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PubMed2006

Soluble-insoluble-soluble transitions of aqueous poly(N-vinylacetamide-co-acrylic acid) solutions.

Several poly(N-vinylacetamide-co-acrylic acid)s with various copolymer compositions have been synthesized, and their unique phase-transition behavior in aqueous salt (Na2SO4 or NaCl) solutions was investigated. Copolymers containing more than 51 mol % N-vinylacetamide (NVA) show reentrant soluble-insoluble-soluble transitions with increasing temperature. The soluble-insoluble transition temperature (T(p1)) increased linearly with increasing NVA content, whereas the insoluble-soluble transition temperature (T(p2)) was almost constant irrespective of the NVA content. Potentiometric titration of the copolymer solutions suggested that the acrylic acid (AA) carboxyl groups form hydrogen bonds with the NVA amide groups even under soluble conditions. Dehydration of the NVA amides and their consequent hydrogen bonding with the AA carboxyl groups during the soluble-insoluble transition process was indicated by FTIR measurements. Addition of salt (Na2SO4 or NaCl) to the aqueous media reduces the solvent quality and enhances the intra- and interchain interactions of the copolymers. Thus, T(p1) was observed to decrease and T(p2) was observed to increase with increasing salt concentration. However, the addition of urea to the media reverses the concentration dependence of T(p1) and T(p2) by disturbing the intra- and interchain interactions of the copolymers.

Journal Article↗

PubMed2006

Reduction of soluble Abeta and tau, but not soluble Abeta alone, ameliorates cognitive decline in transgenic mice with plaques and tangles.

Increasing evidence points to soluble assemblies of aggregating proteins as a major mediator of neuronal and synaptic dysfunction. In Alzheimer disease (AD), soluble amyloid-beta (Abeta) appears to be a key factor in inducing synaptic and cognitive abnormalities. Here we report the novel finding that soluble tau also plays a role in the cognitive decline in the presence of concomitant Abeta pathology. We describe improved cognitive function following a reduction in both soluble Abeta and tau levels after active or passive immunization in advanced aged 3xTg-AD mice that contain both amyloid plaques and neurofibrillary tangles (NFTs). Notably, reducing soluble Abeta alone did not improve the cognitive phenotype in mice with plaques and NFTs. Our results show that Abeta immunotherapy reduces soluble tau and ameliorates behavioral deficit in old transgenic mice.

Alzheimer Disease↗

PubMed1996

Dehydroepiandrosterone sulfate is positively correlated with soluble interleukin 2 receptor and soluble intercellular adhesion molecule in systemic lupus erythematosus.

OBJECTIVE: To determine whether dehydroepiandrosterone sulfate (DHEAS) is linked with soluble immune mediators in systemic lupus erythematosus (SLE). METHODS: DHEAS and various soluble immune mediators were measured by ELISA in the serum of 35 patients with SLE (26 women, 9 men) and in 41 control subjects. RESULTS: DHEAS was lower in patients with SLE compared to controls (male 1.29 +/- 0.32 vs 3.04 +/- 0.33 micrograms/ml, p < 0.001; female 0.75 +/- 0.12 vs 2.16 +/- 0.18 micrograms/ml, p < 0.001). The DHEAS reduction was in part dependent on prior glucocorticosteroid treatment (p < 0.02). After adjustment for multiple comparisons, there was significant negative correlation between steroid dose and DHEAS (RRank = -0.426, p = 0.005), but with none of the soluble immune mediators. No significant difference in the percentage of steroid treated male and female patients was found (p = 0.220). However, there was positive correlation between DHEAS and soluble interleukin 2 receptor in women, but not in men, with SLE [RRank = 0.747 (n = 26, p < 0.0001) vs RRank = -0.1333( n = 9, p = 0.366)] and between DHEAS and soluble intercellular adhesion molecule in women, but not in men, with SLE [RRank = 0.509 (n = 26, p = 0.005) vs RRank = 0.4833 (n = 9, p = 0.094)]. CONCLUSION: These data demonstrate positive interrelation between DHEAS and soluble immune mediators involved in leukocyte function and leukocyte adhesion only in female patients with SLE.

