Unusual solubility behaviour of cyclosporin A in aqueous media.

The solubility of cyclosporin A was determined in water and in Sorensen buffers at pH 1.2 and 6.6 at temperatures ranging from 5 to 37 degrees C. No differences in solubility behaviour were observed among the three aqueous media. Solubility was found to be inversely proportional to the temperature in each medium, indicating that the heat of solution was exothermic in each case.     

Preparation and physicochemical properties of niclosamide anhydrate and two monohydrates

The intent of the study was to prepare and characterize three crystal forms of niclosamide namely the anhydrate and the two monohydrates and to investigate the moisture adsorption and desorption behavior of these crystal forms. The crystal forms were prepared by recrystallization and were characterized by differential scanning calorimetry, thermogravimetric analysis, isoperibol solution calorimetry, Karl Fischer titration, and X-ray powder diffractometry. Moisture adsorption by the anhydrate at increased relative humidities and two temperatures, 30 and 40 degrees C, was measured while the desorption from the monohydrates was determined at 45, 55, and 65 degrees C for monohydrate H(A) and 75, 90, and 100 degrees C for monohydrate H(B). Thermal analysis and solution calorimetry showed that monohydrate H(B) is more stable than monohydrate H(A) and solubility measurements showed the solubility of the crystal forms decreased in the order: anhydrate>monohydrate H(A)>monohydrate H(B). With an increase in temperature and relative humidity niclosamide anhydrate adsorbed moisture to form monohydrate H(A) by a random nucleation process. Dehydration of monohydrate H(A) at increased temperatures followed zero order kinetics and resulted in a change to the anhydrate. Monohydrate H(B) was transformed to the anhydrate at higher temperatures by a three-dimensional diffusion mechanism.     

Solubility and prediction of the heat of solution of sodium naproxen in aqueous solutions

The solubility of sodium naproxen was determined over a range of temperatures from 15.2 degrees C to 39.7 degrees C by two methods: analyses of samples from equilibrated solutions and a recently developed procedure utilizing a focused-beam reflectance method (FBRM). The results demonstrate the utility of the newer and, in some cases, simpler method. A discontinuity in the solubility was observed at 29.8 degrees C, identifying the temperature as which the dihydrate and anhydrous forms of sodium naproxen trade places as being the more stable of the two forms. The heats of solution for the two pseudopolymorphs were obtained from van't Hoff plots of the solubility data. These results were used to demonstrate how the heat of solution of one form can be estimated using the heat of dehydration obtained from differential scanning calorimetry (DSC) and the heat of solution from another form.     

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.     

Diclofenac solubility: independent determination of the intrinsic solubility of three crystal forms

The solubility in water of diclofenac ({2-[(2,6-dichlorophenyl)amino]phenyl}acetic acid), a potent nonsteroidal anti-inflammatory drug, has been investigated. The various solid forms have been characterized by thermogravimetric analysis, differential scanning calorimetry, and X-ray diffraction. The commercially available form of diclofenac is the anhydrous sodium salt. This was recrystallized from ethanol and precipitated as a hydrate containing four diclofenac anions, four sodium cations, and nineteen water molecules per unit cell. This crystal structure is similar to but different from an earlier report of the structure. Crystals of the acid form of diclofenac were anhydrous and corresponded to an earlier crystal structure. Separate solubility measurements on all three of these solid forms of diclofenac gave consistent results for the intrinsic solubility. The aqueous solubility values reported in the literature for diclofenac are spread over a large range, with a factor of 100 separating the largest and the smallest. Our value is at the smaller end of this range. It is the only one supported by three independent procedures and rigorous characterization of the solid forms. The experimental conditions were precisely controlled.     

