The Expanded Hansen Approach to Solubility Parameters. Paracetamol and Citric Acid in Individual Solvents

In this study two solubility-parameter models have been compared using as dependent variables the logarithm of the mole fraction solubility, lnX₂^e, and ln(α)/U (originally used in the extended Hansen method), where α is the activity coefficient and U is a function of the molar volume of the solute and the volume fraction of the solvent. The results show for the first time the proton-donor and -acceptor hydrogen-bonding capacities of paracetamol, as measured by the acidic and basic partial-solubility parameters. The influence of solvents on the differential scanning calorimetry (DSC) pattern of the solid phases was also studied in relation to the solubility models tested. Citric acid was chosen as a test substance because of its high acidity and its proton donor capacity to form hydrogen bonds with basic solvents. The partial acidic and basic solubility parameters obtained from multiple regression were consistent with this property, validating the model chosen. The results show that the more direct lnX₂^e variable was more suitable for fitting both models, and the four-parameter model seemed better for describing the interactions between solvent and solute.     

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.     

Proposition of group molar constants for sodium to calculate the partial solubility parameters of sodium salts using the van Krevelen group contribution method.

The aim of this study is to propose, for the first time, a set of group molar constants for sodium to calculate the partial solubility parameters of sodium salts. The values were estimated using the few experimental partial solubility parameters of acid/sodium salt series available either from the literature (benzoic acid/Na, ibuprofen acid/Na, diclofenac Na) or determined in this work (salicylic acid/Na, p-aminobenzoic acid/Na, diclofenac), the group contribution method of van Krevelen to calculate the partial parameters of the acids, and three reasonable hypothesis. The experimental method used is a modification of the extended Hansen approach based on a regression analysis of the solubility mole fraction of the drug lnX(2) against models including three- or four-partial solubility parameters of a series of pure solvents ranging from non-polar (heptane) to highly polar (water). The modified method combined with the four-parameter model provided the best results for both acids and sodium derivatives. The replacement of the acidic proton by sodium increased the dipolar and basic partial solubility parameters, whereas the dispersion parameter remained unaltered, thus increasing the overall total solubility parameter of the salt. The proposed group molar constants of sodium are consistent with the experimental results as sodium has a relatively low London dispersion molar constant (identical to that of -OH), a very high Keesom dipolar molar constant (identical to that of -NO(2), two times larger than that of -OH), and a very high hydrogen bonding molar constant (identical to that of -OH). The proposed values are: F((Na)d)=270 (J cm(3))(1/2) mol(-1); F((Na)p)=1030 (J cm(3))(1/2) mol(-1); U((Na)h)=17000 J mol(-1). Like the constants for the other groups, the group molar constants proposed for sodium are certainly not the exact values. However, they are believed to be a fair approximation of the impact of sodium on the partial solubility parameters and, therefore, can be used as such in the group contribution method of van Krevelen.     

Avoiding crystallization of lorazepam during infusion

Lorazepam is a strong sedative for intensive care patients and a commonly used method of administering it to the patient is by infusion of a freshly prepared lorazepam solution. During lorazepam infusion often unwanted lorazepam crystallization occurs, resulting in line obstruction and reduced lorazepam concentrations. With the aid of solubility measurements a solid-liquid phase diagram for lorazepam in mixtures of a commercially available lorazepam solution and an aqueous glucose solution was determined. This confirmed that the glucose solution acts as an anti-solvent, greatly reducing the lorazepam solubility in the infusion solution. Three approaches are proposed to obtain stable lorazepam solutions upon mixing both solutions and thus to prevent crystallization during infusion: (1) using a high lorazepam concentration, and thus a lower glucose solution volume fraction, in the mixed solution; (2) using an elevated temperature during solution preparation and administration; (3) reducing the lorazepam concentration in the commercial lorazepam solution.     

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.     

有限采样策略估算心脏移植受者霉酚酸体内暴露的研究

目的 用有限采样策略(LSS)建立心脏移植受者霉酚酸(MPA)血药浓度-时间曲线下面积(AUC)的简化预测模型.方法 共收集20例心脏移植受者,术后按相同剂量连续服用吗替麦考酚酯片或其分散片至少7d后,采集不同时间的全血样本,用LC-MS/MS法测定血浆MPA浓度.用WinNonlin软件以非房室模型计算其药代动力学参...     

