Predicting the solubility of sulfamethoxypyridazine in individual solvents. I: Calculating partial solubility parameters

Sulfamethoxypyridazine, a representative model of a drug molecule, is used to test the extended Hansen method for estimating partial solubility parameters of solid compounds. Solubilities are determined in polar and nonpolar solvents. The method provides reasonable partial parameters for the sulfonamide, and it may be useful in obtaining partial parameters for other drug molecules. A four-parameter extended Hansen approach involving proton donor and acceptor parameters is used in fitting the data to a theoretical model. A term, Wh, is introduced as an empirical measure of solute-solvent interactions due to hydrogen bonding. The use of the empirical term Wh allows the researcher to fit experimental solubilities and thus design regression models and equations which provide a reasonable prediction of solubilities of a polar drug in a number of very different solvents. A Flory-Huggins size correction term improves the prediction of sulfamethoxypyridazine solubilities in these irregular solutions.     

Solubility behaviour of haloperidol in individual solvents determination of partial solubility parameters.

The solubility behaviour of haloperidol in individual solvents ranging from non-polar to highly polar solvents was studied. Extended Hansen's method was used to analyze the solubility data and obtain partial solubility parameters of haloperidol. Flory-Huggin's size connection term 'B' was found to further improve the prediction of solubility. A four parameter extended Hansen's approach involving proton-donor and proton-acceptor parameters was also used in fitting the solubility data to a theoretical model. The term Wh, used as an empirical measure of solute-solvent interaction due to hydrogen bonding was used in calculating B. Different approaches were thus used in fitting the experimental solubility data to obtain regression equations which aim to provide a reasonable prediction of solubility of haloperidol in untested solvents. Solubility parameter was calculated from the partial solubility parameter values obtained from the different methods of data analysis, and compared with the theoretically obtained values. Solubility parameter of haloperidol is fixed at 10.58 H.     

Determination of partial solubility parameters of five benzodiazepines in individual solvents

Three and four component partial solubility parameters for diazepam, lorazepam, oxazepam, prazepam and temazepam were determined using the extended and expanded Hansen regression models. A comparison was made also with solubility parameters calculated by the group contribution method proposed by Van Krevelen. Although a limited number of solvents was used, the results from the present study indicate that the partial solubility parameters obtained from the experimental regression models clearly reflect the structural differences in these five structurally related molecules. High R(2)-values were observed in the regression models (0.932 < or =R(2)< or =0.984), except for lorazepam (0.606 < or =R(2)< or =0.825). This was attributed to difficulties in obtaining reliable values of the temperature and heat of fusion due to thermal decomposition of this compound. Introduction of the Flory-Huggins size correction parameter did not improve the R(2)- and F-values in any of the regression models used.     

Relationship between swelling of hydroxypropylmethylcellulose and the Hansen and Karger partial solubility parameters

A model that relates the equilibrium swelling of hydroxypropylmethylcellulose to the partial solubility parameters of both the polymer and the solvents is proposed to interpret and correlate the experimental data. The non-specific interactions are expressed as the dispersion delta(d) and polar delta(p) solubility parameters of Hansen, or as a combination of both. Hydrogen bonding is represented by the acidic delta(a) and the basic delta(b) Karger solubility parameters. The results are compared with models including the same parameters for non-specific interactions (delta(d) and delta(p)) and the Hansen hydrogen bonding parameter delta(h). Equilibrium swelling of this hydrophilic polymer that is widely used in drug formulation is measured in pure solvents covering a wide polarity range. In a qualitative way, swelling increases in solvents with higher Hildebrand solubility parameters and stronger hydrogen bonding capability, and it decreases in non-polar solvents. Single polarity indexes, such as the Hildebrand solubility parameter or the partition coefficient (PC), do not fit well the overall experimental data. The best correlations were obtained with the proposed model, providing at the same time an interpretation consistent with the physical meaning of the terms included in the equation. Swelling increases as the non-specific interactions of the polymer and the solvents become alike, and as the Lewis acid-base interactions of the polymer (1) and the solvent (2) represented by the products delta(1a)delta(2b) and delta(1b)delta(2a) become greater. Conversely, hydrogen bonding self association of the solvents (the product delta(1a)delta(1b)) lowers swelling. The results show that the Karger hydrogen bonding parameters provide a better approach than the Hansen hydrogen bonding parameter to correlate the swelling behavior of a hydrophilic polymer.     

