Solubility of drugs in aqueous solutions. Part 3: multicomponent mixed solvent

The results obtained previously by Ruckenstein and Shulgin [Int. J. Pharm. 258 (2003a) 193; Int. J. Pharm. 260 (2003b) 283] via the fluctuation theory of solutions regarding the solubility of drugs in binary aqueous mixed solvents were extended in the present paper to multicomponent aqueous solvents. The multicomponent mixed solvent was considered to behave as an ideal solution and the solubility of the drug was assumed small enough to satisfy the infinite dilution approximation.An expression derived for the activity coefficient of a solid solute in a multicomponent solvent was used to obtain an equation for the solubility of a drug in terms of its solubilities in two subsystems of the multicomponent solvent and their molar volumes. Ultimately the solubility can be expressed in terms of those in binary or even in individual solvents and their molar volumes.The method was applied to the solubility of tioconazole and 19-Nor-1alpha,25-dihydrovitamin D(2) in several ternary and in a quaternary aqueous mixed solvents. The predicted solubilities were compared with experimental data and good agreement was found.     

Solubility of drugs in aqueous solutions. Part 1. Ideal mixed solvent approximation

The present paper deals with the application of the fluctuation theory of solutions to the solubility of poorly soluble drugs in aqueous mixed solvents. The fluctuation theory of ternary solutions is first used to derive an expression for the activity coefficient of a solute at infinite dilution in an ideal mixed solvent and, further, to obtain an equation for the solubility of a poorly soluble solid in an ideal mixed solvent. Finally, this equation is adapted to the solubility of poorly soluble drugs in aqueous mixed solvents by treating the molar volume of the mixed solvent as nonideal and including one adjustable parameter in its expression. The obtained expression was applied to 32 experimental data sets and the results were compared with the three parameter equations available in the literature.     

Solubility in binary solvent systems. V. Monomer and dimer models for the solubility of p-tolylacetic acid in systems of non-specific interactions

Solubilities are reported for p-tolylacetic acid in binary mixtures of cyclohexane with n-hexane, n-heptane, n-octane and isooctane at 25 °C. The results are compared to the predictions of equations developed previously for solubility in systems of purely non-specific interactions, with the carboxylic acid considered as either monomeric or dimeric molecules in solution. The dimer model provided the more accurate predictions, with a maximum deviation of 5.6% between observed and predicted solubility in all systems studied.     

Solubility of drugs in aqueous solutions. Part 4. Drug solubility by the dilute approximation

As in our previous publications in this journal [Int. J. Pharm. 258 (2003a) 193; Int. J. Pharm. 260 (2003b) 283; Int. J. Pharm. 267 (2003c) 121], this paper is concerned with the solubility of poorly soluble drugs in aqueous mixed solvents. In the previous publications, the solubilities of drugs were assumed to be low enough for the so-called infinite dilution approximation to be applicable. In contrast, in the present paper, the solubilities are considered to be finite and the dilute solution approximation is employed. As before, the fluctuation theory of solutions is used to express the derivatives of the activity coefficient of a solute in a ternary solution (dilute solute concentrations in a binary solvent) with respect to the concentrations of the solvent and cosolvent. The expressions obtained are combined with a theoretical equation for the activity coefficient of the solute. As a result, the activity coefficient of the solute was expressed through the activity coefficients of the solute at infinite dilution, solute mole fraction, some properties of the binary solvent (composition, molar volume and activity coefficients of the components) and parameters reflecting the nonidealities of binary species. The expression thus obtained was used to derive an equation for the solubility of poorly soluble drugs in aqueous binary solvents which was applied in two different ways. First, the nonideality parameters were considered as adjustable parameters, determined from experimental solubility data. Second, the obtained equation was used to correct the solubilities of drugs calculated via the infinite dilution approximation. It was shown that both procedures provide accurate correlations for the drug solubility.     

