Comparison of measured and calculated oxygen solubilities in fermentation media

A fast physical method is used to measure oxygen solubilities in various solutions of sugars and salts, in nutrition media, and in fermentation broths of Penicillium chrysogenum. The findings were compared with the predictions of a solubility model which assumes that the solubility reduction is log-additive with respect to various compounds (mainly sugars and electrolytes). A striking agreement between experimental results and predictions was found.     

Enhancement of iodinin solubility by encapsulation into cyclodextrin nanoparticles

Phenazine is known to regroup planar nitrogen-containing heterocyclic compounds. It was used here to enhance the bioavailability of the biologically important compound iodinin, which is near insoluble in aqueous solutions. Its water solubility has led to the development of new formulations using diverse amphiphilic α-cyclodextrins (CDs). With the per-[6-desoxy-6-(3-perfluorohexylpropanethio)-2,3-di-O-methyl]-α-CD, we succeeded to get iodinin-loaded nanoformulations with good parameters such as a size of 97.9?nm, 62% encapsulation efficiency and efficient control release. The study presents an interesting alternative to optimizing the water solubility of iodinin by chemical modifications of iodinin.     

不同晶型甘氨酸在水中溶解度的测定与关联

不同晶型甘氨酸溶解度的测定对研究甘氨酸结晶及多晶型现象具有重要意义。采用激光动态法测定了15~80℃范围内α型和γ型甘氨酸在纯水中的溶解度数据,并且采用Apelb lat溶解度经验方程对实验数据进行了关联,回归了溶解度经验方程的参数,关联效果令人满意。实验结果表明,在水中α和γ甘氨酸溶解度均随温度升高而变大;在相同温度下,热力学亚稳的α型甘氨酸比稳态的γ型甘氨酸溶解度大。     

Influence of Position and Size of Substituents on the Mechanism of Partitioning: A Thermodynamic Study on Acetaminophens,Hydroxybenzoic Acids,and Parabens

The objective of the present investigation was to study the influence of size, nature, and topology of substituents on the thermodynamic characteristics of sublimation, fusion, solubility, solvation, and partitioning processes of some drug and druglike molecules. Thermodynamic functions of sublimation process 2-acetaminophen and 3-acetaminophen were obtained on the basis of temperature dependencies of vapor pressure by the transpiration method. Thermodynamic characteristics of solubility processes in water, n-octanol, and n-hexane were calculated from the temperature dependencies of solubility using the solubility saturation method. For evaluation of fusion parameters, differential scanning calorimetry was used. A new approach to distinguishing specific and nonspecific energetic terms in the crystal lattice was developed. Specific and nonspecific solvation terms were distinguished using the transfer from the “inert” n-hexane to the other solvents. For the acetaminophen compounds and for some related drug molecules, the correlation between melting points and a parameter describing the ratio between specific and nonspecific interaction in the crystal lattices was obtained. A diagram enabling analysis of the mechanism of the partitioning process was applied. It was found that for isomers of benzoic acids and for acetaminophens, the position of substituents affects the mechanism of the partitioning process but not the extent of partitioning ( values). In contrast to this, an increased size of substituents (parabens) leads to essential changes in values, but the mechanism of the partitioning process stays the same.     

Application of a PEG precipitation method for solubility screening: A tool for developing high protein concentration formulations

Previous publications demonstrated that the extrapolated solubility by polyethylene glycol (PEG) precipitation method (Middaugh et al., J Biol Chem 1979; 254:367–370; Juckes, Biochim Biophys Acta 1971; 229:535–546; Foster et al., Biochim Biophys Acta 1973; 317:505; Mahadevan and Hall, AIChE J 1990; 36:1517–1528; Stevenson and Hageman, Pharm Res 1995; 12:1671–1676) has a strong correlation to experimentally measured solubility of proteins. Here, we explored the utility of extrapolated solubility as a method to compare multiple protein drug candidates when nonideality of a highly soluble protein prohibits accurate quantitative solubility prediction. To achieve high efficiency and reduce the amount of protein required, the method is miniaturized to microwell plate format for high‐throughput screening application. In this simplified version of the method, comparative solubility of proteins can be obtained without the need of concentration measurement of the supernatant following the precipitation step in the conventional method. The monoclonal antibodies with the lowest apparent solubilities determined by this method are the most difficult to be concentrated, indicating a good correlation between the prediction and empirical observations. This study also shows that the PEG precipitation method gives results for opalescence prediction that favorably compares to experimentally determined opalescence levels at high concentration. This approach may be useful in detecting proteins with potential solubility and opalescence problems prior to the time‐consuming and expensive development process of high concentration formulation.     

