Potential of immobilized artificial membrane chromatography for lipophilicity determination of arylpropionic acid non-steroidal anti-inflammatory drugs

Molecular lipophilicity can be expressed by logP or more conveniently by logk, i.e. determined by the traditional shake-flask technique or by liquid chromatography. The logk of 11 arylpropionic non-steroidal anti-inflammatory drugs (NSAIDs) was determined at pH 7.4 of the eluent using two stationary phases i.e. octadecylsilane phase and an immobilized artificial membrane (IAM.PC.MG) packing. The chromatographic retention factors extrapolated to 100% aqueous phase (logk(wODS) and logk(wIAM)) were correlated with n-octanol/water lipophilicity parameters (logP) and with n-octanol/water partition coefficients corrected for ionization at pH 7.4 (logD7.4). In this series of compounds, significant linear correlations (r>0.94) between the chromatographic parameters (logk(wIAM)) and the reference lipophilicity data (logP and logD7.4) were described. Moreover, regression analysis between the lipophilicity parameters and some pharmacokinetic data for the drugs under study were performed. The logk(wIAM) parameter over n-octanol/water partition data seems to provide a good model to obtain lipophilicity parameters of arylpropionic acid NSAIDs for quantitative structure-activity relationships studies.     

Experimental and Computational Screening Models for Prediction of Aqueous Drug Solubility

Purpose. To devise experimental and computational models to predict aqueous drug solubility. Methods. A simple and reliable modification of the shake flask method to a small-scale format was devised, and the intrinsic solubilities of 17 structurally diverse drugs were determined. The experimental solubility data were used to investigate the accuracy of commonly used theoretical and semiexperimental models for prediction of aqueous drug solubility. Computational models for prediction of intrinsic solubility, based on lipophilicity and molecular surface areas, were developed. Results. The intrinsic solubilities ranged from 0.7 ng/mL to 6.0 mg/mL, covering a range of almost seven log₁₀ units, and the values determined with the new small-scale shake flask method agreed well with published solubility data. Solubility data computed with established theoretical models agreed poorly with the experimentally determined solubilities, but the correlations improved when experimentally determined melting points were included in the models. A new, fast computational model based on lipophilicity and partitioned molecular surface areas, which predicted intrinsic drug solubility with a good accuracy (R ²of 0.91 and RMSE_tr of 0.61) was devised. Conclusions. A small-scale shake flask method for determination of intrinsic drug solubility was developed, and a promising alternative computational model for the theoretical prediction of aqueous drug solubility was proposed.     

Chromatographic behavior of zwitterionic enalapril-exploring the conditions for lipophilicity assessment

The chromatographic behavior of enalapril was investigated under different stationary and mobile phase conditions in an effort to unravel interferences in the underlying retention mechanism, which would affect its relation to octanol-water partitioning. Extrapolated retention factors, logk(w), were used as relevant chromatographic indices. The retention/pH profile was established and the peak split phenomenon, associated with cis/trans interconversion, was also monitored as a function of pH. The pH at maximum retention and minimum peak split occurrence was chosen for further investigation, so that the presence of zwitterionic structure was guaranteed and any effect of cis/trans interconversion could be ignored. Retention of zwitterionic enalapril was found to be very sensitive to mobile phase conditions in regard to organic modifier as well to the aqueous component. The use of morpholine-propanesulfonic acid (MOPS) as buffer and the presence of n-octanol as mobile phase additive proved critical factors for maximum suppression of secondary interactions. Nevertheless, the corresponding extrapolated retention factor was considerably larger than octanol-water logD value at the isoelectric point. However, logk(w) could be successfully converted to logD by means of a calibration equation established for ionized acidic compounds.     

Accuracy of calculated pH-dependent aqueous drug solubility

The aim of the present study was to investigate the extent to which the Henderson–Hasselbalch (HH) relationship can be used to predict the pH-dependent aqueous solubility of cationic drugs. The pH-dependent solubility for 25 amines, carrying a single positive charge, was determined with a small-scale shake flask method. Each sample was prepared as a suspension in 150 mM phosphate buffer. The pH-dependent solubility curves were obtained using at least 10 different pH values. The intrinsic solubility, the solubility at the pK_a and the solubility at pH values reflecting the pH of the bulk and acid microclimate in the human small intestine (pH 7.4 and 6.5, respectively) were determined for all compounds. The experimental study revealed a large diversity in slope, from −0.5 (celiprolol) to −8.6 (hydralazine) in the linear pH-dependent solubility interval, which is in sharp contrast to the slope of −1 assumed by the HH equation. In addition, a large variation in the range of solubility between the completely uncharged and completely charged drug species was observed. The range for disopyramide was only 1.1 log units, whereas that for amiodarone was greater than 6.3 log units, pointing at the compound specific response to counter-ion effects. In conclusion, the investigated cationic drugs displayed compound specific pH-dependent solubility profiles, indicating that that the HH equation in many cases will only give rough estimations of the pH-dependent solubility of drugs in divalent buffer systems.     