Exothermic-endothermic heat of solution shift of cyclosporin a related to poloxamer 188 behavior in aqueous solutions

The solubility of cyclosporin A was determined in water and aqueous solutions of a surface active poly (oxyethylene)-poly(oxypropylene)-poly(oxyethylene) block copolymer (poloxamer 188 or pluronic^R F68 (PF68)) at concentrations and temperatures ranging from 4 to 22 g/1 and from 10 to 50°C, respectively. The solubility behaviour was different between PF68 solutions and water. Solubility values indicated an exothermic heat of solution in each case except for PF68 solutions above 10 g/l at 37–50°C, where a change to endothermic heat of solution was detected. The slopes corresponding to water samples or 4g/l PF68 solutions at temperatures above 37°C do not statistically differ from zero. Aqueous solutions of the poloxamer 188 were also studied using frequency spectrum analysis (dynamic light scattering) and size exclusion chromatography. Below 40°C and 16 g/1 essentially invariant values for the hydrodynamic radius were found with broad polydispersities associated. Increasing temperature and poloxamer concentration, the hydrodynamic radius also increased and the systems showed a narrower size distribution, possibly due to micelle formation according to the closed association model.     

Solubility advantage of amorphous pharmaceuticals: I. A thermodynamic analysis

In recent years there has been growing interest in advancing amorphous pharmaceuticals as an approach for achieving adequate solubility. Due to difficulties in the experimental measurement of solubility, a reliable estimate of the solubility enhancement ratio of an amorphous form of a drug relative to its crystalline counterpart would be highly useful. We have developed a rigorous thermodynamic approach to estimate enhancement in solubility that can be achieved by conversion of a crystalline form to the amorphous form. We rigorously treat the three factors that contribute to differences in solubility between amorphous and crystalline forms. First, we calculate the free energy difference between amorphous and crystalline forms from thermal properties measured by modulated differential scanning calorimetry (MDSC). Secondly, since an amorphous solute can absorb significant amounts of water, which reduces its activity and solubility, a correction is made using water sorption isotherm data and the Gibbs–Duhem equation. Next, a correction is made for differences in the degree of ionization due to differences in solubilities of the two forms. Utilizing this approach the theoretically estimated solubility enhancement ratio of 7.0 for indomethacin (amorphous/γ‐crystal) was found to be in close agreement with the experimentally determined ratio of 4.9. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1254–1264, 2010     

Improvement of dissolution and suppository release characteristics of flurbiprofen by inclusion complexation with heptakis(2,6-di-O-methyl)-beta-cyclodextrin

The inclusion behavior of methylated beta-cyclodextrins, heptakis(2,6-di-O-methyl)-beta-cyclodextrin and heptakis-(2,3,6-tri-O-methyl)-beta-cyclodextrin in solution and the solid state was compared with that of natural beta-cyclodextrin using an anti-inflammatory drug, flurbiprofen, as a guest molecule. Stability constants were determined by the solubility method at various temperatures, and the thermodynamic parameters were calculated for inclusion complex formation in aqueous solution. The solid complexes were obtained in a molar ratio of 1:1, and their dissolution behavior and release from suppository bases were examined. The data suggest that the inclusion mode of the complex with 3 is somewhat different from that of the complexes with 1 and 2. From a practical point of view, 2 seems to be particularly useful for improving the pharmaceutical properties of flurbiprofen in various dosage forms.     

Relating solubility data of parabens in liquid PEG 400 to the behaviour of PEG 4000-parabens solid dispersions

The solid state behaviour of polyethylene glycol 4000 (PEG 4000) and dispersions of a homologous series of parabens (methyl- (MP), ethyl- (EP), propyl- (PP) and butyl- (BP)) were examined and compared to the paraben solubility in liquid PEG 400. Dispersions were prepared by co-melting different amounts of paraben (5–80% (w/w)) and PEG 4000 and were studied using a combination of differential scanning calorimetry (DSC) and small and wide angle X-ray diffraction (SAXD/WAXD). Depending on the concentration of parabens in the dispersions, DSC showed melting peaks from folded and unfolded forms of PEG, a eutectic melting and melting of pure parabens. The fraction of folded PEG increased and the melting temperatures of both PEG forms decreased with increasing paraben content. In an apparent phase diagram of PP–PEG dispersions a eutectic mixture appeared above 5% PP. In addition, a melting peak corresponding to the paraben appeared for dispersion containing more than 60% PP. Similar phase diagrams were shown for the other parabens. The SAXD data and a 1D correlation function analysis revealed that MP and BP were incorporated into the amorphous domains of the lamellae of solid PEG to a higher degree than EP and PP. In addition, the lamellae thickness of PEG and the fraction of amorphous domains increased more for MP and BP compared to EP and PP. BP showed the highest solubility of the parabens followed by MP, EP and PP in both liquid and solid PEG. Furthermore, the thickness of the amorphous domains of the PEG in the different parabens–PEG dispersions could be correlated to the solubility in liquid PEG 400.     

