A new expanded solubility parameter approach

The partial or Hansen solubility parameters (HSP) are important properties of the various substances and very useful tools for the selection of their solvents or the prediction of their behaviour in numerous applications. Their design and evaluation relies on the basic rule of "similarity matching" for solubility. The present work attempts to enhance the capacity of HSPs by incorporating into their evaluation the other basic rule of solubility, namely, the rule of "complementarity matching". This is done in a simple and straightforward manner by splitting the hydrogen bonding HSP into its acidic or proton donor component and its basic or proton acceptor one. The splitting is based on the third σ-moments of the screening charge distributions or sigma profiles of the quantum-mechanics based COSMO-RS theory. The whole development and application does not involve any sophisticated calculations or any strong specific background. The new method has been applied to a variety of solubility data for systems of pharmaceutical interest in order to verify the significant improvement over the classical HSP approach. The application of the new method requires, of course, the knowledge of the HSPs. For this reason, in Appendix A is presented an updated version of a robust and reliable group-contribution method for the calculation of the HSPs. The key features of this combined tool are critically discussed.     

Estimation of the aqueous solubility of weak electrolytes

Jain and Yalkowsky [Jain, N., Yalkowsky, S.H., 2001. Estimation of the aqueous solubility. I. Application to organic non-electrolytes. J. Pharm. Sci. 90, 234-252.] demonstrated that the general solubility equation (GSE) can be used to estimate the aqueous solubility of organic non-electrolytes. In this study the applicability of the GSE was extended to weak electrolytes. It is demonstrated that the GSE estimates the aqueous solubility of 949 compounds, including 367 weak electrolytes with an AAE of 0.58. It is also shown that the intrinsic solubilities of weak acids for which the pK(a)+log S(w)相似文献   

Simultaneous solubility and dissolution rate of sulfamethoxazole and trimethoprim in binary mixture

The solubilities of trimethoprim in solutions with different pH values decreased in the presence of sulfamethoxazole, while that of the latter increased in the presence of the first. The dissolution rate of trimethoprim in HCl (0.1 mol/1) was the same in the presence and absence of sulfamethoxazole. That of sulfamethoxazole however, decreased in the presence of trimethoprim. The different reasons were explained.     

Simultaneous determination of trimethoprim and sulphamethoxazole in veterinary formulations by chromatographic multivariate methods

A comparative chromatographic study was developed for the simultaneous quantitative resolution of trimethoprim (TMP) and sulphamethoxazole (SMX) in veterinary formulations. Multi-wavelength chromatograms were recorded by using diode array detector (DAD) system at the five-wavelength set consisting of 220, 230, 240, 250 and 260 nm. In the first step, five different calibration equations at the above wavelengths for each drug were obtained by using the relationship between concentration and peak area. These calibration graphs were used for the quantitative evaluation of TMP and SMX in samples. These single-wavelength applications were called traditional LC method. In the second step, principal component regression (PCR) and partial least-squares (PLS) calibrations were applied to the above mentioned multi-wavelength chromatograms. The amount of two investigated drugs in samples was determined by the constructed PCR and PLS calibrations. The experimental results obtained from each single-wavelength calibration graph were compared with those obtained by the chemometric approaches and chromatographic multivariate approaches give successful results more than traditional LC method.     

高效液相法测定磷霉素钙甲氧苄啶胶囊中甲氧苄啶的含量

目的建立高效液相色谱法测定磷霉素钙甲氧苄啶胶囊中甲氧苄啶含量的方法。方法采用ODS2(250mm×4.6mm,5μm)色谱柱,以水-乙腈-三乙胺(799∶200∶1)(用氢氧化钠试液或冰醋酸调节pH值至5.9)为流动相,流速1.0mL·min-1,检测波长为240nm。结果甲氧苄啶在0.4152~1.2456μg范围内进样量与峰面积呈良好的线性关系(r=0.9999);平均回收率为98.75%,RSD为1.46%,n=9。结论本方法结果准确,重现性好。     

Estimation of the aqueous solubility I: application to organic nonelectrolytes

The estimation of aqueous solubilities of organic nonelectrolytes by the General Solubility Equation (GSE) as proposed by Valvani and Yalkowsky (1980) is used in this study. The data and assumptions on which the GSE are based are reevaluated, and the equation is revised. The revised GSE is validated on a set of 580 pharmaceutically, environmentally, and industrially relevant nonelectrolytes. The revised equation has a stronger theoretical background and provides a more accurate estimation of aqueous solubility.     