黄芩苷在不同pH值缓冲液中理化常数的测定

目的考察黄芩苷在不同pH值中的平衡溶解度与表观油水分配系数,为制剂研究奠定基础。方法采用摇瓶-紫外分光光度法测定温度为25和37℃时,黄芩苷在不同pH值磷酸盐缓冲溶液中的平衡溶解度及在正辛醇/缓冲液体系中的表观油水分配系数。结果 25℃时,黄芩苷在pH=2.0,3.0,4.0,5.0,6.0,6.8,7.4,8.0和9.0缓冲液中的平衡溶解度分别为0.032,0.034,0.119,0.873,3.329,12.96,11.49,4.605和11.87mg.mL-1,相应条件下表观油水分配系数(P)值分别为0.363,0.244,0.292,0.137,0.057,0.046,0.036,0.028和0.029。37℃时,黄芩苷在pH=2.0,3.0,4.0,5.0,6.0,6.8,7.4,8.0和9.0缓冲液中的平衡溶解度分别为0.028,0.048,0.095,0.950,4.881,14.15,26.65,14.48和17.89mg.mL-1,相应条件下表观油水分配系数(P)值分别为0.234,0.224,0.365,0.103,0.074,0.049,0.034,0.034和0.035。结论黄芩苷的平衡溶解度在酸性及中性条件下受温度影响很小,在碱性条件下随着温度升高而增加;黄芩苷在酸性条件下的P值比在碱性条件下大,Pmax=0.363(T=25℃,pH=2),Pmax=0.365(T=37℃,pH=4),随着碱性的增加P值变化不明显,且温度对黄芩苷的P值几乎无影响。     

Effect of pH and water-soluble polymers on the aqueous solubility of nimesulide in the absence and presence of beta-cyclodextrin derivatives

The aqueous solubility of nimesulide in the absence and presence of beta-cyclodextrin (beta-CD) and its alkyl derivatives hydroxypropyl-beta-CD and methyl-beta-CD was studied. We also investigated the effect of water-soluble polymers, hydroxypropylmethyl-cellulose, sodium-carboxymethyl-cellulose, polyvinylpyrrolidone and polyethyleneglycol on the solubilization efficacy and complexation ability of cyclodextrins with nimesulide. The solubility of nimesulide in the absence and presence of cyclodextrins and polymers was studied using a phase solubility technique combined with a spectrophotometric method. The study was carried out at 25 degrees C and pH values of 6.0 and 7.0. Conditions in terms of polymer concentration and polymer heating with and without sonication were optimized. Values of the solubility enhancement factor of nimesulide in the presence of each cyclodextrin and in the absence and presence of each polymer were determined and the formation constants, K, of the inclusion complexes formed calculated. beta-CDs increased the aqueous solubility of nimesulide in the following order: methyl-beta-CD > beta-CD > hydroxypropyl-beta-CD. Addition of hydroxypropylmethyl-cellulose at a concentration of 0.1% (w/v) had the greatest influence on complexation of all three beta-CDs with nimesulide, while preheating of the polymer at 70 degrees C under sonication resulted in an additional two-fold increase in the aqueous solubility of the drug. Sodium-carboxymethyl-cellulose, polyvinylpyrrolidone and polyethyleneglycol had minor effects on the aqueous solubility of nimesulide. Thus beta-CD, hydroxypropyl-beta-CD and methyl-beta-CD are proposed as good solubilizing agents for nimesulide in the presence and absence of hydroxypropylmethyl-cellulose in order to enhance its oral bioavailability.     