Physical characterization of naproxen sodium hydrate and anhydrate forms

Naproxen sodium (NS) is a nonsteroidal anti-inflammatory drug used in painful and inflammatory diseases. By crystallization from water or by exposure to relative humidities over 43%, the anhydrate form can be hydrated to a dihydrate species. Different techniques have been used to characterize physically anhydrate naproxen sodium (ANS) and hydrate naproxen sodium (HNS): elemental analysis, atomic absorption, electron scanning microscopy, thermomicroscopy, differential scanning calorimetry, Karl Fisher’s titrimetry, thermogravimetry, spectrophotometric analysis and X-ray diffraction study. The hydration/dehydration mechanism, at different relative humidities, was investigated to evaluate their physical stability. When stored up to 43% relative humidity, ANS shows a good stability, whereas with an increase in relative humidity it is hydrated. HNS equilibrium solubility was determined at different temperatures (21, 26, 31, and 37°C). Due to the metastability and the quick phase changes in the water of ANS, its solubility was calculated from intrinsic dissolution measurements at the same temperatures, as solubility measurements of HNS. Water solubility of ANS is greater than HNS, but the solubility difference decreases when the temperature decreases. This is due to the fact that at higher temperatures the intrinsic dissolution rates (IDR) of ANS are considerably faster and decrease as the temperature falls.     

Polymorphism and thermodynamics of m-hydroxybenzoic acid

Solution and solid-state properties of m-hydroxybenzoic acid have been investigated. Two polymorphs were found where the monoclinic modification exhibits a higher stability than the orthorhombic form. The solubility of the monoclinic polymorph was determined between 10 and 50 °C in methanol, acetonitrile, acetic acid, acetone, water and ethyl acetate. The solubility of the orthorhombic polymorph was determined between 10 and 50 °C in acetonitrile, acetic acid, acetone and ethyl acetate. A thermodynamic analysis revealed a marked correlation between the molar solubility and the van’t Hoff enthalpy of solution at constant temperature. In addition, in each solvent increased temperature resulted in increased van’t Hoff enthalpy of solution. It is shown that the solubility data can be used to estimate melting properties for both polymorphs. The solubility ratio of the two forms and the DSC thermogram of the orthorhombic form strongly suggest that the system is monotropic. However, according to the polymorph rules of Burger and Ramberger, the estimated higher melting enthalpy and lower melting temperature of the orthorhombic form points towards an enantiotropic system. Hence, this system appears to be an exception to the Burger and Ramberger melting enthalpy rule, and the probable reason for this is found in the difference in the heat capacity of the two solid forms.     

文拉法新与阿普唑仑治疗广泛性焦虑症的对照研究

目的 比较文拉法新与阿普唑仑治疗广泛性焦虑症的疗效及不良反应。方法 符合CCMD-3诊断标准的广泛性焦虑症病例50例,随机分为文拉法新组(26例)和阿普唑仑组(24例)。分别用文拉法新50～175mg·d-1,阿普唑仑0.8-2.4mg·d-1,治疗观察12周。用汉密尔顿焦虑量表(HAMA)和药物副反应量表(TESS),评定疗效和药物不良反应。结果 文拉法新与阿普唑仑疗效相当,起效时间相当,文拉法新的中长期疗效更佳,无严重不良反应及药物依赖性。结论 文拉法新治疗广泛性焦虑症疗效好,起效较快、副反应轻,患者服药依从性好。     