Adult↗

PubMed2002

Improvement of solubility and oral bioavailability of a poorly water-soluble drug, TAS-301, by its melt-adsorption on a porous calcium silicate.

The aim of the present study was to improve the solubility and oral bioavailability of a poorly water-soluble drug, 3-bis(4-methoxyphenyl) methylene-2-indolinone (TAS-301), by its melt-adsorption on a porous calcium silicate, Florite RE (FLR), without any solvents. The melt-adsorbed products were prepared by two methods: the small-scale batch method and the twin screw extruder method. The drug was melted and adsorbed on FLR (i.e., "melt-adsorption"), above its melting point. Crystallinity of the drug in the melt-adsorbed product was estimated by differential scanning calorimetry (DSC) and powder X-ray diffraction analysis. The dissolution test was conducted by the JP XIII paddle method. Oral absorption of the melt-adsorbed product was studied in fasted and fed dogs. The melt-adsorbed products prepared by the two methods were in powder forms. The drug existed in an amorphous state in the product and hardly recrystallized even after storing at a stressed condition (60 degrees C/80% RH for 3 days). The TAS-301 dissolution rate from the melt-adsorbed product was markedly enhanced compared with drug crystals. The area under the plasma concentration-time curve (AUC) and peak concentration (C(max)) values of the drug after dosing the melt-adsorbed product were significantly greater than those after dosing the drug crystals. The solubility and bioavailability of TAS-301 were improved by its melt-adsorption on FLR. The present findings suggest melt-adsorption is a useful technique for improving solubility and bioavailability of poorly water-soluble drugs.

Administration, Oral↗

PubMed1979

Solubility determination of barely aqueous-soluble organic solids.

Solubility determination of organic molecules having very low solubilities is hampered by such problems as slow equilibration during measurement, influence of impurities, and inherent heterogeneity in the energetic content of the crystalline solid. Three approaches to meeting these problems are presented. The first approach involves enhancing the dissolution rate by the addition of a water-immiscible solvent in which the organic solute is more soluble, thereby increasing the surface area available for dissolution. The second method is a combination of experimental data with a group contribution approach that allows the estimation of extremely insoluble solids. This approach involves measurement of the solubility in an organic solvent and calculation of the aqueous solubility from the estimated partition coefficient and the organic solvent data. The third approach is based on using a large excess of the solid and a highly specific analytical determination of the main component. The first two approaches were explored in detail and tested using norethindrone, norethindrone acetate, methyltestosterone, and methyltestosterone acetate.

Kinetics↗

PubMed1984

General treatment of pH-solubility profiles of weak acids and bases and the effects of different acids on the solubility of a weak base.

The pH-solubility profile of a weak acid or base is shown to be a function of its pKsp, pKa, and uncharged species solubility. Equations are presented that can be used to calculate the solubility as a function of pH. These equations can also be used when there is added salt present. Experimental data was obtained in three cosolvent systems consisting of methanol-water and ethanol-water. Also, the effect of different acids on the solubility of a weak base is reported. A pronounced effect on the solubility by the addition of salt is explained in terms of the Ksp.

Acids↗

PubMed1986

Solubility properties in polymers and biological media: 6. An equation for correlation and prediction of solubilities of liquid organic nonelectrolytes in blood.