The physicochemical properties and the in vivo AChE inhibition of two potential anti-Alzheimer agents, bis(12)-hupyridone and bis(7)-tacrine

The lipophilicity and solubility profiles of bis(12)-hupyridone (B12H) and bis(7)-tacrine (B7T), two novel acetylcholinesterase inhibitors dimerized from huperzine A fragments and tacrine, respectively, were investigated over a broad pH range. Lipophilicity was assessed by both shake flask method with 1-octanol-water system and a reverse-phase HPLC system with methanol-water as mobile phase. The former method was used for determining the lipophilicities of the ionized forms (log D) of the dimers while the latter method was used for that of the neutral forms (log P). The log P values for B12H and B7T were found to be 5.4 and 8.2, respectively, indicating that the two dimers are highly lipophilic. The solubilities of both dimers were found to be affected by pH. The solubility of B12H was >1.41 mg/ml when the pH was <7, but <0.06 mg/ml when the pH was >8. The solubility of B7T was >0.26 mg/ml when the pH was <9, but <0.005 mg/ml when the pH was >12. The ionic strength of a solution could affect the solubilities considerably (11.16 mg/ml for B12H and 12.71 mg/ml for B7T in water; 2.07 mg/ml for B12H and 0.36 mg/ml for B7T in saline). The ionization constants (pK(a)) of the two dimers were determined by UV spectrophotometry. Both dimers were found to have two pK(a) values: 7.5+/-0.1 (pK(a1)) and 10.0+/-0.2 (pK(a2)) for B12H; and 8.7+/-0.1 (pK(a1)) and 10.7+/-0.4 (pK(a2)) for B7T. Furthermore, an in vivo pharmacological assay conducted in mice showed that a maximum AChE inhibition occurred 15 min after the single-dose and intraperitoneal administration of either dimer. This indicates that the two dimers may easily cross the blood-brain barrier. In summary, these physiochemical characteristics suggest that the two dimers may be promising candidates for the development of better drugs for Alzheimer's disease.     

Lipophilic and electrostatic forces encoded in IAM-HPLC indexes of basic drugs: their role in membrane partition and their relationships with BBB passage data

The membrane phospholipid affinity data, log k(w)(IAM), for 14 basic drugs spanning a wide lipophilicity range were measured by HPLC on two different phospholipid stationary phases, i.e. IAM.PC.MG and IAM.PC.DD2. These data related weakly with log P(N) values, the n-octanol/water partition coefficients of the neutral forms; poorer relationships were found with log D(7.0) values, the n-octanol/water partition coefficients of the mixtures of neutral and ionized forms at pH 7.0. The lack of collinearity confirms that, differently from partition in n-octanol/water, partition in phospholipids encodes not only lipophilic/hydrophobic intermolecular recognition forces but also ionic bonds, due to electrostatic interactions between electrically charged species and phospholipids, according to the "pH-piston hypothesis". This component of interaction was parameterized by Δ log k(w)(IAM) values; they are the differences between the log k(w)(IAM) values experimentally measured and the values expected for neutral isolipophilic compounds. Δ log k(w)(IAM) values of the various analytes changed almost linearly from positive to negative values at increasing lipophilicity. This behavior is consistent with an interaction mechanism with membrane phospholipids including two intermolecular interaction forces: (i) lipophilic/hydrophobic interactions, which decrease on ionization proportionally to the lipophilicity of the neutral forms, and (ii) electrostatic interactions, which increase on ionization and are quite constant for all the analytes at a given ionization degree. Since BBB passage of the considered compounds is supposed to be based on passive mechanisms, we investigated the possible relationships between log BB values, i.e. the logarithms of the ratio between brain and blood concentrations, and three physico-chemical parameters, i.e. (i) log P(N) (lipophilic interaction of the neutral form), (ii) log k(w)(IAM) (global interaction with phospholipids), and (iii) Δ log k(w)(IAM) (electrostatic component of interaction with phospholipids). The results suggest that the electrostatic interactions encoded in log k(w)(IAM) values might act as trapping forces in a phospholipid barrier. Actually, we observed an inverse linear dependence of log BB on Δ log k(w)(IAM) values, but only for the compounds showing positive Δ log k(w)(IAM) values. We conclude that the driving force for BBB passage is the lipophilicity of the neutral forms, log P(N), and not the lipophilicity actually displayed at the experimental pH, log D(7.0). Indeed, the latter does not adequately take into account the role played by protonation in the analyte/membrane interactions because protonation, although hindering membrane passage, can either reduce or enhance partition in phospholipids, depending on analyte lipophilicity.     

