hildebrand-Scatchard treatment for regular solutions. The solubility of satranidazole in the binary solvent, dioxane-water shows a bell-shaped profile with a solubility maximum well above the ideal solubility of the drug. This is attributed to solvation of the drug with the dioxane-water mixture, and indicates that the solute-solvent interaction energy is larger than the geometric mean (δ(1)δ(2)) of regular solution theory. The new approach provides an accurate prediction of solubility once the interaction energy is obtained. In this case, the energy term is regressed against a polynomial in δ(1) of the binary mixture. A quartic expression of W in terms of solvent solubility parameter was found for predicting the solubility of satranidazole in dioxane-water mixtures. The method has potential usefulness in preformulation and formulation studies during which solubility prediction is important for drug design.     

Extended Hildebrand solubility approach: sulfonamides in binary and ternary solvents

The extended Hildebrand solubility approach is used to estimate the solubility of sulfonamides in binary and ternary solvent systems. The solubility of sulfisomidine in the binary solvent, dioxane-water, shows a bell-shaped profile with a solubility maximum well above the ideal solubility of the drug. This is attributed to solvation of the drug with the dioxane-water solvent, and indicates that the solute-solvent interaction energy (W) is larger than the geometric mean (delta 1 delta 2) of regular solution theory. The solubilities of sulfadiazine, sulfisomidine, sulfathiazole, and sulfamethoxazole were determined in mixtures of dimethylacetamide, glycerol, and water, and the solubility profiles were well reproduced by use of the extended Hildebrand solubility approach. Since the solubility parameter (delta 1 = 11) of the solvent (dimethylacetamide) was approximately equal to the solubility parameters of the sulfonamides, and because of the powerful solvating power of dimethylacetamide, the solubility profiles did not exhibit peaks as observed for sulfisomidine in dioxane-water. When sulfisomidine was dissolved in a ternary mixture, i.e., butyl acetate (delta 1 = 8.5), dimethylacetamide (delta 1 congruent to 11), and methanol (delta 1 = 14.5), a spike was produced in the solubility profile at the solubility parameter of dimethylacetamide. This sharply peaked profile suggests that the two branches be treated as separate solubility curves, which are then independently well reproduced by the extended Hildebrand solubility approach. None of the four sulfonamides yielded log-linear relationships in the ternary mixtures.     

Enthalpy-entropy compensation for the solubility of drugs in solvent mixtures: paracetamol, acetanilide, and nalidixic acid in dioxane-water

In earlier work, a nonlinear enthalpy-entropy compensation was observed for the solubility of phenacetin in dioxane-water mixtures. This effect had not been earlier reported for the solubility of drugs in solvent mixtures. To gain insight into the compensation effect, the behavior of the apparent thermodynamic magnitudes for the solubility of paracetamol, acetanilide, and nalidixic acid is studied in this work. The solubility of these drugs was measured at several temperatures in dioxane-water mixtures. DSC analysis was performed on the original powders and on the solid phases after equilibration with the solvent mixture. The thermal properties of the solid phases did not show significant changes. The three drugs display a solubility maximum against the cosolvent ratio. The solubility peaks of acetanilide and nalidixic acid shift to a more polar region at the higher temperatures. Nonlinear van't Hoff plots were observed for nalidixic acid whereas acetanilide and paracetamol show linear behavior at the temperature range studied. The apparent enthalpies of solution are endothermic going through a maximum at 50% dioxane. Two different mechanisms, entropy and enthalpy, are suggested to be the driving forces that increase the solubility of the three drugs. Solubility is entropy controlled at the water-rich region (0-50% dioxane) and enthalpy controlled at the dioxane-rich region (50-100% dioxane). The enthalpy-entropy compensation analysis also suggests that two different mechanisms, dependent on cosolvent ratio, are involved in the solubility enhancement of the three drugs. The plots of deltaH versus deltaG are nonlinear, and the slope changes from positive to negative above 50% dioxane. The compensation effect for the thermodynamic magnitudes of transfer from water to the aqueous mixtures can be described by a common empirical nonlinear relationship, with the exception of paracetamol, which follows a separate linear relationship at dioxane ratios above 50%. The results corroborate earlier findings with phenacetin. The similar pattern shown by the drugs studied suggests that the nonlinear enthalpy-entropy compensation effect may be characteristic of the solubility of semipolar drugs in dioxane-water mixtures.     