Gas/blood partition coefficients, Kgb, and molar solubilities in blood, Sb, of 27 liquid aliphatic nonelectrolyte solutes are described by the equation: log Sb congruent to log (Sg/Kgb) = 1.35-3.05V/100-0.28 pi* + 3.58 beta (at 37 degrees C) r = 0.9870 and SD = 0.144 where Sg is the solute concentration in its saturated vapor at 37 degrees C, given by Sg = Patm/25.4; V is the solute molar volume; and pi* and beta are parameters that are measures of solute dipolarity/polarizability and hydrogen bond acceptor basicity, respectively. The above equation applies to compounds with calculated log solubilities greater than -1.5. A nondipolar solubility reservoir provided by hydrophobic pockets in hemoglobin leads to greater than predicted solubilities for the less soluble alkanes, alkylbenzenes, and chlorobenzenes. It is suggested that equations similar to the one above can be constructed to describe and predict gas-lipid and gas-homogenized tissue, and hence blood-lipid, blood-tissue, tissue-lipid, and tissue-tissue partition coefficients of pharmacologically and toxicologically active solutes.

Hemoglobins↗

PubMed1987

Solubility and partitioning. VII: Solubility of barbiturates in water.

The solubility equation of Yalkowsky was used to estimate the aqueous solubility of 33 barbiturates in the temperature range of 5 to 45 degrees C. The equation was extended by adding a term which accounts for the effect of pH on the solubility of the drug. The extended equation is successful in estimating the aqueous solubility of this series of drugs under different conditions of temperature and pH. The results indicate that the extended equation can be used to estimate the aqueous solubility of nonelectrolytes as well as weak electrolytes.

Barbiturates↗

PubMed1989

Predicting the solubility of sulfamethoxypyridazine in individual solvents. I: Calculating partial solubility parameters.

Sulfamethoxypyridazine, a representative model of a drug molecule, is used to test the extended Hansen method for estimating partial solubility parameters of solid compounds. Solubilities are determined in polar and nonpolar solvents. The method provides reasonable partial parameters for the sulfonamide, and it may be useful in obtaining partial parameters for other drug molecules. A four-parameter extended Hansen approach involving proton donor and acceptor parameters is used in fitting the data to a theoretical model. A term, Wh, is introduced as an empirical measure of solute-solvent interactions due to hydrogen bonding. The use of the empirical term Wh allows the researcher to fit experimental solubilities and thus design regression models and equations which provide a reasonable prediction of solubilities of a polar drug in a number of very different solvents. A Flory-Huggins size correction term improves the prediction of sulfamethoxypyridazine solubilities in these irregular solutions.

Chemical Phenomena↗

PubMed1989

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.

Chemical Phenomena↗

PubMed2005

Validation of a screening method for the simultaneous identification of fat-soluble and water-soluble vitamins (A, E, B1, B2 and B6) in an aqueous micellar medium of hexadecyltrimethylammonium chloride.

Simultaneous determination of the fat-soluble vitamins A and E and the water-soluble vitamins B1, B2 and B6 has been carried using a screening method from fluorescence contour graphs. These graphs show different colour zones in relation to the fluorescence intensity measured for the pair of excitation/emission wavelengths. The identification of the corresponding excitation/emission wavelength zones allows the detection of different vitamins in an aqueous medium regardless of the fat or water solubility of each vitamin, owing to the presence of a surfactant which forms micelles in water at the used concentration (over the critical micelle concentration). The micelles dissolve very water insoluble compounds, such as fat-soluble vitamins, inside the aggregates. This approach avoids the use of organic solvents in determining these vitamins and offers the possibility of analysing fat- and water-soluble vitamins simultaneously. The method has been validated in terms of detection limit, cut-off limit, sensitivity, number of false positives, number of false negatives and uncertainty range. The detection limit is about microg L(-1). The screening method was applied to different samples such as pharmaceuticals, juices and isotonic drinks.

Beverages↗

PubMed1986

Identical N-terminal peptide sequences of asymmetric forms and of low-salt-soluble and detergent-soluble amphiphilic dimers of Torpedo acetylcholinesterase. Comparison with bovine acetylcholinesterase.