Protonation equilibrium and lipophilicity of moxifloxacin

This study was performed to characterise the protonation equilibrium at the molecular level and pH-dependent lipophilicity of moxifloxacin. After determining macro- and micro-constants, distribution features of four microspecies in aqueous phase were assessed. The apparent partition coefficient versus pH profile of moxifloxacin showed a parabolic curve in n-octanol/buffer system which reached near pI. The true partition coefficient was calculated from the log P(app) and microconstants values.     

pH-Metric log K calculations of famotidine, naproxen, nizatidine, ranitidine and salicylic acid.

The octanol/water partition coefficient (log K) is one of the most commonly used parameters in structure-activity relationships in many areas such as drug design (including pesticides), pharmacokinetics, anesthesiology, environmental sciences, toxicology, bioaccumulation and predicting skin permeability as a predictive parameter. log K is generally determined using shake flask method, but the possibility of calculating log K using pH-metric titrations and half neutralization points is demonstrated in this study. The potentiometric pH titration technique has been developed as an automatic technique for log K determination but it can be achieved by manual titrations. This technique uses the pKa of the substance. The pKa of the substance shifts pK'a when the titration is repeated in the presence of octanol. log K value of the substance can be determined using pKa, pK'a values and relevant equation. The aim of the study was to determine the log K values of a series of compounds using pH-metric titrations and to compare pH-metric log K determination results with the other methods. The log K values of famotidine, naproxen, nizatidine, ranitidine and salicylic acid were determined using both shake flask method and potentiometric titrations. Their log K values were also calculated theoretically using computer program and all results were compared. The pH-metric log K values were found to be close to the shake flask method results. This method was found to be useful for the determination of log K values as it provides a high degree of accuracy even in the presence of titratable impurities in the solution.     

Determination of lipophilicity of novel potential antituberculotic agents using HPLC on monolithic stationary phase and theoretical calculations

The HPLC analyses on the monolithic stationary phase were employed for rapid determination of lipophilicity of the two sets of newly synthesized potential antituberculotic agents. The analyses utilized the mixture of methanol and phosphate buffer (pH 7.4) as a mobile phase and a flow rate of 4mL/min. Monolithic stationary phase enabled to significantly reduce the time of analyses, achieve appropriate peak shapes for all tested compounds as well as the separation of positional isomers. Furthermore, the theoretical lipophilic parameters (logP) for all compounds were calculated employing the chemical programs (e.g., ACD/logP, HyperChem, miLogP, AlogP, KOWWIN and COSMOFrag, etc.). The experimental data (logk) and calculated logP values were compared by linear regression analysis. The highest correlation for both series was obtained for KOWWIN and miLogP programs. However, capability of particular chemical software to precisely predict lipophilicity of a compound is structurally dependent. Thus the predictive power of the selected program should be verified using experimental method. The results of this study documented that experimental determination of lipophilicity using HPLC on monolithic stationary phase is practical and reasonable for this purpose.     

Ion-pairs of ibuprofen: increased membrane diffusion

The purpose of the present study was to determine the influence of pH and ion-pairing on the permeation of ibuprofen across polydimethylsiloxane (PDMS) membrane. The solubility of ibuprofen sodium was determined at a range of pH values. Saturated solutions were then used to determine the influence of pH on diffusion across PDMS as a model membrane. The apparent partition coefficient of ibuprofen sodium between n-octanol and phosphate buffer at various pH values was also investigated. Organic salts of ibuprofen using ethylamine, diethylamine, triethylamine and ethylene diamine as counter-ions were synthesized and the influence of these counter-ions on the permeation of ibuprofen was studied. The presence of ion-pairing was confirmed using 1H NMR and 13C NMR. Diffusion studies at different pH values (4.0, 5.0, 6.0, 7.0 and 8.0) indicated that ibuprofen sodium flux increased significantly with increasing pH from 4.0 to 7.0. Above pH 7.0 a decrease in diffusion was observed. The permeability coefficient increased with an increase in the amount of unionized acid. The apparent partition coefficient was directly related to the steady-state flux. The steady-state flux of ibuprofen increased up to 16-fold using different counter-ions. The highest flux was measured from ibuprofen triethylamine. The flux of ibuprofen salts across a lipophilic membrane can be increased by formation of ion-pairs. The extent of enhancement is associated with the lipophilicity, extent of ion-pairing and reduction in charge over the drug molecule.     