Determination and evaluation of solubility parameter of satranidazole using dioxane-water system

Satranidazole, a potent broad spectrum antiprotozoal, is a poorly water-soluble drug and has low bioavailability on oral administration. One of the important methods to improve the solubility and bioavailability of a less water-soluble drug is by the use of cosolvents. The solubility enhancement produced by binary blends with a cosolvent (dioxane) was studied against the solubility parameter of solvent blends (δ(1)) to evaluate the solubility parameter of drug (δ(2)). Solubility parameter of drug (δ(2)) was evaluated in blends of dioxane-water system. The results obtained were compared with the δ(2) values obtained using Molar Volume Method and Fedor's Group Substitution Method. The binary blend water-dioxane (10:90) gave maximum solubility with an experimental δ(2) value of 11.34 (Cal/cm(3))(0.5) that was comparable to the theoretical values of 11.34 (Cal/cm(3))(0.5) determined by Molar Volume Method and 11.3928 (Cal/cm(3))(0.5) when determined by Fedor's Group Substitution Method, which is in good agreement with solubility measurement method.     

A Modification of the Extended Hildebrand Approach to Predict the Solubility of Structurally Related Drugs in Solvent Mixtures

Abstract— A modification of the extended Hildebrand equation is proposed to estimate the solubility of an organic drug in solvent mixtures. The equation accurately reproduces the solubility of four sulphonamides in dioxane-water mixtures without requiring the heat of fusion of the solute. A single equation is obtained for predicting the solubility of related drugs using the solubilities of the drugs in the pure solvents, dioxane and water, and solute-solvent interaction terms consisting of the solubility parameter, δ₂, of the solute and the solubility parameter, δ₁, and basic partial solubility parameter, δ_1b, of the solvent mixture. By this procedure a single equation was obtained to estimate the solubilities of three xanthines in dioxane-water and another equation to obtain the solubilities of four sulphonamides. The equation obtained for sulphonamides is able to predict the experimental solubilities of two parent compounds, sulphasomidine and sulphathiazole, and the solubilities of a drug of different structure, p-hydroxybenzoic acid. This suggests that the intermolecular solute-solvent interaction of sulphonamides and p-hydroxybenzoic acid are similar. The results indicate that the solubility behaviour of drugs having different structures may be modelled using a common equation provided that they show similar solute-solvent interactions.     

Aqueous solubility study of salts of benzylamine derivatives and p-substituted benzoic acid derivatives using X-ray crystallographic analysis

Twenty two p-substituted benzoic acid derivates were used to prepare salts of N-methylbenzylamine (II) and N,N-dimethylbenzylamine (III), respectively. Only five salts of (II) and two salts of (III) were obtained in a crystalline state. The solubility of these salts was orders of magnitude higher than those reported for the corresponding salts of benzylamine (I). Thermal analysis indicated that the increased solubility was caused by reduced crystal lattice energy, which was most likely due to the reduced number of strong hydrogen bonds of the salt of (II) and (III). X-ray crystallographic analysis of p-hydroxybenzoic acid salt of (I), (II) and (III) suggested that the reduced number of hydrogen bonds caused the apparent higher solubility. Further analyses of seven salts of (I) were performed. It was not possible to identify any relationship between the number of hydrogen bonds and the corresponding solubility of the salts.     

Prediction of xanthine solubilities using statistical techniques

Mixture response-surface methodology can be used as a technique to predict solubility in mixed solvent systems. The present report shows that if the intent is to predict solubility in nonideal solutions, mixture response-surface methodology is a better technique than one which assumes a particular mechanism to hold true. This is demonstrated by comparing the predictive ability of the mixture response-surface model with that of an extended Hildebrand approach to nonideal solutions. The nonideal systems are those used by Martin and co-workers involving the solubility of theobromine, caffeine, and theophylline in dioxane-water mixtures.     