We have determined partial N-terminal sequences of acetylcholinesterase (AChE) catalytic subunits from Torpedo marmorata electric organs and from bovine caudate nucleus. We obtain identical sequences (23 amino acids) for the soluble ('low-salt-soluble' or LSS fraction) and particulate ('detergent-soluble', or DS fraction) amphiphilic dimers (G2 form) and for the asymmetric, collagen-tailed forms ('high-salt-soluble', or HSS fraction, A12 + A8 forms). There are two amino acid differences, at position 3 (Asp/His) and 20 (Ile/Val), with the sequences obtained for T. californica by MacPhee-Quigley et al. [(1985) J. Biol. Chem. 260, 12185-12189] for the soluble G2 form and the lytic G4 form which is derived from asymmetric AChE. The bovine sequence (12 amino acids) presents an identity of 4 amino acids (Glu-Leu-Leu-Val) with that of Torpedo, at positions 5-8 (Torpedo) and 7-10 (bovine). There is also a clear homology with the sequence of human butyrylcholinesterase [(1986) Lockridge et al. J. Biol. Chem., in press] indicating that these enzymes probably derive from a common ancestor.

Acetylcholinesterase↗

PubMed2002

Estimation of aqueous solubility of organic compounds by using the general solubility equation.

The general solubility equation (GSE) proposed by Jain and Yalkowsky was used to estimate aqueous solubility of 1026 non-electrolytes. The only parameters used in the GSE are melting points (MP) and octanol-water partition coefficients (Kow). No fitted parameters and no training set are employed in the GSE. The experimental solubility values were taken from the AQUASOL dATAbASE. The average absolute error and the root-mean-square error in the solubility estimates are 0.38 and 0.53 log units, respectively. Thus, with an observed MP and calculated Kow; the users can obtain a reasonable estimation of the aqueous solubility of any organic non-electrolyte.

Forecasting↗

PubMed2001

Selection of excipients for melt extrusion with two poorly water-soluble drugs by solubility parameter calculation and thermal analysis.

The aim of this study was to determine the miscibility of drug and excipient to predict if glass solutions are likely to form when drug and excipient are melt extruded. Two poorly water-soluble drugs, indomethacin and lacidipine, were selected along with 11 excipients (polymeric and non-polymeric). Estimation of drug/excipient miscibility was performed using a combination of the Hoy and Hoftzyer/Van Krevelen methods for Hansen solubility parameter calculation. Miscibility was experimentally investigated with differential scanning calorimetry (DSC) and hot stage microscopy (HSM). Studies were performed at drug/excipient ratios, 1:4, 1:1 and 4:1. Analysis of the glass transition temperature (T(g)) was performed by quench cooling drug/excipient melts in the DSC. Differences in the drug/excipient solubility parameters of <7.0 MPa(1/2) were predicted to indicate significant miscibility and, therefore, glass solution formation on melt extrusion. In comparison, differences of >10 MPa(1/2) were expected to indicate a lack of miscibility and not form glass solutions when melt extruded. Experimentally, miscibility was shown by changes in drug/excipient melting endotherms and confirmed by HSM investigations. Experimental results were in agreement with solubility parameter predictions. In addition, drug/excipient combinations predicted to be largely immiscible often exhibited more than one T(g) upon reheating in the DSC. Melt extrusion of miscible components resulted in amorphous solid solution formation, whereas extrusion of an "immiscible" component led to amorphous drug dispersed in crystalline excipient. In conclusion, combining calculation of Hansen solubility parameters with thermal analysis of drug/excipient miscibility can be successfully applied to predict formation of glass solutions with melt extrusion.

Calorimetry, Differential Scanning↗

PubMed2002

Solubility improvement of shellfish muscle proteins by reaction with glucose and its soluble state in low-ionic-strength medium.