延胡索乙素在不同溶剂中平衡溶解度及其油水分配系数的测定

目的测定延胡索乙素在各种溶剂中的平衡溶解度以及在正辛醇-水中的表观油水分配系数,为延胡索乙素经皮给药制剂的制备提供实验基础。方法采用紫外分光光度法测定延胡索乙素在不同pH缓冲液中的平衡溶解度;采用高效液相色谱(HPLC)方法,测定不同介质中延胡索乙素的平衡溶解度;采用摇瓶法测定延胡索乙素的表观油水分配系数。结果 32℃延胡索乙素在pH7.4缓冲液中的平衡溶解度为32.47mg/L,在酸性缓冲液中溶解度增大;32℃延胡索乙素在油酸、吐温80中有较好的增溶能力,其溶解度分别为22165.21mg/L、69653.86mg/L;延胡索乙素的表观油水分配系数为3.12。结论延胡索乙素水溶性差,在油酸和吐温80中有较好的增溶能力。     

Influence of enhancers on the absorption and on the pharmacokinetics of cefodizime using in-vitro and in-vivo models

In the development of novel antibiotics, more and more compounds have been found that cannot be absorbed orally and, therefore, must be administered intravenously or intramuscularly. Because of the obvious drawbacks of drug delivery by injection, the development of alternatives with enhanced oral bioavailability has received much attention in pharmaceutical research. Cefodizime, a novel third-generation cephalosporin with significant advantages in the parenteral treatment of common infections, was used as a model drug. Cefodizime behaves as a highly hydrophilic compound, as shown from its extremely low partition coefficient. The effect of cationic absorption enhancers (hexadecyldimethylbenzylammonium chloride, N-hexadecylpyridinium bromide, dodecyltrimethylammonium bromide and hexadecyltrimethylammonium bromide) on the lipophilicity of cefodizime was investigated by means of the n-octanol/water system. Results showed that the counter-ions had a positive influence on the solubility of cefodizime. These results on partitioning coefficients in the n-octanol/buffer system were confirmed using an in-vitro transport model with artificial and biological membranes (Caco-2-cells). Furthermore, the physiological compatibility of the absorption enhancers was investigated using the active D-glucose transport. The pharmacokinetic profile of cefodizime was evaluated in rabbits after intraduodenal administration with and without an absorption enhancer.     

Ionization, lipophilicity and solubility properties of repaglinide

Potentiometric and spectrophotometric titrations were used for the determination of ionization behaviour, lipophilicity and solubility profile of repaglinide. Acid-base equilibria were characterized by means of protonation macro- and microconstants using Target Factor Analysis of spectrophotometric data. Lipophilicity profiles were evaluated by determination of partition coefficients of neutral and ionized forms of repaglinide in biphasic octanol/water system. The intrinsic solubilities of repaglinide were determined from the solubility data and temperature dependence of intrinsic solubilities were evaluated using van't Hoff equation. Repaglinide possesses two protonation sites and in aqueous solutions exhibits ampholitic properties. At isoelectric pH the zwitterionic form of the molecule predominates over the uncharged form with the tautomeric ratio, logKz=1.9. The difference between calculated and measured logP values, as well as the difference between logP values of uncharged form of repaglinide, HR0, and either one of mono-charged forms indicated the significant partition of zwitterion into octanol. Temperature dependence of solubility data revealed exothermic dissolution process with DeltasolH=-36 kJmol-1 and negative entropy of solution of DeltasolS=-0.19 kJK-1mol-1.     

醋酸氯地孕酮平衡溶解度及表观油水分配系数的测定

目的:测定醋酸氯地孕酮(CA)的平衡溶解度及表观油水分配系数,为CA新剂型的体外评价进行处方前研究。方法:采用高效液相色谱法测定CA在水及不同pH(1·2、2·0、3·0、4·5、5·5、6·8、7·4、8·0)介质及常用9种有机溶剂(包括甲醇、乙醇等)中的平衡溶解度;采用摇瓶法测定其在正辛醇与水及各pH介质组成的体系中的表观油水分配系数(P)。结果:37℃时,CA在水及9种pH值介质中的平衡溶解度依次为0·473、0·533、0·423、0·056、0·309、0·428、0·447、0·428、0·448μg·mL-1,在甲醇、乙醇等中的平衡溶解度为7320·61～344248·70μg·mL-1;CA在水中的lgP值为4·05,不同pH条件下的lgP值差别不大(4·11～4·25)。结论:CA不溶于水,易溶于有机溶剂,在弱酸环境下有一定程度的降解;且其lgP值较大,提示在制剂研究中需采用适当的增溶手段。     