Oestrogenic activity of p-hydroxybenzoic acid (common metabolite of paraben esters) and methylparaben in human breast cancer cell lines

This paper addresses the question of whether p-hydroxybenzoic acid, the common metabolite of parabens, possesses oestrogenic activity in human breast cancer cell lines. The alkyl esters of p-hydroxybenzoic acid (parabens) are used widely as preservatives in consumer products to which the human population is exposed and have been shown previously to possess oestrogenic activity and to be present in human breast tumour tissue, which is an oestrogen-responsive tissue. Recent work has shown p-hydroxybenzoic acid to give an oestrogenic response in the rodent uterotrophic assay. We report here that p-hydroxybenzoic acid possesses oestrogenic activity in a panel of assays in human breast cancer cell lines. p-Hydroxybenzoic acid was able to displace [(3)H]oestradiol from cytosolic oestrogen receptor of MCF7 human breast cancer cells by 54% at 5 x 10(6)-fold molar excess and by 99% at 10(7)-fold molar excess. It was able to increase the expression of a stably integrated oestrogen responsive reporter gene (ERE-CAT) at a concentration of 5 x 10(-4) M in MCF7 cells after 24 h and 7 days, which could be inhibited by the anti-oestrogen ICI 182 780 (Faslodex, fulvestrant). Proliferation of two human breast cancer cell lines (MCF7, ZR-75-1) could be increased by 10(-5) M p-hydroxybenzoic acid. Following on from previous studies showing a decrease in oestrogenic activity of parabens with shortening of the linear alkyl chain length, this study has compared the oestrogenic activity of p-hydroxybenzoic acid where the alkyl grouping is no longer present with methylparaben, which has the shortest alkyl group. Intrinsic oestrogenic activity of p-hydroxybenzoic acid was similar to that of methylparaben in terms of relative binding to the oestrogen receptor but its oestrogenic activity on gene expression and cell proliferation was lower than that of methylparaben. It can be concluded that removal of the ester group from parabens does not abrogate its oestrogenic activity and that p-hydroxybenzoic acid can give oestrogenic responses in human breast cancer cells.     

三棱乙酸乙酯部位HPLC指纹图谱及4种酚类成分含量测定

目的：建立醋炙三棱乙酸乙酯部位HPLC指纹图谱,并同时测定对羟基苯甲酸、香兰素、对香豆酸和阿魏酸4种酚类物质含量,为三棱药材的质量控制提供借鉴。方法：富集醋炙三棱乙酸乙酯部位,采用高效液相色谱（HPLC）法,应用Inert Sustain C₁₈色谱柱（4.6 mm×250 mm,5 μm）,流动相甲醇-0.1%甲酸溶液进行梯度洗脱,检测波长254 nm,流速0.80 mL·min^-1,测定对羟基苯甲酸、香兰素、对香豆酸和阿魏酸4种酚类物质的含量。结果：建立了三棱乙酸乙酯部位的HPLC指纹图谱,检出共有峰16个,各批次药材的相似度均大于0.9;通过与对照品比对,确定了指纹图谱中5,8,9,10号峰分别为对羟基苯甲酸、香兰素、对香豆酸和阿魏酸,并对其进行定量分析,结果对羟基苯甲酸的线性范围为0.008~0.924 μg,平均回收率为98.5%,香兰素的线性范围为0.039~4.712 μg,平均回收率为101.1%,对香豆酸的线性范围为0.054~6.572 μg,平均回收率为100.3%,阿魏酸的线性范围为0.018~2.236 ng,平均回收率为101.0%。结论：HPLC指纹图谱方法与含量测定方法简便,结果准确,重复性好,可作为三棱的质量控制方法。     

Difference spectrophotometric determination of p-hydroxybenzoic acid in presence of its esters

A difference spectrophotometric analytical method was developed for the selective determination of p-hydroxybenzoic acid in the presence of its alkyl esters without prior separation. Based on the spectral shift to a shorter wavelength accompanyint carboxyl dissociation, the procedure measures as little as 2% of this acid in mixtures with the alkyl ester preservatives and has an accuracy of 2% mean relative error over the 0.16-12.0 microgram of p-hydroxybenzoic acid/ml range.     