Thermochemical investigations of associated solutions: 5. Calculation of solute-solvent equilibrium constants from solubility in mixtures containing two complexing solvents

Solubilities are reported for carbazole in binary dibutyl ether plus 1-chlorohexane mixtures at 25 degrees C. Results of these measurements are compared with solution models developed for solubility in systems containing specific solute-solvent interactions. A simple stoichiometric complexation model based on a 1:1 carbazole:dibutyl ether complex could describe the measured solubility to within an average absolute deviation of 1.7%. The calculated equilibrium constant, though, was about one-half of values previously determined from carbazole solubilities in several binary dibutyl ether plus alkane mixtures. A more sophisticated solution model, derived by assuming both 1:1 carbazole: dibutyl ether and carbazole:chlorohexane complexes, could describe the solubilities to within 2.4%. This latter model enables the carbazole-chlorohexane association constant to be calculated from experimental carbazole solubilities and a priori knowledge of the carbazole-dibutyl ether equilibrium constant.     

Molecular connectivity. II: Relationship to water solubility and boiling point.

The connectivity index, easily computed by arithmetic and based upon the degree of connectedness at each vertex in the molecular skeleton, is shown to give highly significant correlations with water solubility of branched, cyclic, and straight-chain alcohols and hydrocarbons as well as with boiling points of alcohols. These correlations are superior to those based on well-founded theory relating to solvent cavity surface area. An empirical modification to the connectivity index gave an improved correlation for both solubilities and boiling points.     

A new method to determine the partial solubility parameters of polymers from intrinsic viscosity.

A modification of the extended Hansen method, formerly used to determine the partial solubility parameters of drugs and non-polymeric excipients is tested with a polymer for the first time. The proposed method relates the logarithm of the intrinsic viscosities of the polymer in a series of solvents and solvent mixtures with the Hansen (three parameter model) and Karger (four parameter model) partial solubility parameters. The viscosity of diluted solutions of hydroxypropyl methylcellulose (HPMC) was determined in pure solvents and binary mixtures of varying polarity. The intrinsic viscosity was obtained from the common intercept of the Huggins and Kraemer relationships. The intrinsic viscosity tends to increase with increasing the solubility parameter of the medium. The results show that hydrogen bonding and polarity of the polymer largely determine polymer-solvent interactions. The models proposed provided reasonable partial and total solubility parameters for the polymer and enable one to quantitatively characterize, for the first time, the Lewis acid-base ability of a polymer thus, providing a more realistic picture of hydrogen bonding for solvent selection/compatibility and to predict drug-polymer interactions. Combination of the dispersion and polar parameters into a single non-specific solubility parameter was also tested. The results extend earlier findings and suggest that the models are quite versatile and may be applied to drugs, non-polymeric and polymeric excipients.     

灰黄霉素提取溶媒的研究

测定了灰黄霉素纯品或干菌体中的灰黄霉素在单一溶媒和混合溶媒中的溶解度。其在极性溶剂和卤代烃中的溶解度较大。极性溶剂对干菌体中的灰黄霉素的溶解度也大，但选择性较差，加入一些非极性溶剂时可提高其选择性。     

HPLC and solubility study of the interaction between pindolol and cyclodextrins

The complexation with beta-cyclodextrin (beta-CD) has been investigated using reversed-phase liquid chromatography. The compounds tested have been pindolol and, for comparison purposes, indole and 4-methoxyindole. The retention behaviour has been analysed on a Kromasil 100 C18 column and the mobile phase used was methanol-pH 6 phosphate buffer (15/85v/v) in which beta-CD was incorporated as a mobile phase additive. The decrease in the retention times with increasing concentrations of beta-CD enables the determination of the apparent stability constants of the complexes. In addition, the low solubility of pindolol, a weak base, in pH 12 aqueous solution has been improved by complexation with different cyclodextrins. The solubility enhancements with 1.4 x 10(-2) M beta-, hydroxypropyl-beta, and gamma-CD have been 1.9, 1.8 and 1.4-fold, respectively, with 2.4 x 10(-2) M methyl-beta-CD it was 2.8-fold whilst no effect was observed with alpha-CD. The stability constants of the complexes at pH 12 have been determined from the solubility isotherms.     

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.     

药物临界相对湿度与溶解度的关系

目的 探索药物临界相对湿度与溶解度之间的关系.方法 以24种药物及化合物为模型,采用平衡空气法测定临界相对湿度,参照药典方法、重量法或查文献得溶解度结果当溶解度以正负离子总质量摩尔浓度表达时,药物临界相对湿度与溶解度呈线性负相关.结论 药物临界相对湿度与溶解度存在线性关系,可相互估算.     