Determination of aqueous solubility by heating and equilibration: A technical note

Summary and Conclusion  A modified shake-flask solubility method, where the equilibration time was shortened through heating, was used to determine the solubility of 48 different drugs and pharmaceutical excipients in pure water at room temperature. The heating process accelerates dissolution of the solid compound and frequently results in supersaturated solution. Seeding with the solid compound after heating and cooling to room temperature promotes precipitation of the solid compound in its original stable form. This modified shake-flask method generates reliable and reproducible solubility data. Published: January 13, 2006     

The Importance of Understanding the Chemical Form of a Metal in the Environment: The Case of Barium Sulfate (Barite)

Environmental assessments of metals are often simplified by referring to metals in terms of their elemental names without further consideration of specific metal compounds. Such simplifications can obscure important information on the fate and effects of the particular metal compounds. Barium sulfate (barite) provides a good example of the importance of knowing the specific compound when evaluating exposure, effects, and risks. We illustrate this by comparing the solubility and toxicity of barite to the soluble barium salts used to derive the U.S. Environmental Protection Agency barium ecological soil screening levels (Eco-SSLs). For ecologically relevant exposure pathways, the toxicity of barium compounds is largely controlled by their solubility. In contrast to soluble barium salts (e.g., barium acetate, barium chloride, and barium nitrate), barite is sparingly soluble and practically nontoxic to invertebrates, plants, or wildlife. No-effect levels for soil invertebrates (17,000 to 1,000,000 mg/kg) are several orders of magnitude higher than the barium Eco-SSL for soil invertebrates (330 mg/kg). And, low solubility likely limits the bioaccumulation of barium associated with barite and potential for effects on wildlife species. The importance of knowing the form of a metal compound is underscored by the fact that barite is one of the most commonly occurring barium compounds in soils and is widely used in commerce. The large differences between barite and the soluble barium compounds used to derive the Eco-SSL indicate that this screening tool cannot be usefully applied to soils containing the most commonly found barium compound, barite. The value of considering the specific metal compounds present in exposure media applies to other metals and indicates a need to go beyond simplified characterizations of metals expressed solely in terms of their elemental names.     

Computational Oral Absorption Simulation for Low‐Solubility Compounds

Bile micelles play an important role in oral absorption of low‐solubility compounds. Bile micelles can affect solubility, dissolution rate, and permeability. For the pH–solubility profile in bile micelles, the Henderson–Hasselbalch equation should be modified to take bile‐micelle partition into account. For the dissolution rate, in the Nernst–Brunner equation, the effective diffusion coefficient in bile‐micelle media should be used instead of the monomer diffusion coefficient. The diffusion coefficient of bile micelles is 8‐ to 18‐fold smaller than that of monomer molecules. For permeability, the effective diffusion coefficient in the unstirred water layer adjacent to the epithelial membrane, and the free fraction at the epithelial membrane surface should be taken into account. The importance of these aspects is demonstrated here using several in vivo and clinical oral‐absorption data of low‐solubility model compounds. Using the theoretical equations, the food effect on oral absorption is further discussed.     

Experimental and numerical determination of odorant solubility in nasal and olfactory mucosa