Phase equilibria and thermodynamics of p-hydroxybenzoic acid

The prevalence of phases and associated solubilities of p-hydroxybenzoic acid have been investigated in methanol, acetonitrile, acetic acid, acetone, water, and ethyl acetate at temperatures from 10 to 50 degrees C. Thermodynamic data was acquired through determination of van't Hoff enthalpy of solution, enthalpy of fusion, and melting temperature. Indications of polymorphic enantiotropy were found primarily through solubility analysis and FTIR-ATR. A comprehensive thermodynamic investigation disclosed correlation between the van't Hoff enthalpy of solution and the solubility in different solvents. A higher solubility is linked to a lower van't Hoff enthalpy of solution. A thermodynamic analysis to discriminate between different solid phases is presented.     

The effect of vehicle on the diffusion of salicylic acid through hairless mouse skin

The solubilities of salicylic acid in, and the fluxes through, hairless mouse skin from isopropyl myristate, 1-octanol, 1-propanol, propylene glycol, and formamide have been determined experimentally. Values for permeability coefficients (Kp) corresponding to the respective fluxes were determined from: flux/solubility = Kp. These values were then compared with values for the respective partition coefficients (P) which were calculated from the known solubility parameters for the vehicles (delta v), salicylic acid (delta i), and skin (delta s). Two different delta i values were used to calculate theoretical P values, one based on the peak solubility method and the other based on calculation from group contributions (11 and 14.4 (cal/cm3)1/2, respectively). There was good correlation between the values for theoretical log P - 1.42 and experimental log Kp for the delivery of salicylic acid from vehicles exhibiting solubility parameters in the range of delta v = 10-18 (cal/cm3)1/2, when delta i was assumed to be 14.4 (cal/cm3)1/2. There was also a good correlation between the values for theoretical log P - 2.09 and experimental log Kp for vehicles exhibiting solubility parameters in the range of delta v = 7.6-10 (cal/cm3)1/2, when delta i was assumed to be 11 (cal/cm3)1/2. Two different delta i values were used because salicylic acid apparently behaves like a polar molecule in polar vehicles and a nonpolar molecule in nonpolar vehicles. Qualitatively, fluxes and permeability coefficients were found to be inversely dependent on drug solubility in the vehicles, with a minimum that corresponded approximately to the point where delta v = delta i, and the minimum within the theoretical P curve.(ABSTRACT TRUNCATED AT 250 WORDS)     

Proposition of group molar constants for sodium to calculate the partial solubility parameters of sodium salts using the van Krevelen group contribution method.

The aim of this study is to propose, for the first time, a set of group molar constants for sodium to calculate the partial solubility parameters of sodium salts. The values were estimated using the few experimental partial solubility parameters of acid/sodium salt series available either from the literature (benzoic acid/Na, ibuprofen acid/Na, diclofenac Na) or determined in this work (salicylic acid/Na, p-aminobenzoic acid/Na, diclofenac), the group contribution method of van Krevelen to calculate the partial parameters of the acids, and three reasonable hypothesis. The experimental method used is a modification of the extended Hansen approach based on a regression analysis of the solubility mole fraction of the drug lnX(2) against models including three- or four-partial solubility parameters of a series of pure solvents ranging from non-polar (heptane) to highly polar (water). The modified method combined with the four-parameter model provided the best results for both acids and sodium derivatives. The replacement of the acidic proton by sodium increased the dipolar and basic partial solubility parameters, whereas the dispersion parameter remained unaltered, thus increasing the overall total solubility parameter of the salt. The proposed group molar constants of sodium are consistent with the experimental results as sodium has a relatively low London dispersion molar constant (identical to that of -OH), a very high Keesom dipolar molar constant (identical to that of -NO(2), two times larger than that of -OH), and a very high hydrogen bonding molar constant (identical to that of -OH). The proposed values are: F((Na)d)=270 (J cm(3))(1/2) mol(-1); F((Na)p)=1030 (J cm(3))(1/2) mol(-1); U((Na)h)=17000 J mol(-1). Like the constants for the other groups, the group molar constants proposed for sodium are certainly not the exact values. However, they are believed to be a fair approximation of the impact of sodium on the partial solubility parameters and, therefore, can be used as such in the group contribution method of van Krevelen.     

