Prediction of the optimized solvent composition for solubilization of drugs in water-cosolvent mixtures

The capability of the Jouyban-Acree model for predicting the optimized solvent composition of binary solvents for solubilization of drugs is shown employing solubility of drugs in aqueous mixtures of dioxane, ethanol and polyethylene glycol 400. The established model constants of the Jouyban-Acree model and solubility of drugs in water and cosolvent are used to predict the maximum solubility of in the binary solvent mixture (log Xm(max)) and the corresponding solvent composition (f1,max). The accuracy of the predicted log Xm(max) and f1,max is studied using average absolute error (AAE) of predicted and observed values. The AAEs were 0.10 +/- 0.12 and 0.08 +/- 0.10, respectively for log Xm(max) and f1,max. The method provided acceptable predictions and is recommended for practical applications. The main advantage of the proposed method is its extension to temperatures higher/lower than room temperature.     

Skin permeation of testosterone and its ester derivatives in rats

To establish the optimum conditions for improving the transdermal delivery of testosterone, we studied the relationship between the lipophilicity of testosterone ester derivatives and the rat skin permeation rate of testosterone. We performed a rat skin permeation study of testosterone and its commercially available ester derivatives, testosterone hemisuccinate, testosterone propionate and testosterone-17beta-cypionate, using an ethanol/water co-solvent system. The aqueous solubility and rat skin permeation rate of each drug, saturated in various compositions of an ethanol/water system, was determined at 37 degrees C. The aqueous solubility of testosterone and its ester derivatives increased exponentially as the volume fraction of ethanol increased up to 100% (v/v). The stability of testosterone propionate in both the skin homogenate and the extract was investigated to observe the enzymatic degradation during the skin permeation process. Testosterone propionate was found to be stable in the isotonic buffer solution and in the epidermis-side extract for 10h at 37 degrees C. However, in the skin homogenate and the dermis-side extract testosterone propionate rapidly degraded producing testosterone, implying that testosterone propionate rapidly degraded to testosterone during the skin permeation process. The steady-state permeation rates of testosterone in the ethanol/water systems increased exponentially as the volume fraction of ethanol increased, reaching the maximum value (2.69+/-0.69 microg cm(-2)h(-1)) at 70% (v/v) ethanol in water, and then decreasing with further increases in the ethanol volume fraction. However, in the skin permeation study with testosterone esters saturated in 70% (v/v) ethanol in water system, testosterone esters were hardly detected in the receptor solution, probably due to the rapid degradation to testosterone during the skin permeation process. Moreover, a parabolic relationship was observed between the permeation rate of testosterone and the log P values of ester derivatives. Maximum flux was achieved at a log P value of around 3 which corresponded to that of testosterone (log P = 3.4). The results showed that the skin permeation rate of testosterone and its ester derivatives was maximized when these compounds were saturated in a 70% ethanolic solution. It was also found that a log P value of around 3 is suitable for the skin permeation of testosterone related compounds.     

Structure-toxicity relationships for selected halogenated aliphatic chemicals

Toxicity to the ciliate Tetrahymena pyriformis (log(IGC(50)(-1))) for 39 halogen-substituted alkanes, alkanols, and alkanitriles were obtained experimentally. Log(IGC(50)(-1)) along with the hydrophobic term, logK(ow) (1-octanol/water partition coefficient) and the electrophilic parameter, E(lumo) (the energy of the lowest unoccupied molecular orbital) were used to develop quantitative structure-activity relationships (QSARs). Two strong hydrophobic dependent relationships were obtained: one for the haloalkanes and a second for the haloalcohols. The relationship for the haloalkanes [log(IGC(50)(-1))=0.92 (logK(ow))-2.58; n=4, r(2)=0.993, s=0.063, f=276, Pr>f=0.0036] was not different from baseline toxicity. With the rejection of 1,3-dibromo-2-propanol as a statistical outlier, the relationship [log(IGC(50)(-1))=0.63(logK(ow))-1.18; n=19, r(2)=0.860, s=0.274, f=104, Pr>f=0.0001] was observed for the haloalcohols. No hydrophobicity-dependent model (r(2)=0.165) was observed for the halonitriles. However, an electrophilicity-dependent model [log(IGC(50)(-1))=-1.245(E(lumo))+0.73; n=15, r(2)=0.588, s=0.764, F=18.6, Pr>f=0.0009] was developed for the halonitriles. Additional analysis designed to examine surface-response modeling of all three chemical classes met with some success. Following rejection of statistical outliers, the plane [log(IGC(50)(-1))=0.60(logK(ow))-0.747(E(lumo))-0.37; n=34, r(2)=0.915, s=0.297, F=162, Pr>F=0.0001] was developed. The halogenated alcohols and nitriles tested all had observed toxicity in excess of non-reactive baseline toxicity (non-polar narcosis). This observation along with the complexity of the structure-toxicity relationships developed in this study suggests that the toxicity of haloalcohols and halonitriles is by multiple and/or mixed mechanisms of action which are electro(nucleo)philic in character.     