Odorant deposition in the nasal and olfactory mucosas is dependent on a number of factors including local air/odorant flow distribution patterns, odorant mucosal solubility and odorant diffusive transport in the mucosa. Although many of these factors are difficult to measure, mucosal solubility in the bullfrog mucus has been experimentally determined for a few odorants. In the present study an experimental procedure was combined with computational fluid dynamic (CFD) techniques to further describe some of the factors that govern odorant mucosal deposition. The fraction of odorant absorbed by the nasal mucosa (eta) was experimentally determined for a number of odorants by measuring the concentration drop between odorant 'blown' into one nostril and that exiting the contralateral nostril while the subject performed a velopharyngeal closure. Odorant concentrations were measured with a photoionization detector. Odorants were delivered to the nostrils at flow rates of 3.33 and 10 l/min. The velopharyngeal closure nasal air/odorant flows were then simulated using CFD techniques in a 3-D anatomically accurate human nose modeland the mucosal odorant uptake was numerically calculated. The comparison between the numerical simulations and the experimental results lead to an estimation of the human mucosal odorant solubility and the mucosal effective diffusive transport resistance. The results of the study suggest that the increase in diffusive resistance of the mucosal layer over that of a thin layer of water seemed to be general and non-odorant-specific; however, the mucosa solubility was odorant specific and usually followed the trend that odorants with lower water solubility were more soluble in the mucosa than would be predicted from water solubility alone. The ability of this approach to model odorant movement in the nasal cavity was evaluated by comparison of the model output with known values of odorant mucosa solubility.     

Enhancement of Oral Bioavailability of Cilostazol by Forming its Inclusion Complexes

The study was designed to investigate the effect of cyclodextrins (CDs) on the solubility, dissolution rate, and bioavailability of cilostazol by forming inclusion complexes. Natural CDs like β-CD, γ-CD, and the hydrophilic β-CD derivatives, DM-β-CD and HP-β-CD, were used to prepare inclusion complexes with cilostazol. Phase solubility study was carried out and the stability constants were calculated assuming a 1:1 stoichiometry. Solid cilostazol complexes were prepared by coprecipitation and kneading methods and compared with physical mixtures of cilostazol and cyclodextrins. Prepared inclusion complexes were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC), and X-ray diffraction (XRD) studies. In vitro dissolution study was performed using phosphate buffer pH 6.4, distilled water, and HCl buffer pH 1.2 as dissolution medium. The optimized inclusion complex was studied for its bioavailability in rabbit and the results were compared with those of pure cilostazol and Pletoz-50. Phase solubility study showed dramatic improvement in the solubility of drug by formation of complexes, which was further increased by pH adjustment. The dissolution rate of cilostazol was markedly augmented by the complexation with DM-β-CD. DSC and XRD curves showed sharp endothermic peaks indicating the reduction in the microcrystallinity of cilostazol. Selected inclusion complex was also stable at ambient temperature up to 6 months. The in vivo study revealed that DM-β-CD increased the bioavailability of cilostazol with low variability in the absorption. Among all cilostazol–cyclodextrins complexes, cilostazol–DM-β-CD inclusion complex (1:3) prepared by coprecipitation method showed 1.53-fold and 4.11-fold increase in absorption along with 2.1-fold and 2.97-fold increase in dissolution rate in comparison with Pletoz-50 and pure cilostazol, respectively.     

Physicochemical Characterization of Efavirenz–Cyclodextrin Inclusion Complexes

Efavirenz (EFV) is an oral antihuman immunodeficiency virus type 1 drug with extremely poor aqueous solubility. Thus, its gastrointestinal absorption is limited by the dissolution rate of the drug. The objective of this study was to characterize the inclusion complexes of EFV with β-cyclodextrin (β-CD), hydroxypropyl β-CD (HPβCD), and randomly methylated β-CD (RMβCD) to improve the solubility and dissolution of EFV. The inclusion complexation of EFV with cyclodextrins in the liquid state was characterized by phase solubility studies. The solid-state characterization of various EFV and CD systems was performed by X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy analyses. Dissolution studies were carried out in distilled water using US Pharmacopeia dissolution rate testing equipment. Phase solubility studies provided an A_L-type solubility diagram for β-CD and A_P-type solubility diagram for HPβCD and RMβCD. The phase solubility data enabled calculating stability constants (K _s) for EFV-βCD, EFV-HPβCD, and EFV-RMβCD systems which were 288, 469, and 1,073 M⁻¹, respectively. The physical and kneaded mixtures of EFV with CDs generally provided higher dissolution of EFV as expected. The dissolution of EFV was substantially higher with HPβCD and RMβCD inclusion complexes prepared by the freeze drying method. Thus, complexation with HPβCD and RMβCD could possibly improve the dissolution rate-limited absorption of EFV.     

