Predicting the solubility of sulfamethoxypyridazine in individual solvents. II: Relationship between solute-solvent interaction terms and partial solubility parameters

In the first paper in the series, an expanded system of parameters was devised to account for orientation and induction effects, and the term Wh was introduced to replace delta 1h delta 2h of the extended Hansen solubility approach. In the present report, a new term, Kh = Wh/delta 1h delta 2h is observed to take on values larger or smaller than unity depending on whether the hydrogen bonded solute-solvent interaction is larger or smaller than predicted by the term delta 1h delta 2h. The acidic delta a and basic delta b solubility parameters are used to represent two parameters, sigma and tau, suggested by Small in his study of proton donor-acceptor properties. The Small equation, including a heat of mixing term for hydrogen bonded species, is shown to be capable of semiquantitative evaluation. A partial molar heat delta H2h of hydrogen bonding is calculated using delta h and Wh terms; delta H2h is found to be correlated with the logarithm of the residual activity coefficient, In alpha R, a term representing strong solute-solvent interaction. The terms Wh, delta H2h, and In alpha 2R may be used to test the deviation from the geometric mean assumed in regular solution theory, and to replace the hydrogen bonding terms of the extended Hansen three-parameter model. The solubility of sulfamethoxypyridazine in 30 solvents is used to test the semiempirical solubility equations. The results are interpreted in terms of partial solubility parameters and the proton donor-acceptor properties of the solvents.     

Application of Hansen solubility parameters for understanding and prediction of drug distribution in microspheres

In an emulsion solvent extraction/evaporation process for the preparation of microspheres the employed solvents have a tremendous influence on the characteristics of the resulting particles. Nevertheless the solvent selection is often based on empirical data rather than on calculated values. The purpose of this investigation was to use the concept of solubility parameters for interpretation and improved understanding of solvent effects in the process of microparticle preparation. Partial solubility parameters of 3-{2-[4-(6-Fluor-1,2-benzisoxazol-3-yl)piperidino]ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-on, which was used as a model drug, were determined experimentally using an extended Hansen regression model. Poly(lactide-co-glycolide) microparticles were prepared with an emulsion solvent removal process employing methylene chloride and its mixtures with benzyl alcohol and n-butanol. It could be shown, that the encapsulation efficiency was influenced by the change of the solvent composition during the extraction process. Furthermore the solvent selection had an essential influence on the morphological state of the drug and it could be shown and explained, that by a decrease of the dissolving power a completely amorphous product was obtained.     

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.     

Determination of partial solubility parameters of lactose by gas-solid chromatography

On the basis of the Snyder/Karger-Hansen interaction model, where delta EA = Vi(delta di delta dj + delta pi delta pi + delta hi delta nj), the partial solubility parameters of a solid used as the stationary phase may be determined through gas-solid chromatography by null-injection of solutes with known solubility parameters. Using n-decane, acetonitrile, and 1-propanol as molecular probes, the values found for unhydrated lactose were 9.6, 12.8, 11.3, and 19.5 (cal1/2/cm3/2) for delta d, delta p, delta h, and delta t, respectively; relative standard errors were better than 3%. The choice and the minimum number of the best molecular probes were determined by optimization of the experimental matrix according to the D-criterion, which permits considerable reduction of experimental time yet enhances total precision.     

Interactions between liposomes and hydroxypropylmethylcellulose

The characteristics of the adsorption process of hydroxypropylmethylcellulose (HPMC) of molecular weight 35400 Da and nominal viscosity 100 cps onto liposomes prepared with different egg lecithin-cholesterol molar ratios were examined. Adsorption isotherms were constructed and analysed to investigate the mechanisms implicated in the incorporation of the polymer to the interface. Only the isotherms obtained with cholesterol-free liposomes were fitted with Langmuir model. When cholesterol is present in the composition they present a sigmoidal slope. The mechanism of adsorption depends on liposome composition being the main force that drives polymer adsorption of hydrophobic nature. The apparent volumes of HPMC indicate that the conformation of the adsorbed macromolecules depends on liposome composition. Hydration enthalpy values show that adsorbed polymers do not give more hydrophilic systems after freeze-drying as expected with the hydrophilic characteristics of the HPMC.     