Solubility of drugs in aqueous solutions. Part 5. Thermodynamic consistency test for the solubility data

This paper is devoted to the verification of the quality of experimental data regarding the solubility of sparingly soluble solids, such as drugs, environmentally important substances, etc. in mixed solvents. A thermodynamic consistency test based on the Gibbs-Duhem equation for ternary mixtures is suggested. This test has the form of an equation, which connects the solubilities of the solid, and the activity coefficients of the constituents of the solute-free mixed solvent in two mixed solvents of close compositions. The experimental data regarding the solubility of sparingly soluble substances can be verified with the suggested test if accurate data for the activity coefficients of the constituents of the solute-free mixed solvent are available. The test was applied to a number of systems representing the solubilities of sparingly soluble substances in mixed solvents. First, the test was scrutinized for four nonaqueous systems for which accurate solubility data were available. Second, the suggested test was applied to a number of systems representing experimental data regarding the solubility of sparingly soluble substances in aqueous mixed solvents.     

Solubility in binary solvent systems: 8. Estimation of binary alkane plus p-dioxane solvent nonideality from measured anthracene solubilities

Experimental solubilities are reported for anthracene in binary solvent mixtures containing p-dioxane with n-hexane, cyclohexane, n-heptane, methylcyclohexane, n-octane, cyclooctane, and isooctane at 25 degrees C. Results of these measurements, used in conjunction with the nearly ideal binary solvent (NIBS) model, enabled excess Gibbs free energies, delta GBCfh, of the seven binary solvent mixtures to be estimated. Estimated values for p-dioxane plus cyclohexane, p-dioxane plus n-heptane, and p-dioxane plus methylcyclohexane mixtures are in reasonable agreement with published values based on vapor pressure measurements.     

Dissolution of cellulose in ionic liquids and their mixed cosolvents: A review

Because of increasing environmental awareness and over-extrapolation of non-renewable materials, the application and processing of carbohydrate polymers (polysaccharides) have attracted immense courtesy as they are most abundant natural and biorenewable materials on the Earth. However, insolubility of the most of the polysaccharides in most of the common solvents including water limits their applications. Limited solubility of the polysaccharides is attributed because of the strong intermolecular interactions between polymeric chains that offer them high degree of crystallinity. More so, some organic solvents such as morpholine, N-methylmorpholine-N-oxide (NMMO), N-methylmorpholine (NMM), urea and thiourea in association with sodium hydroxide etc. were used to solubilise carbohydrate polymers with particular emphasis of cellulose. However, processing of the polysaccharides with these solvents is not only toxic to surrounding environment and living beings but also release several environmental malignant chemicals that can cause several side reactions and adversely affect their physiological properties. Present review paper features the collection of some major works that have been carried out in the area of cellulose dissolution in ionic liquids with and without co-solvents (DMSO, DMF, DMAc etc.).     

Thermodynamics of solutions: II. Flurbiprofen and diflunisal as models for studying solvation of drug substances

Three independent methods (sublimation, solubility and solution calorimetry) were used to study the dissolution and solvation processes of diflunisal (DIF) and flurbiprofen (FBP). Thermodynamic functions for the sublimation of DIF and FBP were obtained. Concentrations of saturated solutions and standard solution enthalpies of DIF and FBP in aliphatic alcohols and individual organic solvents were measured. Correlation analysis between: (a) the thermodynamic functions for a substance in various solvents, and (b) the same functions for different compounds was carried out. The investigated substances can be arranged with increasing Gibbs energy of solvation as follows: benzoic acid_H) and in terms of entropies (_S) was analyzed. Based on the experimental data, a compensation effect of thermodynamic solubility functions of the investigated substances both in alcohols and in organic solvents was found.     

非无菌水性基质药品中洋葱伯克霍尔德菌群控制的一般考虑

洋葱伯克霍尔德菌群（Burkholderia cepacia complex,BCC）在营养有限的水性环境中有较强的生存能力,对一些治疗用抗菌药和常用抑菌剂具有耐药性,可引起囊性纤维化、慢性肉芽肿患者或低免疫力易感人群的严重感染。BCC已被美国食品药品监督管理局（FDA）明确归为不可接受微生物,因此,非无菌水性基质药品中BCC的预防及控制对药品安全至关重要。主要对BCC的特性、检测方法及风险评估和控制策略进行阐述,为非无菌水性基质药品中BCC的研究和控制提供参考。     