HPLC法同时测定千里光中对羟基苯甲酸和邻羟基苯甲酸的总含量及对羟基苯乙酸的含量

建立同时测定千里光药材中对羟基苯甲酸和邻羟基苯甲酸总含量及对羟基苯乙酸含量的方法。方法：采用HPLC法,色谱柱：Shiseido（Fine Chemicals）Capcell Pak C18柱（250mmx4.6mm,5μm）;流动相：甲醇：水：甲酸（13：87：0．5）;流速：1.0ml·min^-1;检测波长：240nm;柱温为室温。结果：对羟基苯甲酸和邻羟基苯甲酸的总浓度在0．025～0．400mg·ml^-1范围内线性关系良好（r=0．9998）,平均加样回收率为97．59％,RSD=1．22％（n=6）;对羟基苯乙酸的浓度在0．05—0．80mg·ml6-1范围内线性关系良好（r：0．9998）,平均加样回收率为98．07％,RSD=1．90％（n=6）。结论：该方法操作简单。重现性好,适用于千里光中对羟基苯甲酸、邻羟基苯甲酸和对羟基苯乙酸的含量测定。     

Solubility behavior of polymorphs I and II of mefenamic acid in solvent mixtures

The dissolution profile and solubility of two polymorphic forms of mefenamic acid were studied in solvent mixtures of ethanol-water and ethyl acetate-ethanol. The solubility parameter (delta) was used to study the effect of polarity on the solubility behavior of the two polymorphs. Differential scanning calorimetry and infrared spectroscopy were performed on the original powders and on the solid phases after contact with the solvent systems for the characterization and identification of the polymorphs. The dissolution rates of both polymorphs is greater in the less polar mixtures (ethyl acetate-ethanol) of lower solubility parameter values. Form II showed larger dissolution rates and saturation concentrations than Form I in all the solvent systems studied. The solid phase of Form II converts totally to Form I after equilibration with the solvents. The rate of conversion was faster in the least polar mixtures. The solubility of both polymorphs reaches a single maximum at 80% ethyl acetate in ethanol, delta = 20.09 MPa1/2. The modified extended Hildebrand method was used to predict the solubility profile of each polymorph. A single equation was obtained for both polymorphs which includes the solubility parameter of the mixtures and the logarithm of the solubility mole fraction of each polymorph in water. The Hildebrand solubility parameter of mefenamic acid is independent of the crystalline form and was determined from two methods giving quite similar values, delta 2 = 20-21 MPa1/2.     

甘草酸对紫杉醇增溶作用考察

目的：考察甘草酸对紫杉醇溶解度的增溶作用。方法：将不同比例甘草酸和紫杉醇,不同比例乙醇和紫杉醇进行配伍,采用高效液相色谱法检测紫杉醇的浓度;并采用电导率法检测甘草酸-紫杉醇溶液的临界胶束浓度。结果：在乙醇比例为7.5%且甘草酸浓度为10 mmol·L^-1时,紫杉醇达到最佳溶解度（823.38±14.41）μg·mL^-1,较紫杉醇水中溶解度增加约1 000倍（0.67→823 μg·mL^-1）,较紫杉醇在7.5%乙醇液中溶解度增加约100倍（8.51→823 μg·mL^-1）。紫杉醇-甘草酸溶液（含7.5%乙醇）的临界胶束浓度为0.42 mmol·L^-1,证明其在更低浓度下能形成胶束状态。结论：首次发现在甘草酸和低体积分数乙醇的协同作用下,紫杉醇水中溶解度得到有效增加,鉴于甘草酸的两亲性,安全性和一些特殊的药理活性,为制备基于甘草酸为载体的新型紫杉醇制剂奠定基础。     

Antisickling activity of hydroxybenzoic acids in Cajanus cajan.