Effect of thermocycling on hardness, absorption, solubility and colour change of soft liners

doi: 10.1111/j.1741‐2358.2010.00447.x
Effect of thermocycling on hardness, absorption, solubility and colour change of soft liners Objective: The effect of artificial ageing on the hardness, absorption, solubility, and colour of soft denture liners was investigated. Materials and methods: Liner materials based on acrylic resin (Trusoft) or silicone (Dentusil, Ufi Gel P, and Ufi Gel SC) were tested before and after 2000 thermal cycles. A total of 20 specimens of each material were tested. Half of the specimens were used for hardness and colour evaluation, and the remainder for absorption and solubility tests. The hardness evaluation was carried out using a Shore A durometer, while absorption and solubility tests were performed by storing samples in a desiccator and weighing daily until reaching constant mass (W1). After thermocycling, the samples were again weighed (W2) and dried (W3). Colour was measured using a spectrophotometer. Statistical analysis was performed using GraphPad InStat at the p < 0.05 level. Results: Thermocycling significantly affected the hardness of the specimens. The Trusoft material exhibited the highest absorption (1.48 ± 0.48), solubility (1.26 ± 0.28), and colour change (3.92 ± 0.33), significantly different from the other materials. There were no significant differences among the silicones in terms of absorption, solubility, and colour change, except for the colour of Dentusil, which changed (0.83 ± 0.11). Conclusion: It can be concluded that silicone liners performed significantly better compared to acrylic resin.     

The diffusion-solubility of oxygen in lipid bilayers

The product, D_oα, of the oxygen diffusion coefficient, D_o, and the oxygen solubility, α, is determined in phosphatidylcholine bilayers at temperatures above the lipid phase transitions from ESR spin-exchange measurements. The resulting values of D_oα are in good agreement with those obtained from fluorescence-quenching experiments. The use of fatty acid spin labels makes it possible to measure D_oα as a function of the coordinate perpendicular to the bilayer surface. The results indicate that D_oα is a strong function of this coordinate; it is greatest in the bilayer center and least near the bilayer head groups.     

Preformulation Considerations for Controlled Release Dosage Forms: Part II—Selected Candidate Support

Practical examples of preformulation support of the form selected for formulation development are provided using several drug substances (DSs). The examples include determination of the solubilities vs. pH particularly for the range pH 1 to 8 because of its relationship to gastrointestinal (GI) conditions and dissolution method development. The advantages of equilibrium solubility and trial solubility methods are described. The equilibrium method is related to detecting polymorphism and the trial solubility method, to simplifying difficult solubility problems. An example of two polymorphs existing in mixtures of DS is presented in which one of the forms is very unstable. Accelerating stability studies are used in conjunction with HPLC and quantitative X-ray powder diffraction (QXRD) to demonstrate the differences in chemical and polymorphic stabilities. The results from two model excipient compatibility methods are compared to determine which has better predictive accuracy for room temperature stability. A DSC (calorimetric) method and an isothermal stress with quantitative analysis (ISQA) method that simulates wet granulation conditions were compared using a 2 year room temperature sample set as reference. An example of a pH stability profile for understanding stability and extrapolating stability to other environments is provided. The pH-stability of omeprazole and lansoprazole, which are extremely unstable in acidic and even mildly acidic conditions, are related to the formulation of delayed release dosage forms and the resolution of the problem associated with free carboxyl groups from the enteric coating polymers reacting with the DSs. Dissolution method requirements for CR dosage forms are discussed. The applicability of a modified disintegration time (DT) apparatus for supporting CR dosage form development of a pH sensitive DS at a specific pH such as duodenal pH 5.6 is related. This method is applicable for DSs such as peptides, proteins, enzymes and natural products where physical observation can be used in place of a difficult to perform analytical method, saving resources and providing rapid preformulation support. Presented at the 41st Annual Pharmaceutical Technologies Arden Conference—Oral Controlled Release Development and Technology, January 2006, West Point NY.     