Preformulation study of methazolamide for topical ophthalmic delivery: Physicochemical properties and degradation kinetics in aqueous solutions

Methazolamide (MTZ) is an anti-glaucoma drug. The present paper aims to characterize the physicochemical properties and degradation kinetics of MTZ to provide a basis for topical ophthalmic delivery. With the increase in pH (pH 5.5–8.0) of aqueous solution, the solubility of the compound increased while the partition coefficient (Ko/w) which was estimated in the system n-octanol/aqueous solution decreased. The degradation of MTZ in aqueous solution followed pseudo-first-order kinetic. The degradation rate k_pH is the rate in the absence of buffer catalysis. Plotting the natural logarithm of k_pH versus the corresponding pH value gave a V-shaped pH-rate profile with a maximum stability at pH 5.0. The degradation rate constants as a function of the temperature obeyed the Arrhenius equation (R² = 0.9995 at pH 7.0 and R² = 0.9955 at pH 9.0, respectively). A decrease in ionic strength and buffer concentration displayed a stabilizing effect on MTZ. Buffer species also influenced the MTZ hydrolysis. Phosphate buffer system was more catalytic than tris and borate buffer systems. In brief, it is important to consider the physicochemical properties and the stability of MTZ during formulation.     

Partial molal heat capacity of the peptide group in aqueous solutions

Integral enthalpies of solution at very high dilution of sodium salts of N-acetyl amino acids, N-acetyl peptides, and N-benzoyl glycine have been measured in water at 298.15 and 308.15 K. Standard heat capacities of solution at 303.15 K have been derived from the enthalpy of solution data. The peptide backbone-unit (CH₂CONH) contribution toward the limiting partial molal heat capacities derived from these experimental results is compared with those obtained from C_p2 of other model compounds, viz. oligopeptides, pyrrolidones, piperidones, diketopiperazine, and amides. C_p2 of the peptide backbone unit observed in the sodium salts of the N-substituted amino acids and peptides is also correlated with the structural details of the compounds and it is concluded that C_p2 contribution of the whole CH₂CONH group, rather than that of CONH group, should be used for predicting the heat capacities of polypeptides and proteins in aqueous solution.     

Photochemical decomposition of phenazone derivatives. Part 7: Mechanism of decomposition in aqueous solutions

Kinetic studies, supplemented by the isolation and identification of the products of decomposition, have proved the process of photochemical decomposition of phenazone derivatives to be a complex reaction, involving several successive parallel reactions, one of which is predominant depending on the concentration of the solution and the atmosphere above it. In an oxygen-free atmosphere and at low concentrations (10(-4) mol/dm3) decomposition is almost wholly the result of second photolysis of zero order to aziridine derivative----aniline----isonitrile. At higher concentrations (10(-3)-10(-2) mol/dm3), the contribution from the reaction of water photoaddition to the double bond C3-C4 increases. Whereas at concentrations of order greater than or equal to 10(-2) mol/dm3, photoisomerization to imidazole derivatives is predominant. In air, one onserves additionally a second reaction of photooxidation to 4-hydroxy-phenazone----1-acetylo-1-methyl-2-phenyl-hydrazine, a reaction of photodemethylation at N2 with simultaneous oxidation to the 4-ketoderivative, and reactions of hydrolysis characteristic for the individual derivatives. The principal primary photolytic reaction for the group of compounds studied consists in cleavage of the N1-N2 bond of the pyrazoline ring.     

Comparative trials in registration files of cardiovascular drugs: Comparator drugs and dosing schemes.

Registration files of 13 cardiovascular drugs were analysed with respect to the number of doubleblind phaseIII clinical trials, the use of placebo and active comparator drugs and their dosing schemes. Half of the 146 doubleblind trials used active comparator drugs. The majority of files included firstchoice reference drugs, but we also found trials in three files with lower dosing schemes of comparator drugs and four files which included only placebo or active controlled doubleblind trials. To allow a better interpretation of the information provided in European Public Assessment Reports, which are published for every product approved for marketing in the European Union, uniform reporting is recommended on basic details of trial design, such as comparator drugs used and dosing schemes.     