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.     

Hansen solubility parameter as a tool to predict cocrystal formation

The objective of this study was to investigate whether the miscibility of a drug and coformer, as predicted by Hansen solubility parameters (HSPs), can indicate cocrystal formation and guide cocrystal screening. It was also our aim to evaluate various HSPs-based approaches in miscibility prediction. HSPs for indomethacin (the model drug) and over thirty coformers were calculated according to the group contribution method. Differences in the HSPs between indomethacin and each coformer were then calculated using three established approaches, and the miscibility was predicted. Subsequently, differential scanning calorimetry was used to investigate the experimental miscibility and cocrystal formation. The formation of cocrystals was also verified using liquid-assisted grinding. All except one of the drug-coformers that were predicted to be miscible were confirmed experimentally as miscible. All tested theoretical approaches were in agreement in predicting miscibility. All systems that formed cocrystals were miscible. Remarkably, two new cocrystals of indomethacin were discovered in this study. Though it may be necessary to test this approach in a wide range of different coformer and drug compound types for accurate generalizations, the trends with tested systems were clear and suggest that the drug and coformer should be miscible for cocrystal formation. Thus, predicting the miscibility of cocrystal components using solubility parameters can guide the selection of potential coformers prior to exhaustive cocrystal screening work.     

Uptake of trimethoprim by renal cortex

The purpose of this study was to examine the mechanisms involved in the uptake of the urinary antibacterial drug trimethoprim by incubated slices of rat renal cortex. Concentration-dependent studies of the uptake process demonstrated that a saturable component was involved. The results of inhibitor studies as well as the time-course pattern support the conclusion that at least two processes are involved in the uptake of trimethoprim. These include active transport via the organic cation system, accounting for about 40% of the total uptake, and a second component that continues to operate under conditions of inhibited cellular metabolism. Chromatographic examination of post-incubation bathing medium and slice extracts failed to demonstrate renal cortex metabolism of trimethoprim.     

In vitro percutaneous absorption of prednisolone derivatives based on solubility parameter

A series of ester derivatives of prednisolone (I–VII) with various lipophilicities was synthesized to investigate their in vitro percutaneous absorption and their distribution and accumulation in the skin. Experimental findings were supported with theoretical calculations, using the solubility parameter as an indicator of the lipophilicity of the derivatives. The solubility parameters of the derivatives were well correlated with their partition coefficients in an octanol-water system and increase in lipophilicity was well correlated with the theoretical and experimental values of drug distribution into the skin. Drug distribution into the skin was increased, but the drug diffusion rate was decreased with increasing derivative lipophilicity. These findings indicated that accumulation of the derivatives in the skin increased with increasing derivative lipophilicity. This suggests that retention of prednisolone derivatives in the skin is a function of their solubility parameters and that derivatives are partitioned in the skin relative to their lipophilicities.     

高效液相色谱法测定甲氧苄啶片的含量

目的建立甲氧苄啶片含量的高效液相色谱（HPLC）测定法。方法采用十八烷基硅烷键合硅胶柱;流动相为乙腈-水．三乙胺：200：799：1（冰醋酸调pH至5．9）;检测波长271nm;流速1．0ml·min^-1。甲氧苄啶易溶于醋酸,用少量冰醋酸溶解甲氧苄啶,用水稀释后测定含量。结果甲氧苄啶质量浓度在5—70mg·L^-1范围内与峰面积呈良好线性关系,r=0．9999,平均回收率为98．9％,RSD为0．36％（n=6）。结论本法操作简单,结果准确,重现性好,可用于甲氧苄啶片的含量测定。     

Densitometric determination of the solubility parameter and molal volume of compounds of medicinal relevance

A procedure is described for the simultaneous determination of molal volumes (v02) and solubility parameters (delta) of compounds of medicinal interest. These include alkanoic acids of various chain length and branching (some solid at room temperature), cholesterol, and cholesteryl esters. The procedure is based on the determination of partial molal volumes (v2) from high-precision density measurements of dilute solutions of these compounds in reference solvents, which range in polarity from carbon tetrachloride (delta = 8.6) to nitrobenzene (delta = 10.0). In some cases, the present results do not agree with values of delta published in the literature. Values calculated from group contributions proposed by other authors are prone to error particularly in the case of branched acids and cholesteryl esters.     