Solubilization by cosolvents. Establishing useful constants for the log-linear model

The purpose of this study was to develop constants for the log-linear cosolvent model, thereby allowing accurate prediction of solubilization in the most common pharmaceutical cosolvents: propylene glycol, ethanol, polyethylene glycol 400, and glycerin. The solubilization power (sigma) of each cosolvent was determined for a large number of organic compounds from the slope of their log-solubility vs. cosolvent volume fraction plots. The solubilization data at room temperature were either experimentally determined or obtained from the literature. The slopes of the nearly linear relationship between solubilization power and solute hydrophobicity (logK(ow)) were obtained by linear regression analysis for each considered cosolvent. Thus, knowing or calculating a compound's partition coefficient is all that is needed to predict solubilization.     

Comparison of the octanol/water partition coefficients calculated by ClogP, ACDlogP and KowWin to experimentally determined values

The experimental octanol/water partition coefficient data, of 108 compounds from the data set [Rytting, E., Lentz, K.A., Chen, X., Qian, F., Venkatesh, S., 2004. A quantitative structure-property relationship for predicting drug solubility in PEG 400/water cosolvent systems. Pharm. Res. 21, 237-244] was compared to calculated values using the computer programs ClogP, ACD/logPdb and KowWin. It was found that all the three programs have a user friendly interface but ClogP appears to be the more accurate predictor of log K(ow).     

A new definition of solubilization power of a cosolvent

The solubilization power of a cosolvent is defined based on the maximum solubility of a solute in the water-cosolvent mixtures (X(m,max)) and the corresponding solvent composition (f(c,max)) predicted by trained versions of the Jouyban-Acree model. The applicability of the proposed definition was checked using solubility data of three cosolvent systems where the solubilization power was ordered as: dioxane > ethanol > polyethylene glycol 400. Using this definition, one could select the most appropriate cosolvent for solubilization of a poorly water soluble drug. There are linear relationships between the solubilization power of a cosolvent and the solute's logarithm of partition coefficients.     

The influence of drug partition coefficient on follicular penetration: in vitro human skin studies.

The aim of this study was to employ the novel skin sandwich system in order to quantify the influence of the octanol-water partition coefficient on follicular drug absorption in human skin. To this end, seven different drugs - estradiol, corticosterone, hydrocortisone, aldosterone, cimetidine, deoxyadenosine and adenosine - exhibiting a wide range of log octanol-water partition coefficients (logK(o/w)) but relatively similar molecular weights were selected as candidate solutes. Application of the skin sandwich technique yielded an interesting relationship between % follicular contribution and logK(o/w). The follicular contribution to total flux was small (4 and 2%) for the two most lipophilic drugs but varied between 34 and 60% for the remaining drugs of intermediate and low logK(o/w) values. Lipophilicity seems to be an important modulator of drug absorption into follicular orifices only above a critical logK(o/w) threshold. Below this critical logK(o/w) value, lipophilicity does not apparently influence the follicular contribution in an obvious way and the process is probably governed by other molecular properties. Identification of these other active properties would require performing this kind of a study on a much larger set of candidate drugs.     

