Stability of chosen beta-adrenolytic drugs of different polarity in basic environment

The stability of atenolol, acebutolol, and propranolol was investigated in sodium hydroxide solutions at concentrations of 0.1, 0.3, 0.5, and 1 M at 3 temperatures ranging from 37 to 95 degrees C. The degradation processes that occurred in drugs under investigation were described with kinetic parameters (k, t0.1, and t0.5) and energy of activation (Ea). It was found that the stability of the drugs increased toward lipophilic propranolol in the assumed experimental model. The rate constants k decreased, contrary to t0.1, t0.5, and Ea, which varied comparably to log P (partition coefficient), thus increasing from the most hydrophilic atenolol, through acebutolol of lower polarity, to the most lipophilic propranolol. The identification of degradation products was performed with the application of proton nuclear magnetic resonance spectrometry and thin-layer chromatography-densitometry and data from the literature.     

胶束液相色谱法同时测定血浆中的苯巴比妥、艾司唑仑和氯硝西泮

采用胶束液相色谱法(MLC)分离测定血浆中苯巴比妥、艾司唑仑和氯硝西泮,运用三相平衡理论探讨了流动相中表面活性剂浓度(CM)、氢离子浓度(CH)、助表面活性剂浓度(Cφ)对溶质保留行为的影响,同时运用多元线性回归建立了保留因子的对数(log k)与溶质性质参数和流动相组成之间的相关模型。结果表明,溶质保留因子(k)随CM、Cφ和CH的增加而减小,与理论模型完全一致。而且log k与溶质的疏水性常数的对数(log P)和电离常数(Ka)以及CM、CH和Cφ之间呈现良好的多元线性关系。在确定的色谱条件下,血浆中的3种药物与其他组分之间有较好的分离效果。3种药物的血药浓度分别在2.5～50 mg/L、0.25～5.0 mg/L和0.05～5.0 mg/L间具有良好的线性关系。本方法简便、准确、重现性良好、灵敏度高。3种药物的最低检出限(S/N=3)分别为10.27、1.17、0.867 ng,平均加标回收率范围分别为99.80%～102.9%, 94.00%～98.20%和96.30%～98.70%。     

Theoretical predictions of the initial decomposition steps of dimethylnitramine

The structures and energies of the reactants, products, and transition states of the initial steps in the gas-phase decomposition of dimethylnitramine (DMNA) have been determined by quantum chemical calculations at the B3LYP density-functional theory, MP2, and G2 levels. The pathways considered are NO2 elimination, HONO elimination, and nitro-nitrite rearrangement. The NO2 elimination is predicted to be the main channel of the gas-phase decomposition of DMNA in accord with experiment. The values of the Arrhenius parameters, log A=16.6+/-0.5 and Ea=40.0+/-0.6 kcal/mol, for the N-NO2 bond-fission reaction were obtained using a canonical variational theory with B3LYP energies and frequencies. The HONO-elimination channel has the next lowest activation energy of 44.7+/-0.5 kcal/mol (log A=13.6+/-0.5) and is characterized by a five-member transition-state configuration in which a hydrogen atom from one of the methyl groups is transferred to an oxygen atom of NO2. Tunneling contributions to the rate of this reaction have been estimated. The nitro-nitrite rearrangement reaction occurs via a transition state in which both oxygen atoms of NO2 are loosely bound to the central nitrogen atom, for which Rice-Ramsperger-Kassel-Marcus theory predicts log A=14.4+/-0.6 and Ea=54.1+/-0.8 kcal/mol.     

Lipophilicity assessment of basic drugs (log P(o/w) determination) by a chromatographic method

A previously reported chromatographic method to determine the 1-octanol/water partition coefficient (log P(o/w)) of organic compounds is used to estimate the hydrophobicity of bases, mainly commercial drugs with diverse chemical nature and pK(a) values higher than 9. For that reason, mobile phases buffered at high pH to avoid the ionization of the solutes and three different columns (Phenomenex Gemini NX, Waters XTerra RP-18 and Waters XTerra MS C(18)) with appropriate alkaline-resistant stationary phases have been used. Non-ionizable substances studied in previous works were also included in the set of compounds to evaluate the consistency of the method. The results showed that all the columns provide good estimations of the log P(o/w) for most of the compounds included in this study. The Gemini NX column has been selected to calculate log P(o/w) values of the set of studied drugs, and really good correlations between the determined log P(o/w) values and those considered as reference were obtained, proving the ability of the procedure for the lipophilicity assessment of bioactive compounds with very different structures and functionalities.     