红霉素在丙酮—水系统中的溶解度

测定了红霉素在不同温度下丙酮－水系统中的溶解度。当丙酮含量低时,呈反溶解度;丙酮含量高时,呈正溶解度,其临界点在丙酮浓度为２６％（ｖ／ｖ）左右。考虑到生产实际情况,还测定了含０．１ｍｏｌ／Ｌ乳酸并以氨水调ｐＨ１０时,丙酮－水系统中的溶解度,发现溶解度要增大很多。还提出了选择最适结晶条件的若干建议。     

A Quantitative Model to Evaluate Solubility Relationship of Polymorphs from Their Thermal Properties

Purpose The objective of the study is to develop a model to estimate the solubility ratio of two polymorphic forms based on the calculation of the free energy difference of two forms at any temperature. This model can be used for compounds with low solubility (a few mole percent) in which infinite dilution can be approximated.Methods The model is derived using the melting temperature and heat of fusion for apparent monotropic systems, and the solid–solid transition temperature and heat of transition for apparent enantiotropic systems. A rigorous derivation also requires heat capacity (C_p) measurement of liquid and two solid forms. This model is validated by collecting thermal properties of polymorphs for several drugs using conventional or modulated differential scanning calorimetry. From these properties the solubility ratio of two polymorphs is evaluated using the model and compared with the experimental value at different temperatures.Results The predicted values using the full model agree well with the experimental ones. For the purpose of easy measurement, working equations without C_p terms are also applied. Ignoring C_p may result in an error of 10% or less, suggesting that the working equation is applicable in practice. Additional error may be generated for the apparent enantiotropic systems due to the inconsistency between the observed solid–solid transition temperature and the true thermodynamic transition temperature. This inconsistency allows the predicted solubility ratios (low melt/high melt) to be smaller. Therefore, a correction factor of 1.1 is recommended to reduce the error when the working equation is used to estimate the solubility ratio of an enantiotropic system.Conclusions The study of the free energy changes of two crystalline forms of a drug allows for the development of a model that successfully predicts the solubility ratio at any temperature from their thermal properties. This model provides a thermodynamic foundation as to how the free energy difference of two polymorphs is reflected by their equilibrium solubilities. It also provides a quick and practical way of evaluating the relative solubility of two polymorphs from single differential scanning calorimetry runs.     

Drug–Drug Coamorphous Systems: Characterization and Physicochemical Properties of Coamorphous Atorvastatin with Carvedilol and Glibenclamide

Purpose

In this study, coamorphous form of atorvastatin calcium (ATC) with two drugs, i.e., carvedilol (CVD) and glibenclamide (GLN) in 1:1 stoichiometry, were prepared from solvent evaporation method and they were characterized and their physicochemical properties determined.

Methods

The coamorphous forms were characterized using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), and powder X-ray diffraction (PXRD). The kinetic solubility of coamorphous form of ATC with CVD (ATC–CVD) and GLN (ATC–GLN) were determined along with stability of supersaturated state of coamorphous forms using developed accurate and precise UV-net analyte signal standard addition method (chemometrics-based approach) and HPLC.

Results

The results of DSC and analysis of glass transition temperatures (T _g), PXRD, and FT-IR indicated that the crystalline studied drugs were converted to coamorphous forms, with unique thermal behaviors, revealing a molecular interaction between two components. The kinetic solubility data revealed that coamorphous forms have better metastable solubility than those of crystalline state. In addition, these systems showed greater solution stability than those for amorphous form of single components reported in the literature.

Conclusion

Coamorphous ATC–CVD and ATC–GLN were shown to have improved physicochemical and solution stability properties as compared to crystalline components.     