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.     

Highly accurate predictor of eye irritation utilizing potential parameters of a reconstructed human cornea epithelium model calculated based on Hansen solubility parameters

Concerns regarding animal welfare have led to the need for alternatives to animal eye irritation tests. The reconstructed human cornea-like epithelium (RhCE) test is described in the OECD TG 492 as an alternative to animal eye irritation tests. However, the accuracy and labor investment of this method can be improved if the results can be predicted before the experiment. In this study, we evaluated whether Hansen solubility parameter (HSP) values can be used to predict the results of RhCE method using the LabCyte CORNEA-MODEL for 65 test substances. We found that HSP values can predict the RhCE method with high correlation (accuracy 84.6% (55/65), false-negative rate of 16.2% (7/43), and false-positive rate of 13.6% (3/22). These results indicate that HSP values can be used to predict the results RhCE method using LabCyte CORNEA-MODEL with high reproducibility, and thus are useful for evaluating the safety of substances.     

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.     

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.     

The modified extended Hansen method to determine partial solubility parameters of drugs containing a single hydrogen bonding group and their sodium derivatives: benzoic acid/Na and ibuprofen/Na

Sodium salts are often used in drug formulation but their partial solubility parameters are not available. Sodium alters the physical properties of the drug and the knowledge of these parameters would help to predict adhesion properties that cannot be estimated using the solubility parameters of the parent acid. This work tests the applicability of the modified extended Hansen method to determine partial solubility parameters of sodium salts of acidic drugs containing a single hydrogen bonding group (ibuprofen, sodium ibuprofen, benzoic acid and sodium benzoate). The method uses a regression analysis of the logarithm of the experimental mole fraction solubility of the drug against the partial solubility parameters of the solvents, using models with three and four parameters. The solubility of the drugs was determined in a set of solvents representative of several chemical classes, ranging from low to high solubility parameter values. The best results were obtained with the four parameter model for the acidic drugs and with the three parameter model for the sodium derivatives. The four parameter model includes both a Lewis-acid and a Lewis-base term. Since the Lewis acid properties of the sodium derivatives are blocked by sodium, the three parameter model is recommended for these kind of compounds. Comparison of the parameters obtained shows that sodium greatly changes the polar parameters whereas the dispersion parameter is not much affected. Consequently the total solubility parameters of the salts are larger than for the parent acids in good agreement with the larger hydrophilicity expected from the introduction of sodium. The results indicate that the modified extended Hansen method can be applied to determine the partial solubility parameters of acidic drugs and their sodium salts.     

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.     

The influence of drugs on the properties of gels and swelling characteristics of matrices containing methylcellulose or hydroxypropylmethylcellulose

The cloud points, matrix swelling and gel layer formation in matrices containing cellulose ethers and indomethacin, propranolol hydrochloride or tetracycline hydrochloride have been investigated. The two hydrochloride salts contributed to the matrix swelling and gel layer formation, maintaining the integrity of matrices containing methylcellulose. Gel layer formation, measured by thermomechanical analysis was most rapid, and the layer thickest, in matrices containing propranolol hydrochloride. This mimicked cloud point determination where propranolol salted the cellulose ethers into solution to a greater extent than tetracycline. The poorly soluble indomethacin failed to contribute to swelling and gel layer formation. Studies, using U-tube viscometry, indicated that the viscosity of gels containing HPMC E4M, HPMC F4M, HPMC K4M and methylcellulose reduced on storage. This appeared to be further catalysed by the inclusion of drugs, and especially of tetracycline hydrochloride in the gels.     