Analysis of anticancer platinum(II)-complexes by microemulsion electrokinetic chromatography: separation of diastereomers and estimation of octanol-water partition coefficients

Microemulsion electrokinetic chromatography (MEEKC) was applied for the separation and lipophilicity estimation of oxaliplatin and eight novel anticancer oxaliplatin derivatives. Solubility and permeability have to be balanced in modern drug development, and the octanol-water partition coefficient (log P) still represents one of the most useful quantifiable parameters providing a reasonable estimation of a drug's lipophilicity. Therefore, the capacity factors from MEEKC were correlated to log P values derived by the traditional shake flask method. The MEEKC method was accomplished using a microemulsion of heptane/sodium dodecyl sulfate (SDS)/butanol in phosphate buffer at pH 7.4 and 37 degrees C with all analytes being in a neutral state during the run. This experimental setup allowed a baseline separation of all platinum complexes within 11 min. Remarkably, beside the very good resolution and precision of the measurements, separation of diastereomers of the complexes and quantification of the diastereomeric ratios could be achieved. Correlating the capacity factors with the corresponding log P values resulted in a linear dependency with a correlation factor of r = 0.9935. Consequently, the applied MEEKC method was found to be a highly valuable technique not only for the separation of platinum complexes but as well for the estimation of the octanol-water partition coefficient with many advantages in comparison to other methods.     

Direct time-resolved study of the gas-phase reactions of germylene with ethyl- and diethylgermane: absolute rate constants, temperature dependences, and mechanism

Time-resolved studies of germylene, GeH2, generated by the 193 nm laser flash photolysis of 3,4-dimethyl-1-germacyclopent-3-ene, have been carried out to obtain rate constants for its bimolecular reactions with ethyl- and diethylgermanes in the gas phase. The reactions were studied over the pressure range 1-100 Torr with SF6 as bath gas and at five temperatures in the range 297-564 K. Only slight pressure dependences were found for GeH2 + EtGeH3 (399, 486, and 564 K). The high pressure rate constants gave the following Arrhenius parameters: for GeH2 + EtGeH3, log A = -10.75 +/- 0.08 and Ea = -6.7 +/- 0.6 kJ mol-1; for GeH2 + Et2GeH2, log A = -10.68 +/- 0.11 and Ea = -6.95 +/- 0.80 kJ mol-1. These are consistent with fast, near collision-controlled, association processes at 298 K. RRKM modeling calculations are, for the most part, consistent with the observed pressure dependence of GeH2 + EtGeH3. The ethyl substituent effects have been extracted from these results and are much larger than the analogous methyl substituent effects in the SiH2 + methylsilane reaction series. This is consistent with a mechanistic model for Ge-H insertion in which the intermediate complex has a sizable secondary barrier to rearrangement.     

Screening of octanol-water partition coefficients for pharmaceuticals by pressure-assisted microemulsion electrokinetic chromatography

A rapid screening assay for the determination of octanol-water partition coefficients (log P(OW)) of pharmaceuticals was developed by using pressure-assisted microemulsion electrokinetic chromatography (MEEKC). The microemulsion system contains 50 mM sodium dodecyl sulfate, 0.87 M l-butanol, 82 mM heptane, and 50 mM borate-phosphate (2:3) at pH 10. Ten standard compounds with known log P(OW) values from -0.26 to 4.88 were used for constructing the calibration curve of log P(OW) against the MEEKC retention factor, log k. The log P(OW) values of the compounds were calculated based on the log k values measured by MEEKC and the slope and intercept of the calibration curve. For 13 literature and 32 Roche compounds, about 90% of the log P(OW) values measured by MEEKC are within 0.5 log units of the values from the literature and potentiometric titration. The throughput is about 2 samples/h using +20 kV voltage plus 5 mbar air pressure for separation. This MEEKC method is applicable for log P(OW) screening of weakly basic, weakly acidic, and neutral pharmaceuticals with log P(OW) = 0-5 and pKa < or = 10.     