Structure-toxicity relationships for benzenes evaluated with Tetrahymena pyriformis

Toxicity data for 200 substituted benzenes tested in the two-day Tetrahymena pyriformis population growth impairment assay representing the neutral narcosis, polar narcosis, respiratory uncoupling, and weak and strong electrophilic mechanisms of toxic action were evaluated. A quantitative structure-toxicity model correlating toxic potency [log(IGC(50)(-)(1))] with hydrophobicity quantified by the 1-octanol/water partition coefficient (log K(ow)) and electrophilic reactivity quantified by the molecular orbital parameter, maximum superdelocalizability (S(max)), was developed. This model [log(IGC(50)(-)(1)) = 0.50(log K(ow)) + 9.85(S(max)) - 3.47; n = 197, r(2) = 0.816, s = 0.34, F = 429, Pr > F = 0.0001] allows for the prediction of acute potency without the a priori identification of the mechanism of action. The examination of residuals reveals that neutral narcotics with high volatility (e.g., methyl- and chloro-substituted benzenes) and highly reactive fluoro- and nitro-containing derivatives are fitted poorly. A comparison of observed (obs) and predicted (pred) toxicities on the additional set of derivatives [log(obs IGC(50)(-)(1)) = 1.05[log(pred IGC(50)(-)(1))] + 0.02; n = 20, r(2) = 0.979, s = 0.13, F = 825, Pr > F = 0.0001] validated the model as a good predictor of toxicity regardless of the mechanism of toxic action.     

Investigation of drug partition property in artificial sebum

Targeted delivery of a therapeutic agent into the hair and sebaceous follicles greatly depends on the extent of drug partitioning/diffusion in the sebum. The objective of the present research was to develop a method to determine the sebum partition coefficient in order to facilitate the selection of sebum-targeted drug candidates. Partition coefficients of model drugs with different chemical structures and 4-hydroxybenzoate series compounds were measured in artificial sebum/water (K(sebum)) and human stratum corneum/water (K(sc)) at 37 degrees C. The relationship was evaluated between logK(sebum), logK(sc) and clogP. The results of the partition coefficient studies indicate that the K(sebum) of some drugs was significantly higher than the K(sc), whereas some drugs showed lower or similar K(sebum) when compared with K(sc). Overall, a relatively poor correlation was observed between logK(sebum), logK(sc) and clog P. However, a linear relationship exists between logK(sebum) and clog P in the 4-hydroxybenzoate series compounds, indicating that K(sebum) depends on the lipophilicity and chemical structure of the compounds. The results of the present study demonstrate that K(sebum) is different from K(sc) and calculated P and is likely to be a critical parameter reflecting drug delivery into hair and sebaceous follicles.     

基于HPLC法测定醋酸甲羟孕酮的平衡溶解度与油水分配系数

目的对醋酸甲羟孕酮(MPA)在不同溶剂中的平衡溶解度及其在正辛醇-缓冲液体系中的油水分配系数进行测定。方法采用HPLC法测定MPA的质量浓度,测定MPA在水、有机溶剂、缓冲溶液和加十二烷基硫酸钠的缓冲溶液中的平衡溶解度,采用摇瓶法结合HPLC法测定MPA在正辛醇-缓冲液体系中的质量浓度,从而计算油水分配系数。结果 37℃时,MPA在蒸馏水和丙酮中的平衡溶解度分别为0.52±0.04和238.70±0.47μg·mL~(-1);在体积分数为90%的乙醇溶液中的平衡溶解度最大;在加十二烷基硫酸钠的缓冲溶液中的平衡溶解度增大;在水中的表观油水分配系数为1.99(lgP=0.30),脂溶性较强;在pH值为1.2~6.8的缓冲溶液中,平衡溶解度随pH值的升高而减小,油水分配系数随pH值的升高而增大。结论该实验建立的测定方法可准确测定MPA的平衡溶解度和油水分配系数。     

Influence of solute structure on deviations from the log-linear solubility equation in propylene glycol:water mixtures

The solubilities of the methyl, ethyl, propyl, and butyl esters of p-hydroxy- and p-aminobenzoates have been determined in propylene glycol:water mixtures. The log of the observed solubility data in propylene glycol:water mixtures was examined for deviations from the following equation: In Xi = f In (Xc) + (1 - f) In (Xw), where Xi is the calculated mole fractional solubility of the solute, f is the volume fraction of cosolvent, Xc is the observed mole fractional solubility in the neat cosolvent, and Xw is the solubility in water. In each case, the deviations from the predicted solubilities demonstrated a characteristic pattern. Positive deviations were observed at high volume fractions of cosolvent, while negative deviations were observed at low volume fractions. The magnitude of the deviations at low volume fractions of cosolvent was related to the carbon chain length within each group of esters. A similar phenomenon was not observed at high volume fractions of cosolvent; however, the magnitude of the deviations was dependent on the nature of the polar group on the ester. The data are interpreted in terms of the possible effects of solvent structure on the solubility of the solutes.     