Relationship between solubility and hemolytic effects of toxic dusts

Two varieties of native and chemically treated slate dust were tested in vitro for their hemolytic effects and the extent of silicic acid dissolution in various physiological fluids. The extent of hemolysis was found to be proportional to the degree of dissolution of dust constituents. Membrane lysis by the dust appeared to be prevented by coating it with polyvinyl pyrrolidone, serum proteins and pulmonary lavage lipids. The significance of the findings is discussed.     

Molecular interaction between riboflavin and salicylic acid derivatives in nonpolar solvents

The interaction of riboflavin-2',3',4',5'-tetrabutyrate (I) with salicylic acid (II), aspirin (acetylsalicylic acid, III), and salicylamide (IV) has been spectroscopically investigated to determine the binding mechanism. NMR and absorption spectra were measured in nonpolar solvents. The association constant K of the formation of complex was calculated from the absorption spectra. Compounds I and II form a 1:1 cyclic hydrogen-bonded dimer through the N-3 proton and the C-2 carbonyl oxygen of the isoalloxazine ring, and the carboxylic hydroxyl proton and carbonyl oxygen of II. Compounds I and III form a 1:1 cyclic hydrogen-bonded dimer by the same mode. Compound IV forms a 1:1 cyclic hydrogen-bonded dimer with I through the N-3 proton and the C-2 carbonyl oxygen of the isoalloxazine ring, and the amino proton and the carbonyl oxygen of IV. Salicylates produce marked changes in the absorption spectra of I. These spectral changes are attributed to the formation of the hydrogen-bonded dimer. It appeared that the strongest complex was formed with salicylic acid, a weaker one with aspirin, and an even weaker one with salicylamide.     

Theoretical derivation of solute-solvent interaction parameter in binary solution: case of the deviation from Raoult's law

In a binary mixture, partial vapor pressure may show either a positive or negative deviation from the predicted value of an ideal solution. In this report we derive the deviation from Raoult's law from the heat of mixing, delta H mix, and the molal volume, V, of each of the components of a binary solution. This derivation is then tested for seven sets of combinations of two different solvents, taken at random from the literature. Each set consists of several different ratios of solute-solvent. The correlation between the reported experimental values of the partial vapor pressure of a given component, P1, and the theoretically derived values is excellent. The same derivation is further applied to calculate the solute-solvent interaction parameter, beta 12, independently from the geometric mean assumption of regular solution theory. In a number of cases, especially in hydrocarbon-alcohol mixtures, beta 12 proves to be significantly different from the calculated geometric mean square root beta 11 beta 22 or from the Walker interaction parameter term, K.     

Relationship between haemoglobin and the other clinical and laboratory parameters in rheumatoid arthritis.

A retrospective study is reported of 160 patients with definite or classical rheumatoid arthritis, in which changes in haemoglobin concentration were analysed against changes in various routine clinical and laboratory indices of disease activity over a period of time. Although statistically significant correlations were found between haemoglobin concentrations and the articular index of joint tenderness, serum albumin concentration, and erythrocyte sedimentation rate at one point in time, significant relationships in changes in haemoglobin concentration were only found with changes in the latter two laboratory indices. The significant correlations were weak and less important than the cumulative effect of unknown variables in determining haemoglobin level. The study shows that the routine clinical and laboratory parameters of disease activity in rheumatoid arthritis are of no value in predicting the haemoglobin concentration.     

Characterization of protein and peptide stability and solubility in non-aqueous solvents

Small molecule parenterals have often been formulated as solutions or suspensions in non-aqueous conditions, however, this technology has not found widespread use in the formulation of macromolecules. Formulation of proteins and peptides has primarily been achieved through aqueous solutions or reconstituted lyophilized cakes. The incorporation of non-aqueous techniques has been limited by the lack of general applicability. For example, prediction of solubility, chemical stability, conformational stability (unfolding/denaturation processes), and activity can be difficult. Therefore, macromolecule non-aqueous preformulation work must be performed on a case by case basis. In addition, only a few solvents are pharmaceutically acceptable. This article reviews the characterization of proteins and peptides in a variety of non-aqueous or co-solvent conditions (both acceptable and unacceptable for pharmaceutical applications), and discusses the applicability of non-aqueous conditions for increasing solubility, stability and activity.