气相色谱法测定及预测有机磷阻燃剂的蒸气压

以p,p′-二氯二苯三氯乙烷(p,p′-DDT)为参考化合物,采用气相色谱法(GC)测定了14种有机磷阻燃剂(OPFRs)在不同温度(T)条件下的蒸气压(P_(GC))及其蒸发热。根据获得的蒸气压值,发现14种OPFRs的log P_(GC)随着温度的增加而减小。初步探讨了分子结构与log P_(GC)的相关性,结果发现卤代烷基磷酸酯的log P_(GC)低于烷基和芳基磷酸酯,且随着分子摩尔体积的增大,相应的log P_(GC)呈下降趋势。采用逐步回归的方法,建立了OPFRs的相对保留时间(RRT)与log P_(GC)之间的定量构效关系(QSPR)模型,模型的累计交叉有效判别系数Q2cum为0.946。模型对OPFRs的log P_(GC)预测值与实验值有良好的相关性(r=0.980),结果表明所建模型具有良好的稳健性和预测能力。利用建立的方法,通过测定的保留时间参数以及定量构效关系模型,可有效预测目前没有标准品的OPFRs的log P_(GC)值。     

Estimation of soil organic partition coefficients: from retention factors measured by soil column chromatography with water as eluent

The retention factors (k) of 104 hydrophobic organic chemicals (HOCs) were measured in soil column chromatography (SCC) over columns filled with three naturally occurring reference soils and eluted with Milli-Q water. A novel method for the estimation of soil organic partition coefficient (Koc) was developed based on correlations with k in soil/water systems. Strong log Koc versus log k correlations (r>0.96) were found. The estimated Koc values were in accordance with the literature values with a maximum deviation of less than 0.4 log units. All estimated Koc values from three soils were consistent with each other. The SCC approach is promising for fast screening of a large number of chemicals in their environmental applications.     

Hydrophobicity parameters determined by reversed-phase liquid chromatography. XV: optimal conditions for prediction of log P(oct) by using RP-HPLC procedures

The use of log k derived from reversed phase (RP)-HPLC retention times provides a convenient method for estimating log P(oct) values (P(oct): 1-octanol/water partition coefficient). In order to establish optimal HPLC conditions, the difference between chromatographic (C18 modified column and aqueous methanol eluents) and bulk solvent systems was examined by use of a batch-like equilibration with octane/aqueous methanol. Comparison of values for log P(O/M-W) (log P for the Octane/MeOH-Water partitioning system) and log k measured for monosubstituted pyrazines at different methanol concentrations, showed closest correlation (r, 0.94) with 50% aqueous methanol; and importantly, under these conditions, log k shows even better correlation (r, 0.99) with log P(oct). Effects of residual silanols on HPLC retention with C18 stationary phases were examined. The results show that, in the presence of a small quantity of accessible silanols, the use of 50% aqueous methanol (M50) as eluent yields values of log k directly proportional to log P(oct) in accord with our earlier proposal that use of log k(M50) provides a convenient means for rapid estimation and prediction of log P(oct).     

Prediction of retention time of phenols in liquid chromatography

The chromatographic behavior of phenols in reversed-phase mode liquid chromatography differs from that of non-ionic compounds such as alkyl alcohols, alkylbenzenes, halogenated benzenes, polyaromatic hydrocarbons, and aromatic acids. Therefore, the retention times of 61 phenols were measured in a system of an octadecyl bonded silica gel and acetonitrile/water mixtures. The logarithm of the capacity ratio (log k') was found to be a linear function of the hydrophobicity (log P) in acidic acetonitrile/water mixtures. This result was applied to a different octadecyl bonded silica gel. Eight phenols were selected as standard compounds, and their log k' values were measured in 0.05 M phosphoric acid in 10 to 90% acetonitrile/water mixtures. An empirical polynomial relation was obtained between the concentration of acetonitrile and the slope of the log k' vs log P curve. Finally the capacity ratio of all phenols were calculated in given eluents by the equations derived from the measurements of standard compounds and the calculated log P values. The difference between predicted capacity ratios and measured ones was within 10%.     