Preparation of nanomagnetic absorbent for partition coefficient measurement

In this paper, we report a new method based on supercritical carbon dioxide (scCO(2)) to fill and distribute the porous magnetic nanoparticles with n-octanol in a homogeneous manner. The high solubility of n-octanol in scCO(2) and high diffusivity and permeability of the fluid allow efficient delivery of n-octanol into the porous magnetic nanoparticles. Thus, the n-octanol-loaded magnetic nanoparticles can be readily dispersed into aqueous buffer (pH 7.40) to form a homogenous suspension consisting of nano-sized n-octanol droplets. We refer this suspension as the n-octanol stock solution. The n-octanol stock solution is then mixed with bulk aqueous phase (pH 7.40) containing an organic compound prior to magnetic separation. The small-size of the particles and the efficient mixing enable a rapid establishment of the partition equilibrium of the organic compound between the solid supported n-octanol nano-droplets and the bulk aqueous phase. UV-vis spectrophotometry is then applied to determine the concentration of the organic compound in the aqueous phase both before and after partitioning (after magnetic separation). As a result, logD values of organic compounds of pharmaceutical interest determined by this modified method are found to be in excellent agreement with the literature data.     

VBE-1平衡溶解度和表观油水分配系数的测定及其酸碱稳定性的考察

目的：测定VBE-1的平衡溶解度和表观油水分配系数,并考察其酸碱稳定性,为药物的制剂设计提供实验依据。方法：采用平衡法和摇瓶法测定VBE-1在不同溶剂中的平衡溶解度以及在正辛醇-水/缓冲溶液中的表观油水分配系数,采用高效液相色谱法测定两者的浓度,并用紫外分光光度法考察VBE-1的酸碱稳定性。结果：VBE-1在PEG-400中的溶解度较大,为（677.47±48.09）g·L^-1。在pH4.0~8.0范围内,pH对VBE-1的表观油水分配系数有影响,表现出表观油水分配系数随着pH升高而降低的趋势。pH的升高会引起VBE-1颜色的改变,但此变化为可逆反应。结论：VBE-1具有一定的透过能力,可满足经皮给药的一般要求,其对pH较敏感,实验过程中应避免在强碱条件下操作。     

Estimation of logP(ow) values for neutral and basic compounds by microchip microemulsion electrokinetic chromatography with indirect fluorimetric detection (muMEEKC-IFD)

Microchip microemulsion electrokinetic chromatography with indirect fluorimetric detection (muMEEKC-IFD) was used to obtain logP octanol/water (logP(ow)) values for neutral and basic compounds. Six compounds, with logP(ow) values between 0.38 and 5.03, were used to create a calibration curve relating the log of retention factors (logk) obtained from muMEEKC-IFD with the known logP(ow) values. The logP(ow) values for six additional compounds were determined using the logk values obtained by muMEEKC-IFD and the linear relationship between logP(ow) and logk established for the standard compounds. The muMEEKC-IFD buffer was composed of 50 mM 3-[cyclohexylamino]-1-propane-sulfonic acid (CAPS) buffer (pH 10.4) containing 1.2% n-heptane (v/v), 2% sodium dodecylsulfate (w/v), 8% 1-butanol (v/v) and 4 microM 5-carboxytetramethyl-rhodamine (TAMRA) as the fluorophore probe for indirect detection. The muMEEKC-IFD provided an accurate method for estimating logP(ow) values and also a means for analyzing compounds that are non-fluorescent.     

雷公藤甲素及其氨基葡萄糖结合物的表观溶解度、表观油水分配系数和解离常数的测定

目的 测定雷公藤甲素及其氨基糖结合物的表观溶解度、表观油水分配系数和解离常数(pKTa).方法 采用平衡溶解度法、摇瓶法测定雷公藤甲素及其氨基糖结合物的表观溶解度和油水分配系数;采用分光光度指示剂法测定雷公藤甲素-氨基糖结合物的解离常数.结果 雷公藤甲素的表观溶解度随pH的增加而增加,其表观油水分配系数随pH的增加而降低,但变化并不显著.雷公藤甲素-氨基葡萄糖结合物的表观油水分布系数随pH的增加而增加,在纯水中的表观溶解度为1.9325±0.1373 g,pKT =5.938 ±0.191.结论 雷公藤甲素是一个难溶性的亲脂性化合物,而雷公藤甲素-氨基葡萄糖结合物是一个弱碱性的亲水性化合物.