Quercetin/β-Cyclodextrin Solid Complexes Prepared in Aqueous Solution Followed by Spray-drying or by Physical Mixture

The present study was designed to investigate the influence of operating conditions (temperature, stirring time, and excess amount of quercetin) on the complexation of quercetin with β-cyclodextrin using a 2³ factorial design. The highest aqueous solubility of quercetin was reached under the conditions 37°C/24 h/6 mM of quercetin. The stoichiometric ratio (1:1) and the apparent stability constant (Ks = 230 M⁻¹) of the quercetin/β-cyclodextrin complex were determined using phase-solubility diagrams. The semi-industrial production of a 1:1 quercetin/β-cyclodextrin solid complex was carried out in aqueous solution followed by spray-drying. Although the yield of the spray-drying process was adequate (77%), the solid complex presented low concentration of quercetin (0.14%, w/w) and, thus, low complexation efficiency. The enhancement of aqueous solubility of quercetin using this method was limited to 4.6-fold in the presence of 15 mM of β-cyclodextrin. Subsequently, an inclusion complex was prepared via physical mixture of quercetin with β-cyclodextrin (molar ratio of 1:1 and quercetin concentration of 23% (w/w)) and characterized using infrared spectroscopy, differential scanning calorimetry, nuclear magnetic resonance spectroscopy, and scanning electron microscopy analyses. The enhancement of aqueous solubility of quercetin using this method was 2.2-fold, similar to that found in the complex prepared in aqueous solution before the spray-drying process (2.5-fold at a molar ratio of 1:1, i.e., 6 mM of quercetin and 6 mM of β-cyclodextrin).     

A method for simultaneous determination of solubility and transfer coefficient of oxygen in aqueous media using off-gas mass spectrometry

A static method was developed that simultaneously determined the solubility of oxygen and the oxygen-transfer coefficient in a stirred bioreactor. It was based on the static method developed by van Sonsbeek et al. to determine the ka in a liquid-impelled loop reactor. Only physical properties of the liquid were used to determine both parameters using a mass spectrometer. Data about the solubility of oxygen in water are available from the literature. Therefore, the solubility of oxygen in water was used to compare our data with published data. Furthermore, the solubility of oxygen in trypticase soy broth was compared to literature data. No significant deviations between our data and literature data could be observed. Our static method and the commonly applied dynamic method to determine the oxygen-transfer coefficient yielded similar results. The effect of temperature on the oxygen-transfer coefficient could be expressed as the activation energy needed for the transition of oxygen from the gas to the water phase. This was verified using the Arrhenius equation. (c) 1994 John Wiley & Sons, Inc.     

Improving Tenoxicam Solubility and Bioavailability by Cosolvent System

The formulation study of tenoxicam, a poorly water-soluble drug, was developed by use of a ternary cosolvent system and has significantly enhanced the solubility. Additionally, the relative bioavailability of testing formulation was also evaluated by New Zealand rabbit with a single i.m. injection. The three-phase diagram for dimethylsulfoxide (DMSO)/propylene glycol/water, DMSO/ethanol/water, and DMSO/polyethoxylated castor oil/ethanol system was developed. The volume ratio of 5:4:1 in the DMSO/polyethoxylated castor oil/ethanol system resulted in a more suitable vehicle than other systems, with a high solubility (20.73 mg/ml) and low viscosity (10.0 Cp). A pharmacokinetic study of bioequivalence (F _rel = 0.89) was also obtained. The present study not only provides a novel strategy improving tenoxicam solubility but also helps further scientific knowledge for the development of parenteral formulations.     

Proteomics investigation of molecular mechanisms affected by EnBase culture system in anti-VEGF fab fragment producing E. coli BL21 (DE3)

Aggregation of recombinant proteins, a major problem in E. coli expression system, is improved by using EnBase culture system based on slow release of glucose. In the present study, to understand the intracellular mechanisms involved in increased solubility of the target recombinant protein through EnBase system, the effect of this system was investigated on E. coli cells proteome profile. The proteome profile of E. coli cells cultured in EnBase and conventional batch mode was analyzed by two-dimensional gel electrophoresis. The proteins with significant expressional changes were identified through MALDI-TOF/TOF mass spectrometry. In EnBase system, the expressions of carbon metabolism-related proteins, sugar transport system-related proteins, and amino acids metabolism-related proteins were significantly altered. Furthermore, the expression of Thioredoxin 1 as the facilitator of protein folding was up-regulated in EnBase system that could be related to the increased solubility of recombinant protein.

The proteomics analysis of E. coli cells cultured in EnBase system revealed that Thioredoxin 1 can be a potential candidate for future studies aiming at increased anti-VEGF fab fragment solubility. Studying proteomics is a valuable tool for revealing the target proteins that play the central role in EnBase culture system for increasing the solubility.