Lorazepam solubility in and sorption from intravenous admixture solutions

The solubility of lorazepam in aqueous i.v. solutions and the potential for lorazepam sorption from i.v. admixtures in flexible polyvinyl chloride (PVC) bags and tubing were determined. The solubility of triplicate samples containing 15 mg of lorazepam and 20 ml of deionized water, 5% dextrose, lactated Ringer's, or 0.9% sodium chloride injections was determined. The decrease in lorazepam concentration from a 40-micrograms/ml admixture solution in 5% dextrose injection stored in PVC bags was calculated. Duplicate samples of (1) 50 ml in 50-ml PVC bags, (2) 100 ml in 50-ml PVC bags, and (3) 100 ml in 250-ml PVC bags were laid flat to approximate surface areas of 80, 160, and 270 sq cm, respectively, to determine sorptive loss. The continuous flow sorption of lorazepam from duplicate admixtures was tested at three rates through 180- and 350-cm PVC tubing. The solubility of lorazepam in deionized water, 5% dextrose, lactated Ringer's, and 0.9% sodium chloride injections was 0.054, 0.062, 0.055, and 0.027 mg/ml, respectively. Lorazepam solubility was pH dependent. The decrease in lorazepam concentration from the admixture solution stored in PVC bags for up to 121 hours followed biexponential kinetics that account for both the sorptive loss of the drug and the increasing ratio of bag surface area to solution volume. At least 90% of the initial concentration was maintained for five and two hours when the ratio was less than 2.0 and 2.7-2.8 sq cm/ml, respectively. The admixture solution retained a minimum of 95% of initial concentration when 50-ml aliquots were delivered at 600, 200, and 100 ml/hr through both sizes of PVC tubing. Because of its adequate aqueous solubility and slow sorption by PVC delivery components, lorazepam is suited for dilution in i.v. admixtures for treating conditions with intermittent or continuous infusions.     

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.     

Management of acute agitation in patients with bipolar disorder: efficacy and safety of intramuscular aripiprazole

To investigate the efficacy and safety of intramuscular (IM) aripiprazole for the treatment of agitation in patients with bipolar I disorder, manic or mixed episodes. In total, 301 patients experiencing acute agitation were randomized to IM aripiprazole 9.75 mg per injection (n = 78), IM aripiprazole 15 mg per injection (n = 78), IM lorazepam 2 mg per injection (n = 70), or IM placebo (n = 75) in this double-blind multicenter study. Patients could receive up to 3 injections over 24 hours. Primary efficacy measure was mean change in Positive and Negative Syndrome Scale Excited Component score from baseline at 2 hours after first injection. Mean improvements in Positive and Negative Syndrome Scale Excited Component score at 2 hours were significantly greater with IM aripiprazole (9.75 mg, -8.7; 15 mg, -8.7) and IM lorazepam (-9.6) versus IM placebo (-5.8; P 相似文献   

Chemometric Models for Quantification of Carbamazepine Anhydrous and Dihydrate Forms in the Formulation

Carbamazepine (CBZ) exists in anhydrous and dihydrate forms. These forms differ in their solubility, dissolution rate, and subsequently in their oral bioavailability. The objective of this study is to develop multivariate chemometric models for estimation of the low level of carbamazepine dihydrate (CBZ-DH) in the CBZ formulations containing excipients of the commercial formulation. The selected excipients were mixed in proportions to make sample matrices ranging from 0% to 50% CBZ-DH. Fourier transform infrared (FTIR), near infrared (NIR), and hyperspectral imaging data were mathematically pretreated before the development of partial least square and principal component analysis regression models. The developed partial least squares regression and principal component analysis models demonstrated predictability of CBZ and CBZ-DH by multiple scattering correction and standard normal variate processing methods. Among the spectroscopic techniques used the model performance parameters such as root-mean-square error, standard error, and bias were found to be low for NIR compared to FTIR. The treated data have shown better model fitting than without treatment, which was demonstrated by correlation coefficient of 0.9778, 0.9824, and 0.9852 for FTIR, NIR, and hyperspectral imaging, respectively. Furthermore, the predicted values were found to be very close to the selected low level of independent samples having 5% CBZ-DH in tablet formulation.     