Development of solubility screening methods in drug discovery

We developed two methods for solubility screening of drug candidates in drug discovery. The first is a solution-precipitation (SP) method, in which the sample solutions are prepared by adding the drug solution in dimethylsulfoxide (DMSO) to buffers followed by filtering off the precipitate using 96-well filterplate. The second is a powder-dissolution (PD) method, in which the solid samples are dissolved to the buffer in the HPLC vial equipped with the filter membrane in the HPLC autosampler. An HPLC equipped with a photodiode array detector is used to measure the concentration of the sample solutions in both methods. The SP method was used for high throughput screening the solvating process of the candidates in aqueous solutions with lower sample consumption, and the PD method was used for screening both inter-molecular interaction in solid state and solvation in aqueous solution with more sample amount than that of SP method. Therefore, the solubility screening from early to final stage of lead optimization process would be successfully accomplished by using both methods complementarily.     

Improved group contribution parameter set for the application of solubility parameters to melt extrusion

Hot-melt extrusion is gaining importance for the production of amorphous solid solutions; in parallel, predictive tools for estimating drug solubility in polymers are increasingly demanded. The Hansen solubility parameter (SP) approach is well acknowledged for its predictive power of the miscibility of liquids as well as the solubility of some amorphous solids in liquid solvents. By solely using the molecular structure, group contribution (GC) methods allow the calculation of Hansen SPs. The GC parameter sets available were derived from liquids and polymers which conflicts with the object of prediction, the solubility of solid drugs. The present study takes a step from the liquid based SPs toward their application to solid solutes. On the basis of published experimental Hansen SPs of solid drugs and excipients only, a new GC parameter set was developed. In comparison with established parameter sets by van Krevelen/Hoftyzer, Beerbower/Hansen, Breitkreutz and Stefanis/Panayiotou, the new GC parameter set provides the highest overall predictive power for solubility experiments (correlation coefficient r = −0.87 to −0.91) as well as for literature data on melt extrudates and casted films (r = −0.78 to −0.96).     

贝叶斯法估算丙戊酸药动学参数及个体化给药

目的:采用癫痫患者丙戊酸群体药动学参数结合贝叶斯(Bayesian)法估算癫痫患者丙戊酸的个体药动学参数;制定或优化欲达预期血药浓度所应实施的给药方案,使癫痫患者丙戊酸给药有效、合理、毒副作用小.方法:癫痫患者口服丙戊酸达稳态,取其每天早晨服药前10 min血样57人次,用荧光偏振免疫法(Fluorescence Polarization Immunoassay,FPIA)测得血清中丙戊酸和游离丙戊酸血药浓度谷值.用Bayesian法估算其药动学参数,并用逐步回归法分析个体的性别、年龄等18种因素对其药动学参数的影响.结果:按口服一房室一级吸收和消除的开放模型用Bayesian法估算得丙戊酸药动学参数清除率CL,平均值为(8.7±0.6)mL·h-1·kg-1,逐步回归方程:CL(mL·h-1·kg-1)=3.972 1.631X5 1.608X11;稳态血药浓度谷值Cp0逐步回归方程:Cp0(mg·L-1)=57.58-0.71X4-12.145X5 2.705X7 0.403x17.式中X4表示体重(kg),X5表示身高(cm)体重(kg)比,X7表示每日每千克体重的给药剂量(mg·d-1·kg-1),x11表示当合并用苯妥英钠时系数为1,否则为0,x17表示血清肌酐(μmol·L-1).实测丙戊酸稳态血药浓度谷值(52.4±5.4)mg·L-1与估算值(53.5±5.2)mg·L-1间差异无统计学意义,P＞0.05.结论:可采用Bayesian法估算癫痫患者丙戊酸动力学参数和进行个体化给药的拟定或调整给药方案.     

Increasing the solubility and permeability of pharmacons with pharmaceutical technological methods

During the last years the trend in drug discovery has been to produce more and more compounds that exhibit high lipophilicity and poor water solubility. If a drug candidate has reasonable membrane permeability--the pharmacon belongs to the second group of the biopharmaceutical classification system (BCS)--then often the rate-limiting process of absorption is the drug dissolution step. There are a number of formulation strategies that could be used to improve the bioavailability of these materials. In this article the author would like to collect the technological possibilities, and gives some samples from the results of the research group of the Department of Pharmaceutical Technology, University of Szeged.