Use of solubility parameter to design dry suspension of cefaclor as a dual pack system

One of the important methods to improve the solubility of a less water-soluble drug is by the use of co solvents. The solubility enhancement produced by two binary blends with a common co solvent (water-propylene glycol and propylene glycol-ethyl acetate) was studied against the solubility parameter of solvent blends (δ(1)) to evaluate the solubility parameter of drug (δ(2)). The binary blend water:propylene glycol (20:80) gave maximum solubility with an experimental δ(2) value of 16.52 (Cal/cm(3))(0.5) that was comparable to the theoretical value of 16.52 (Cal/cm(3))(0.5) determined by molar volume method and 16.35 (Cal/cm(3))(0.5) when determined by method proposed by Lin and Nash. The solvent blend water:propylene glycol (20:80) in which the drug exhibited maximum solubility was used as the reconstituting medium for formulation of dry suspension of cefaclor. The percentage cumulative drug release of cefaclor from the formulation F7 was compared to the marketed formulation by calculating the f1 (dissimilarity factor) and f2 (similarity factor) factors. A higher f1 value and f2 value below 50 indicates difference between the two dissolution profiles.     

Advancing prediction of tissue distribution and volume of distribution of highly lipophilic compounds from a simplified tissue-composition-based model as a mechanistic animal alternative method

It has been reported that values of tissue-plasma ratios (K(p)) and resulting volume of distribution at steady state (V(ss)) are substantially overpredicted for several highly lipophilic drugs. This effect was observed particularly with the published version of the tissue-composition-based model, which used experimentally determined unbound fraction in plasma (fu(p)) as input for drugs. The reasons for the unreasonably high V(ss) predictions were investigated in this study for 14 highly lipophilic compounds with a log n-octanol-water partition coefficient (log P(ow)) of at least 5.8. Here, we argue that the experimentally determined fu(p) is inaccurate for these compounds, which affected the prediction of K(p) and V(ss). Alternatively, the tissue-plasma ratio of neutral lipids (nl) equivalent was used as the main factor governing K(p), and hence V(ss), in addition to log P(ow). The average fold error of deviation between the predicted and observed human V(ss) is 124 for the published model, whereas it significantly decreased to 1.5 for the proposed model. The sensitivity analysis confirmed the importance of nl content and drug lipophilicity. Overall, this study proposes a generic and simplified tissue-composition-based model for highly lipophilic drugs and chemicals, which is a step forward toward improving prediction of V(ss) into physiologically based pharmacokinetic (PBPK) models.     

A predictive model for the release of slightly water-soluble drugs from HPMC matrices

A model to predict the fraction of slightly water-soluble drug released as a function of release time (t, h), HPMC concentration (C(H), w/w), drug solubility in distilled water at 37 degrees C (C(s), g/100 mL), and volume of drug molecule (V, nm3) was derived when theophyline, tinidazole, and propylthiouracil were selected as model drugs. The model is log (M(t)/M(infinity)) = 0.8683 logt-0.1930C(s) logt + 0.5406V logt-1.227C(H) + 0.1594C(s) + 0.4423C(H)C(s) - 0.8655 (n = 130, r = 0.9969), where Mt is the amount of drug released at time t, Minfinity is the amount of drug released over a very long time, which corresponds in principle to the initial loading, n is the number of samples, and r is the correlation coefficient. The model was validated using sulfamethoxazole and satisfactory results were obtained. The model can be used to predict the release fraction of variousslightly water-soluble drugs from HPMC matrices having different polymer levels.     

Investigation of the solubility relationships of polar,semi-polar and non-polar drugs in mixed co-solvent systems

The solubility relationships of a non-polar (tioconazole), polar (oxfenieine) and semi-polar (caffeine) drug have been investigated in aqueous ethanol, propylene glycol and polyethylene glycol 400 (PEG 400) binary co-solvent systems. A semi-empirical equation was deduced to describe the relationship between the amount of drug dissolved and the volume fraction of co-solvent employed. The data for tioconazole and oxfenicine followed the expected semi-logarithmic relationship between solubility and fraction co-solvent. However, the semi-polar drug, caffeine followed this relationship only with PEG 400; the other two co-solvents yielded parabolic relationships.Using the binary solubility data, multiple linear regression was used to deduce an equation for the solubility of tioconazole in ternary ethanol, propylene glycol and PEG 400 co-solvent systems. The derived relationship gave excellent prediction of the drug solubility throughout the complete volume fraction range. This allowed a graphical representation of the drug solubility-co-solvent fraction relationship to be established. This visualization of are drug solubility relationship was then used to demonstrate its utility to optimize drug solubility within the competing constraints of the pharmaceutical system.     