辅酶Q_(10)纳米混悬剂的粒径和溶解度之间的关系

目的测定不同粒径辅酶Q10(coenzyme Q10,CoQ10)纳米混悬剂的溶解度,研究粒径和溶解度之间的关系。方法采用改良沉降法和逆向沉降法制备CoQ10纳米混悬剂,建立一种新的溶解度测定方法—逐步稀释法,并用于测定不同粒径CoQ10纳米混悬剂的溶解速度和平衡溶解度。同时采用经典平衡法测定CoQ10原料药的平衡溶解度,用于验证粒径和平衡溶解度之间的关系。结果逐步稀释法测得粒径分别约为100、300、700 nm的CoQ10纳米混悬剂的平衡溶解度均约为40 mg.L-1,平衡法测得CoQ10原料药的平衡溶解度也约为40 mg.L-1。结论 CoQ10纳米混悬剂的粒径和溶解度无关,粒径只能影响其溶解速度。奥斯特瓦尔德-弗罗因德利希方程中阐明的粒径与溶解度之间的关系,在0.1~1.0μm内是不成立的,CoQ10纳米混悬剂的粒径对平衡溶解度没有影响。     

计算机分析胎心率监护与围产儿预后的关系

目的探讨计算机分析电子胎心率监护(EFM)与围产儿预后的相关性.方法对2 935份胎心监护曲线(CTG)的计算机评分及其临床资料做回顾性分析.按不同的CTG评分分5组:≥8分组,7分组,6分组,5分组和≤4分组.分别对各组新生儿出生后记录Apgar评分,羊水量、羊水污染度及围产儿预后不良发生率等项进行统计对比.结果CTG评分7分组和≥8分组各项对比无显著差异,P》0.05;6分组与≥7分组相比,新生儿Apgar低评分有显著性差异,P《0.05,羊水污染及围产儿预后不良发生率差异非常显著,P《0.01;5分组与≥6分组相比,羊水污染、Apgar低评分及围产儿预后不良发生率各项对比均有非常显著性差异,P《0.01;≤4分组,围产儿预后全部不良,各项指标与其他组相比均有非常显著性差异,P《0.01.结论计算机分析电子胎心率监护(EFM)对预测围产儿预后有重要价值.     

Relationship between zero point of charge and solubility product for hydroxides of polyvalent cations.

The zero point of charge (ZPC) of slightly soluble compounds is the pH at which their particles suspended in water have zero charge. The ZPC values of slightly soluble hydroxides were compared with their solubility product in the form of its negative logarithm, pKSP, and with th pH of their suspensions in pure water, pHSP, which is a function of pKSP. The ZPC-pKSP relation was nonlinear while the ZPC-pHSP relation was linear. Either equation can used to estimate the ZPC value of a hydroxide from its solubility product. The ZPC of a given hydroxide was higher than its pHSP because polyvalent cations are more extensively adsorbed and less extensively desorbed from the particle surface than the monovalent hydroxide ion. At the pHSP, there are equivalent amounts of the cation and of the hydroxide anion in solution, but the surface layer of the hydroxide particle contains an excess cation on an equivalent basis. This imbalance confers a positive charge to the particle. The solubility product of aluminum hydroxide, redetermined at 25 degrees by means of pH measurements, was 8 X 10(-33). Its ZPC, redetermined by microelectrophoresis, was 8.5 +/- 0.1.     

Relationship between hematopoietic parameters and behavioral measures in lead-exposed rats

The effects of low level lead (Pb) exposure on learning tasks in developing rats were investigated and the results correlated with individual hematopoietic indices. Pups received exposure via the dams milk; dams were exposed to either 0-, 545-, or 1090-ppm Pb during the lactation period. At Day 30 of age, half of the high Pb group was placed on distilled water; the remaining groups continued on the same exposure regimens as their dams. On Days 20, 30, and 90, blood samples for all rats were obtained via cardiac puncture. Each sample was analyzed for Pb concentration, free erythrocyte protoporphyrin (FEPs), hematocrit, and hemoglobin. Beginning at Day 90, all rats were tested on a battery of tasks designed to investigate the following questions: (1) to what degree lead exposure interferes with reversal learning; (2) whether changing of task requirements adversely affects acquisition of a new task; (3) to what extent task difficulty contributes to lead-induced deficits; and (4) whether lead exposure affects the capacity to retain information over short or long periods of time. The actual testing paradigms included spatial discrimination with reversal, visual discrimination with reversal, and visual discrimination task with delay. No significant differences were observed among any of the groups on any of the tasks. Correlation of individual learning scores with individual measures of hematopoietic function also failed to reach significance. These findings indicate that at low exposure levels, lead has little appreciable effect on learning and memory function as measured by these tasks.     

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

Summary

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 albumim 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.