Thermochemical investigations of associated solutions: 4. Calculation of carbazole-dibutyl ether association constants from measured solubility in binary solvent mixtures

Experimental solubilities are reported for anthracene and carbazole in binary dibutyl ether plus n-hexadecane and dibutyl ether plus squalane solvent mixtures at 25 degrees C. Results of these measurements, used in conjunction with the extended nearly ideal binary solvent (NIBS) model, enabled calculation of the carbazole-dibutyl ether association constant. The numerical value obtained was independent of the hydrocarbon cosolvent, and compared favorably with previously reported values based on carbazole solubilities in solvent mixtures containing much smaller alkane cosolvents.     

Liposomes as potential masking agents in sport doping. Part 1: analysis of phospholipids and sphingomyelins in drugs and biological fluids by aqueous normal‐phase liquid chromatography‐tandem mass spectrometry

In the present work, aqueous normal‐phase liquid chromatography coupled to tandem mass spectrometry (LC‐MS/MS), in different acquisition modes, was employed for the direct analysis and profiling of nine phospholipid classes (phosphatidic acids, phosphatidylserines, phosphatidylethanolamines, lysophosphatidylethanolamines, phosphatidylglycerols, phosphatidylinositols, phosphatidylcholines, lysophosphatidylcholines, and sphingomyelins) in biological and pharmaceutical matrices. After chromatographic separation by a diol column, detection and elucidation of phospholipid and sphingomyelin classes and molecular species were performed by different scan acquisition modes. For screening analysis, molecular ions [M + H]⁺ were detected in positive precursor ion scan of m /z 184 for the classes of phosphatidylcholines, lyso‐phosphatidylcholines and sphingomyelins; while phosphatidylethanolamines and lyso‐phosphatidylethanolamines were detected monitoring neutral loss scan of 141 Da; and phosphatidylserines detected using neutral loss scan of 184 Da. Molecular ions [M‐H]^‐ were instead acquired in negative precursor ion scan of m /z 153 for the classes of phosphatidic acids and phosphatidylglycerols; and of m /z 241 for the phosphatidylinositols. For the identification of the single molecular species, product ion scan mass spectra of the [M + HCOO]^‐ ions for phosphatidylcholines and [M + H]⁺ ions for the other phospholipids considered were determined for each class and compared with the fragmentation pattern of model phospholipid reference standard. By this approach, nearly 100 phospholipids and sphingomyelins were detected and identified. The optimized method was then used to characterize the phospholipid and sphingomyelin profiles in human plasma and urine samples and in two phospholipid‐based pharmaceutical formulations, proving that it also allows to discriminate compounds of endogenous origin from those resulting from the intake of pharmaceutical products containing phospholipidic liposomes. Copyright © 2016 John Wiley & Sons, Ltd.     

The last decade of solvent research in animal models of abuse: mechanistic and behavioral studies

The Last Decade of Animal solvent Abuse Research: Mechanistic and Behavioral Studies. Bowen, S. E., Batis, J.C., Paez-Martinez, N., and Cruz, S.L. Neurotoxicology and Teratology, XX, 2006. The abuse of volatile organic solvents (inhalants) leads to diverse sequelae at levels ranging from the cell to the whole organism. This paper reviews findings from the last 10 years of animal models investigating the behavioral and mechanistic effects of solvent abuse. In research with animal models of inhalant abuse, NMDA, GABA_A, glycine, nicotine, and 5HT₃ receptors appear to be important targets of action for several abused solvents with emerging evidence suggesting that other receptor subtypes and nerve membrane ion channels may be involved as well. The behavioral effects vary in magnitude and duration among the solvents investigated. The behavioral effects of acute and chronic inhalant abuse include motor impairment, alterations in spontaneous motor activity, anticonvulsant effects, anxiolytic effects, sensory effects, and effects on learning, memory and operant behavior (e.g., response rates and discriminative stimulus effects). In addition, repeated exposure to these solvents may produce tolerance, dependence and/or sensitization to these effects.