When myofibrillar proteins of scallop striated adductor muscle were reacted with glucose through the Maillard reaction, the change in the solubility of myofibrillar proteins in 0.05-0.5 M NaCl solutions during glycosylation and their soluble states were investigated. The solubility in low-ionic-strength media increased greatly with the progress of the Maillard reaction. The solubility in 0.1 M NaCl reached 83% when more than 60% of lysine residues in myofibrillar proteins were modified by glucose. However, the excess progress of the Maillard reaction impaired the improved solubility of myofibrillar proteins in a low-ionic-strength medium. Myosin, actin, and paramyosin in glycosylated myofibrillar proteins were solubilized independently regardless of NaCl concentration. In addition, the glycosylated myosin lost its filament-forming ability and existed as a monomer in 0.1 M NaCl.

Actins↗

PubMed2004

Design, synthesis, and biological activity of 1,3-disubstituted ureas as potent inhibitors of the soluble epoxide hydrolase of increased water solubility.

The soluble epoxide hydrolase (sEH) is involved in the metabolism of endogenous chemical mediators that play an important role in blood pressure regulation and inflammation. 1,3-Disubstituted ureas are potent inhibitors of sEH that are active both in vitro and in vivo. However, their poor solubility in either water or lipid reduces their in vivo efficacy and makes them difficult to formulate. To improve these physical properties, the effect of incorporating polar functional groups into one of the alkyl chains was evaluated on their inhibitor potencies, water solubility, octanol/water partition coefficients (log P), and melting points. No loss of inhibition potency was observed when a polar functional group was incorporated at least five atoms ( approximately 7.5 A) from the central urea carbonyl. In addition, the presence of a polar group at least 11 atoms away from the urea carbonyl group for the mouse and human sEHs, respectively, did not alter the inhibitor potency. The resulting compounds have better water solubility and generally lower log P values and melting points than nonfunctionalized liphophilic ureas. These properties will make the compounds more bioavailable and more soluble in either water- or oil-based formulations.

Animals↗

PubMed1988

Limiting solubilities and ionization constants of sparingly soluble compounds: determination from aqueous potentiometric titration data only.

A new method is described for the concomitant determination of limiting solubilities and ionization constants of sparingly soluble compounds, i.e., drugs. Aqueous potentiometric titration data were recorded both before and after precipitation of the compound and subjected to computer-assisted analysis. Limiting solubilities and ionization constants were obtained for nucleoside transport inhibitors, viz., dilazep, soluflazine, and hexobendine. The method was validated by comparison of titration results for known antidepressants with data from the literature. The procedure was found to be rapid and reliable for compounds with limiting solubilities as low as 30 microM, and it circumvents problems of direct methods for measuring limiting solubilities.

Chlorpromazine↗

PubMed1996

Subunit structure of Ca++ dependent soluble goat hepatic lectin: evidence that it has antigenic structural relationship with soluble 14K lectin family.

The subunit structure of soluble goat hepatic lectin was studied by determining molecular weight under nondenaturing conditions by gel filtration and denaturing conditions by SDS PAGE. Affinity purified lectin was subjected to HPLC on asahipack column equilibrated with 10 mM Tris-HCl pH 7.5, containing 1 mM CaCl2, 1mM 2-mercaptoethanol and 0.1M NaCl. The lectin was eluted under single peak at retention time of 12 min. corresponding to molecular weight of 38Kd. On SDS-PAGE in the presence and absence of 2-mercaptoethanol protein moved as single band with Rm 0.45, which corresponds to molecular weight of 20 Kd. The results suggest that soluble goat hepatic lectin is a dimmer of identical subunits which are linked together by noncovalent interactions. The interaction of monoclonal antibodies raised against soluble goat hepatic lectin (MGHL/20) with hemagglutinin from different species as sheep, human, rat, bovine and chicken was studied in PBS by solid phase binding assay. MGHL/20 showed 29.89% binding with these lectin. However no binding was found with Ca++ dependent membrane bound lectin. These results indicate that soluble goat hepatic lectin possesses antigenic structural relationship with soluble 14 K lectin family.

Animals↗