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PubMed2005

Comparison of a miniaturized shake-flask solubility method with automated potentiometric acid/base titrations and calculated solubilities.

Solubility is one of the most important parameters for lead selection and optimization during drug discovery. Its determination should therefore take place as early as possible in the process. Because of the large numbers of compounds involved and the very low amounts of each compound available in the early development stage, it is highly desirable to measure the solubility with as little compound as possible and to be able to improve the throughput of the methods used. In this work, a miniaturized shake-flask method was developed and the solubility results were compared with those measured by semiautomated potentiometric acid/base titrations and computational methods for 21 poorly soluble compounds with solubilities mostly in the range 0.03-30 microg/mL. The potentiometric method is very economical (approximately 100 microg of a poorly soluble compound is needed) and is able to create a pH/solubility profile with one single determination, but is limited to ionizable compounds. The miniaturized shake-flask method can be used for all compounds and a wide variety of media. Its precision and throughput proved superior to the potentiometric method for very poorly soluble compounds. Up to 20 compounds a week can be studied with one set-up. Calculated solubility data seem to be sufficient for a first estimate of the solubility, but they cannot currently be used as a substitute for experimental measurements at key decision points in the development process.

Algorithms↗
PubMed2004

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.

Algorithms↗
PubMed2003

Solubility enhancement of low soluble biologically active compounds--temperature and cosolvent dependent inclusion complexation.

The solubility enhancement of biologically active compounds was analysed in dependence on temperature, amount of cosolvents and on beta-cyclodextrin as complexing agent. The analysis was performed for the systemic fungicide triflumizole (TF), a poorly water soluble compound. All parameters lead to an improvement of the solubility, the largest effect was obtained for host-guest complexation with beta-cyclodextrin. Generally, the combination of cosolvents and beta-cyclodextrin does not increase the solubility of the compound, because cosolvents destabilize the inclusion complex. At higher cosolvent concentrations the solubility of TF is mainly determined by the solubility of the free non-complexed compound in the solvent mixtures. Raising temperature enhances the solubility in any cases. It could be shown that the temperature dependence of the solubility of TF is controlled by the solubility in the solvent mixtures and not by the inclusion reaction.

Cyclodextrins↗
PubMed2000

pH-metric solubility. 2: correlation between the acid-base titration and the saturation shake-flask solubility-pH methods.

PURPOSE: The objective of this study was to compare the results of a normal saturation shake-flask method to a new potentiometric acid-base titration method for determining the intrinsic solubility and the solubility-pH profiles of ionizable molecules, and to report the solubility constants determined by the latter technique. METHODS: The solubility-pH profiles of twelve generic drugs (atenolol, diclofenac.Na, famotidine, flurbiprofen, furosemide, hydrochlorothiazide, ibuprofen, ketoprofen, labetolol.HCl, naproxen, phenytoin, and propranolol.HCl), with solubilities spanning over six orders of magnitude, were determined both by the new pH-metric method and by a traditional approach (24 hr shaking of saturated solutions, followed by filtration, then HPLC assaying with UV detection). RESULTS: The 212 separate saturation shake-flask solubility measurements and those derived from 65 potentiometric titrations agreed well. The analysis produced the correlation equation: log(1/S)titration = -0.063(+/- 0.032) + 1.025(+/- 0.011) log(1/S)shake-flask, s = 0.20, r2 = 0.978. The potentiometrically-derived intrinsic solubilities of the drugs were: atenolol 13.5 mg/mL, diclofenac.Na 0.82 microg/mL, famotidine 1.1 mg/ mL, flurbiprofen 10.6 microg/mL, furosemide 5.9 microg/mL, hydrochlorothiazide 0.70 mg/mL, ibuprofen 49 microg/mL, ketoprofen 118 microg/mL, labetolol.HCl 128 microg/mL, naproxen 14 microg/mL, phenytoin 19 microg/mL, and propranolol.HCl 70 microg/mL. CONCLUSIONS: The new potentiometric method was shown to be reliable for determining the solubility-pH profiles of uncharged ionizable drug substances. Its speed compared to conventional equilibrium measurements, its sound theoretical basis, its ability to generate the full solubility-pH profile from a single titration, and its dynamic range (currently estimated to be seven orders of magnitude) make the new pH-metric method an attractive addition to traditional approaches used by preformulation and development scientists. It may be useful even to discovery scientists in critical decision situations (such as calibrating computational prediction methods).