化学药品对照品的吸湿性、溶解性与比表面积相关性研究

目的 初步研究药物(化学药品对照品)吸湿性溶解性与其比表面积的相关性,为药物制备工艺和防潮技术提供参考。方法 分析《化学药品对照品图谱集—动态水分吸附》中631种药物的水分吸附动力学图,把图中RH80%放180 min的最大吸湿率(质量变化率)、比表面积、水溶性、乙醇溶解性输入excel表,分析平均吸湿率、平均比表面积、水溶性、乙醇溶解性、水和乙醇中相同溶解性的相关性;分析极具引湿性药物的吸湿官能团及放湿情况;初步比较不同吸湿官能团的吸湿性强弱。结果 631种药物比表面积为0.00~396.11 m_².g_^-1、吸湿率为0.02%~81.00%。药物平均吸湿率与平均比表面积、水溶性、吸湿官能团均正相关,与乙醇溶解性、水和乙醇相同溶解性的相关性较复杂。吸湿官能团可能包括氨基、羟基、羧基、钠盐、钾盐、铵盐、硅酸铝、寡糖等20种,药物吸湿后在低相对湿度环境中会发生不放湿、部分放湿、完全放湿等现象。药物溶解性与平均比表面积关系：水中略溶以上负相关,以下正相关;乙醇中微溶以上不相关,以下负相关。结论 化学药品对照品的吸湿性溶解性与比表面积具有相关性,为药物防潮工艺和难溶性药物溶出度提高技术提供参考。     

Mechanistic analysis of pH-dependent solubility and trans-membrane permeability of amphoteric compounds: application to sildenafil

This study was aimed at investigating the pH-dependent solubility and in vitro transmucosal permeability of sildenafil, an amphoteric compound with limited aqueous solubility, across parallel artificial membrane. The aqueous solubility and permeability of sildenafil as a function of solution pH were theoretically derived from the individual contributions of all species (cationic, neutral and anionic). The stability, octanol-water distribution coefficient (log D), and solubility of sildenafil were then determined at various pHs, the permeability study was also performed at different pHs using parallel artificial membrane. The pH-solubility and -permeability profiles were then fitted to theoretical equations using non-linear regression. The experimental pH-solubility profile was fitted very well to the theoretical equations (R(2)=0.9996). The in vitro permeability of saturated sildenafil solution at different pH values also showed similar trend as the predicted one (R(2)=0.7829). The two optimum pH (pH(max)) values were found to be 4.50 and 10.24, where the maximum solubility of either cationic or neutral species, or anionic and neutral species is simultaneously obtained, and the maximal transmucosal fluxes (J(ss)) are achieved. The above method can be applied to optimize the transmucosal delivery of other amphoteric drugs with low aqueous solubility.     

Systematic study of the flow behaviour and mechanical properties of Carbopol Ultrez 10 hydroalcoholic gels.

Flow behaviour and mechanical properties of 0:100, 15:85, and 30:70 v/v gelled ethanol:water mixtures are studied as a function of pH (4.0-7.0) and Carbopol Ultrez 10 concentration (0.1-0.5%). As previously reported individually for 30% v/v alcoholic Ultrez 10 gels, flow curves were adjusted to the Ostwald's model, and similar sigmoidal dose response functions were obtained to describe the pH dependence of consistency index and mechanical properties of the systems. The concentration dependence of flow indexes was also best adjusted to one-phase exponential decay functions. As a result, the influence of ethanol content on polymer network is meaningfully assessed by means of the obtained empirical parameters: bottom value of each variable (Y(max)), pH value required for a 50% polymer network development (pH(50)), and asymptotic flow index value for the fully structured gels (n(min)). Also, it is assessed the influence of cosolvent on the above-mentioned empirical variables, by studying pH-dependence of gelation in methanol:water, 1-propanol:water and 1-butanol:water 15:85% v/v mixtures. As a result, the alcohol induced variations in consistency and mechanical properties of hydroalcoholic gels were well correlated to modifications in the solubility parameter (delta(T)).