Structure-release relationship of physical polymer/drug combinations. 2. Diffusion of 3-methylpyrazole through a synthetic polymer matrix

The diffusion of 3-methylpyrazole through a synthetic polymer matrix and the effect of the solubility of the bioactive agent in polymers on the release behaviour of polymer combinations were studied. With increasing hydrophilicity of the polymer both the diffusion and the diffusion coefficient of 3-methylpyrazole increased and the solubility of the agent in the polymer decreased. The hydrophilicity of various polymers is discussed on the basis of a parameter determined by turbidimetric titrations.     

盐酸文拉法辛缓释片的初步研究

目的：制备盐酸文拉法辛缓释片并考察其体外释放特性。方法：利用正交设计优化处方，建立释放度测定方法，根据不同时间累积释放度考察药物的释放情况，并采用不同方程拟合释放曲线。结果：用55％ HPMC K100M制得缓释片，其释放曲线可用一级方程动力学拟合。结论：用55％ HPMC K100M制备的盐酸文拉法辛缓释片具有良好的释药效果。     

Solubility measurement of polymorphic compounds via the pH-metric titration technique

In drug development, the thermodynamically most stable form of a compound is preferred because metastable forms are prone to transform to the stable form during processing, formulation, or storage [Guillory, J.K., 1999. Generation of polymorphs, hydrates, solvates, and amorphous solids. In: Brittain, H.G. (Ed.), Polymorphism in Pharmaceutical Solids. Marcel Dekker, New York, pp. 183–226]. It is therefore important to discover and characterize the stable form as early as possible. One of the most important properties to determine is thermodynamic solubility. However, due to compound and time constraints this solubility value is usually not determined until late in discovery. This report explores the ability of the pH-metric titration method to measure intrinsic solubility of the stable form of compounds that exist in one or more polymorphic forms. One metastable form and the stable form of eight compounds were examined. Intrinsic solubility was measured via pH-metric titration. The technique was performed on a larger scale in order to monitor polymorphic form changes by powder X-ray diffraction. Shake-flask solubility and corresponding X-ray diffraction data of each form was also determined. The results of this study indicate that, in general, when starting with a metastable polymorph, the pH-metric titration method is able to achieve the solubility of the stable form by the third titration, while the traditional shake-flask solubility method is unable to consistently determine the stable form solubility.     

An improved empirical model to calculate solute solubility in supercritical carbon dioxide

To provide more accurate solubility predictions in supercritical carbon dioxide (SC-CO2) using an empirical model employing density as an independent variable, the density of SC-CO2 at different temperatures and pressures has been calculated and compared with experimental densities. The average percentage deviation (APD) has been determined as an accuracy criterion and the obtained APD for the equations studied were between 1.3 (+/-1.4)-11.6 (+/-8.9)%. To show the effects of density values on solubility prediction, the solubility of 18 drug compounds in SC-CO2 has been calculated using an empirical equation with respect to temperature, pressure and density. The APD values for correlative analysis was 8.5 (+/-5.8)% for the most accurate density values calculated by BACK equation of state. A minimum number of experimental data (i.e. 6 points) has been used to train the model then the solubility at other temperatures and pressures has been predicted and the APD value for the most accurate densities obtained was 14.2 (+/-9.4)%. This prediction error could be considered as acceptable when it is compared with RSD values for repeated measurements (approximately 10%) and the proposed predictive method could be employed in industry to calculate the solubility of a drug using a limited number of experimental data.     

Dramatic recovery of paclitaxel-disabling neurosensory toxicity following treatment with venlafaxine

Venlafaxine is an antidepressant which acts through the inhibition of the reuptake of norepinephrine and serotonin. Venlafaxine is active against neuropathic and chronic pain. We report the case of a 69-year-old woman who presented a paclitaxel-induced neuropathy. She presented paresthesias, pin pricks in both hands with functional impairment. Venlafaxine hydrochloride was introduced at 37.5 mg twice daily. The patient noticed a dramatic recovery of her symptoms within 2 days, with both reduction of the paresthesias and functional improvement. This is the first report of efficacious use of venlafaxine for the treatment of paclitaxel cumulative neurosensory toxicity.