QSAR models for isoindolinone-based p53-MDM2 interaction inhibitors using linear and non-linear statistical methods

The design and optimization of p53-MDM2 interaction inhibitors has attracted a great deal of interest in the development of new anticancer agents. Systematical 2D-QSAR studies on 98 isoindolinone-based p53-MDM2 interaction inhibitors were carried out using linear and the non-linear mathematical methods. At first, a forward stepwise-multiple linear regression model (FS-MLR) was proposed with reasonable statistical parameters (R(2)(train) =0.881, Q(2)(loo) =0.847, R(2)(test) =0.854). Then, enhanced replacement method-multiple linear regression (ERM-MLR) and support vector machine regression (SVMR) were applied to set up more accurate models (ERM-MLR: R(2)(train) =0.914, Q(2)(loo) =0.894 and R(2)(test) =0.903; SVMR: R(2)(train) =0.924, Q(2)(loo) =0.920 and R(test) (2) of 0.874). Furthermore, the reliability and application value of the ERM and SVMR model was also validated in virtual screening through receiver operating characteristic studies.     

The central nervous system effects of the partial GABA-Aα2,3-selective receptor modulator AZD7325 in comparison with lorazepam in healthy males

Aims

AZD7325 is a novel α_2,3-subtype-selective partial GABA-A-receptor modulator. This study investigated the pharmacodynamics of single oral doses of AZD7325 2 mg and 10 mg on the central nervous system (CNS) compared with placebo and lorazepam 2 mg.

Methods

This double-blind, randomized, four way crossover study enrolled 16 healthy males and administered two validated CNS test batteries to measure drug effects on cognitive, neurophysiologic and psychomotor function and subjective feelings. The pharmacological selectivity of AZD7325 was compared with lorazepam by plotting saccadic peak velocity change from baseline (ΔSPV) against body sway (ΔSway) and visual analogue scale for alertness(ΔVAS_alertness). This analysis has previously been used to identify α_2,3-subtype-selectivity.

Results

In contrast with the robust impairment caused by lorazepam (all P < 0.05 vs. placebo), neither dose of AZD7325 induced statistically significant effects on any pharmacodynamic measurements. Lorazepam-induced SPV-reduction was linearly related to changes in other neurophysiologic biomarkers. In contrast, the slopes of the regression lines were flatter for AZD7325, particularly for the Δlog(Sway) −ΔSPV relation (estimate slope, AZD7325 10 mg vs. lorazepam, difference [95% confidence interval], P value −0.00036 vs. −0.00206, 0.001704 [0.000639, 0.002768], P = 0.0018) and the ΔVAS_alertness−ΔSPV relationship (0.01855 vs. 0.08216, −0.06360 [−0.1046, −0.02257], P = 0.0024). AZD7325 10 mg and lorazepam induced different response patterns on VAS ‘feeling high’ and electro-encephalography.

Conclusion

The characteristic ΔSPV-relative effect profiles of AZD7325 vs. lorazepam suggest anxio-selectivity related to α_2,3-selective GABA_A agonism. However, exploration of higher doses may be warranted. The paucity of effects on most CNS−PD parameters also indicates a mitigated side effect pattern, with potentially lower cognitive and neurophysiological side effect burden than non-selective benzodiazepines.     

Physico-chemical determinants of dermal drug delivery: effects of the number and substitution pattern of polar groups.

The aim of this study was to investigate the effect of number and substitution pattern of -OH groups of a set of phenols on the in vitro permeation of heat-separated human epidermis. The diffusion was calculated from Log(D/x)=logk(p)-0.59logK(oct)+0.024 (D, diffusion coefficient; x, pathlength; k(p), permeability coefficient (cm/h); and K(oct), octanol-water partition coefficient). The main factors reducing D were the dipolar and hydrogen bonding capabilities of the permeants quantified as their Hansen partial solubility parameters delta(p) and delta(h). These parameters are significantly reduced by the degree of symmetry of the molecule, so that phloroglucinol (1,3,5-benzenetriol), with three -OH groups, diffuses more rapidly that phenol. When symmetry is absent, as in 1,2,4-benzenetriol, the number of -OH groups results in very slow diffusion. D/x (cm/h) was related to the combined solubility parameter delta(a) defined as radical(delta(p)(2)+delta(h)(2)) by: (D/x)=0.0024-0.000065delta(a) (n=7, R(2)=0.70, P=0.012).