The amounts of phenylalanine and hydroxybenzoic acid in a Cajanus cajan methanolic extract were estimated. Results showed that the amount of phenylalanine and hydroxybenzoic acid per gram weight of bean was 4.92 mg +/- 0.13 mg and 21.0 mg +/- 3.0 micrograms, respectively. Sickling inhibition was observed to be efficient with the extract which contains a mixture of phenylalanine (0.69 mg/ml) and p-hydroxybenzoic acid (10.5 micrograms/ml), equivalent to those found in bean extract. The additive antisickling effect of both compounds can be therapeutically exploited for the treatment of sickle cell anemia.     

三维HPLC法同步测定犬血浆中的葛根素及阿魏酸

以对 羟基苯甲酸为内标 ,甲醇 水 醋酸 (5 6 2 5mol/L ) (39∶5 8∶3 ,v/v)为流动相 ,InertsilODS 3色谱柱 (15 0mm× 4 6mm ,5 μm)为固定相 ,流速 0 9mL/min。以二极管阵列检测器同时获取 2 48nm和 32 1nm两个波长下的数据 ,并通过三维图观察其紫外吸收定性 ,以沸水浴法处理血浆样品。结果 :葛根素和内标及阿魏酸分离完全 ,葛根素在 0 2 35 4～ 1 883μmol/L范围内线性关系良好 (r =0 9943) ,变异系数 <10 % ,平均回收率为 10 1 0 2 % ,最低检测限为 0 33ng ,最低检测浓度为 0 0 396 μmol/L;阿魏酸则在 1 0 341～ 5 35 6 μmol/L范围内线性关系良好 (r =0 9942 ) ,变异系数 <10 % ,平均回收率为 10 0 88% ,最低检测限为 0 45ng ,最低检测浓度为1 115 9μmol/L。此法可用于不同波长下同步以内标法测定血浆中两种或多种成分     

Antioxidant and DNA damage protection potentials of selected phenolic acids

In this study, ten different phenolic acids (caffeic, chlorogenic, cinnamic, ferulic, gallic, p-hydroxybenzoic, protocatechuic, rosmarinic, syringic, and vanillic acids) were evaluated for their antioxidant and DNA damage protection potentials. Antioxidant activity was evaluated by using four different test systems named as β-carotene bleaching, DPPH free radical scavenging, reducing power and chelating effect. In all test systems, rosmarinic acid showed the maximum activity potential, while protocatechuic acid was determined as the weakest antioxidant in β-carotene bleaching, DPPH free radical scavenging, and chelating effect assays. Phenolic acids were also screened for their protective effects on pBR322 plasmid DNA against the mutagenic and toxic effects of UV and H₂O₂. Ferulic acid was found as the most active phytochemical among the others. Even at the lowest concentration value (0.002 mg/ml), ferulic acid protected all of the bands in the presence of H₂O₂ and UV. It is followed by caffeic, rosmarinic, and vanillic acids. On the other hand, cinnamic acid (at 0.002 mg/ml), gallic acid (at 0.002 mg/ml), p-hydroxybenzoic acid (at 0.002 and 0.004 mg/ml), and protocatechuic acid (at 0.002 and 0.004 mg/ml) could not protect plasmid DNA.     

Investigation of solubility properties of nifluminic acid containing cyclodextrins and polyvidone

One of the most important task of the pharmaceutical technology is to reach a possible high gastrointestinal absorbtion of the active ingredient. Therefore, it is necessary to have a good solubility in the gastric/intestinal medium. In this way the applied drug quantity and unwanted side effects can be reduced with solubility increasing. The water-insoluble drug's solubility and bioavailability can be increased by the alteration of their physicochemical properties. Nifluminic acid is a frequently used anti-inflammatory drug with low aqueous solubility. Inclusion complexation with cyclodextrins is an efficacious method to improve the solubility, stability and bioavailability. Ternary systems were prepared and investigated to use nifluminic acid, hydoxypropyl-beta-cyclodextrin and polyvidone. The aims of the study were to investigate the solubility rate, the in vitro diffusion ability, to determine the n-octanol/water partition coefficient, and to study the thermoanalitycal properties of products. The results suggested that complexation with cyclodextrin and the use of polyvidone is better method than to prepare binary systems. Inclusion complexation was presumed in the event of the ternary composition to improve the bioavailability of nifluminic acid.