Lipophilicity measurement of drugs by reversed phase HPLC over Wide pH range using an alkaline-resistant silica-based stationary phase, XBridge Shield RP(18)

We propose a reversed phase HPLC (RP-HPLC) with an alkaline-resistant silica-based stationary phase, XBridge Shield RP(18), for the determination of the lipophilicity of drugs with diverse chemical nature ranging from acidic to basic. A set of 40 model compounds with well-defined solvatochromic parameters was selected to allow a broad distribution of structural properties. The chromatographic results showed that the lipophilicity index log k(w) obtained with XBridge Shield RP(18) was well correlated with experimental log P(oct) values (r(2)=0.96). Linear solvation free-energy relationship (LSER) analyses revealed that the retention mechanism of the stationary phase and 1-octanol/water partitioning were controlled by almost the same balance of intermolecular forces (hydrophobicity as expressed by the van der Waals volume V(w), H-bond acceptor basicity beta, and dipolarity/polarizability pi*). The results showed that XBridge Shield RP(18) phase overcomes the shortcomings of the silica-based stationary phases, the application of which to lipophilicity measurements had been limited to neutral and acidic compounds.     

N-in-one determination of retention factors for drugs by immobilized artificial membrane chromatography coupled to atmospheric pressure chemical ionization mass spectrometry.

Immobilized artificial membrane (IAM) chromatography is widely used in drug discovery for ranking the absorption properties of drug candidates. In this work an IAM chromatography method using atmospheric pressure chemical ionization mass spectrometric detection (IAM/APCI-MS) was developed for the determination of log k(IAM) values for a mixture of compounds (9-in-one). Values were calculated from isocratic runs (0, 10, 20, 30, 35% acetonitrile) in both positive and negative modes. Good correlation (r(2) = 0.97) was achieved for n-in-one results obtained with ammonium acetate buffer and mass spectrometry, compared with the traditional method involving single compound analysis with phosphate buffered saline and an ultraviolet detector. A gradient elution method providing fast determination of relative log k(IAM) values in a single IAM/APCI-MS run was demonstrated for the same compounds.     

具有油水分配系数测算功能的中药指纹图谱

建立了一种能同时测算中药中主要成分的油水分配系数Pow的功能化中药指纹图谱。采用微乳液电动色谱,以中药女贞子为例,对运行缓冲液浓度、pH值、十二烷基硫酸钠浓度等参数进行了优化。利用SPSS程序对磺胺等从女贞子中提取的6种标准化合物组分的迁移时间tm与其log Pow文献值进行非线性拟合,得到女贞子提取组分的标准方程线性关系良好（r=0.9880）。在相同的实验条件下测得化合物的log Pow与文献报道值较好的符合,证明该方法可靠。获得了能代表组分疏水化学特征的中药指纹图谱,测得女贞子的主要有效成分齐墩果酸的log Pow为3.63。该指纹图谱较为可靠地提供了女贞子中各种成分的log Pow,直观地反映出各组分油水分配性质的分布,对中药有效成分提取溶剂的选择、剂型的设计及制剂工艺的改进具有指导意义。     

Effect on kinetics by deuterium in the 1,5-hydrogen shift of a cisoid-locked 1,3(Z)-pentadiene, 2-methyl-10-methylenebicyclo[4.4.0]dec-1-ene: evidence for tunneling?

Prompted by extensive theoretical interest in the role of tunneling in the intramolecular 1,5-hydrogen shift in 1,3(Z)-pentadienes and the large uncertainty in the published values of the theoretically relevant kinetic deuterium-isotope effect and its dependence on temperature, we have examined a degenerate bicyclic version, 2-methyl-10-methylenebicyclo[4.4.0]dec-1-ene, which is locked into the rearrangement-competent cisoid conformation, in the hope of obtaining more precise and accurate values. From rate constants determined over a range of 33 degrees C from 167.7 to 201.6 degrees C, Arrhenius parameters, Ea = 32.8 +/- 0.4 kcal mol(-1) and log A = 11.1 +/- 0.2, were obtained. An average kinetic isotope effect of 4.2 +/- 0.5 obtained from all values for kH/kD and k-H/k-D may be compared with a value of 5.0 +/- 0.3, recalculated from data in the pioneering publication of Roth and K?nig. From a highly problematic extrapolation of the temperature dependence, a value of kH/kD of 16.6 (standard error between 6.5 and 43) is calculated for the kinetic isotope effect at 25 degrees C (Roth and K?nig: 12.2). With curvature in Arrhenius plots being one of the three types of experimental evidence considered indicative of tunneling, the kinetic study of the previously published rearrangement of 1-phenyl-5-p-tolyl-1,3(Z)-pentadiene has been extended over a period of 339 days to a range of 108 degrees C (77-185 degrees C) without discerning any deviation from a straight-line Arrhenius plot: Ea = 28.7 +/- 0.5 (kcal mol(-1)) and log A = 9.41 +/- 0.30.