Hydrogen-Ion Concentration↗
PubMed1997

Prognostic value of increased soluble thrombomodulin and increased soluble E-selectin in ischaemic heart disease.

Endothelial cell dysfunction is likely to be important in the pathophysiology of ischaemic heart disease and increased levels of endothelial cell markers soluble E-selectin and soluble thrombomodulin may reflect this damage. To determine whether increased levels of these markers were predictive of disease progression, we obtained plasma from 54 patients who had survived a myocardial infarction. Soluble E-selectin and soluble thrombomodulin were measured by ELISA. After 49 months, 24 patients had suffered an additional cardiovascular event such as a second myocardial infarction or requirement for arterial surgery. Soluble E-selectin was 60+/-30 ng/mL in patients who suffered an end-point and was 54+/-23 ng/mL in those without an end-point (p=0.43). Soluble thrombomodulin was 65+/-24 ng/mL in patients who suffered an end-point and was 49+/-19 ng/mL in patients who were free of an end-point (p=0.009). The major risk factors for atherosclerosis (hypercholesterolaemia, hypertension, smoking) or peak creatinine kinase levels were unable to predict the development of an end-point. Using life tables, soluble thrombomodulin had a significant effect on survival free of an end-point (p=0.011). We conclude that the measurement of soluble E-selectin is of limited value in epidemiological studies, and that raised soluble thrombomodulin is a new marker for the progression of atherosclerosis in patients with ischaemic heart disease.

Adult↗
PubMed2004

The solubilization of the poorly water soluble drug nifedipine by water soluble 4-sulphonic calix[n]arenes.

In this study, the solubilizing effect of 4-sulphonic calix[n]arenes on the poorly water soluble drug nifedipine was investigated. 4-Sulphonic calix[n]arenes are water-soluble phenolic cyclooligomers that form complexes with neutral molecules such as nifedipine. Solubility experiments were performed at 30 degrees C using the Higuchi rotating bottle method. The amount of nifedipine in solution was determined by HPLC. The results showed that the size of the 4-sulphonic calix[n]arenes, the pH of solubility medium, and the concentration of the calix[n]arenes all significantly changed the solubility of nifedipine. 4-Sulphonic calix[8]arene improved the solubility of nifedipine the most, about 3 times the control at 0.008 M and pH 5, followed by 4-sulphonic calix[4]arene, about 1.5 times the control at 0.008 M and pH 5, while in the presence of 4-sulphonic calix[6]arene, the solubility of nifedipine was decreased. The possible mechanisms involving in the complexation between 4-sulphonic calix[4]arenes, 4-sulphonic calix[8]arene and nifedipine may be a combination of hydrogen bonding, hydrophobic bonding, and possibly electron donor-acceptor interactions. However, the degree to which these forces promote the formation of nifedipine:4-sulphonic calix[n]arene complexes with increased solubility was limited by conformational changes in the 4-sulphonic calix[n]arene molecules.

Calixarenes↗
PubMed2006

Parallel screening approach to identify solubility-enhancing formulations for improved bioavailability of a poorly water-soluble compound using milligram quantities of material.

In this article, we present a parallel experimentation approach to rapidly identify a solubility-enhancing formulation that improved the bioavailability of a poorly water-soluble compound using milligrams of material. The lead compound and a panel of excipients were dissolved in n-propanol and dispensed into the wells of a 96-well microtiter plate by a TECAN robot. Following solvent evaporation, the neat formulations were diluted with an aqueous buffer, and incubated for 24h. The solubilization capacity of the excipients for the compound at 24h (SC(24h)), was determined by HPLC, and compared with its solubility in the corresponding neat formulations determined by a bench-scale method. The ranking order of solubilization capacity of the five tested formulations for this compound by this microscreening assay is same as the ranking order of the compound solubility in the neat formulations. Several formulations that achieved the target aqueous solubility were identified using the screening method. One of the top formulations, an aqueous solution of the compound containing 20% Tween 80 by weight, increased the compound solubility from less than 2 microg/mL to at least 10mg/mL. In a rat pharmacokinetic (PK) study, the Tween 80 formulation achieved 26.6% of bioavailability, a significant improvement over 3.4% of bioavailability for the aqueous Methocel formulation (p<0.01). The results in the study suggest that this parallel screening assay can be potentially used to rapidly identify solubility-enhancing formulations for an improved bioavailability of poorly water-soluble compounds using milligram quantities of material.

Animals↗
PubMed2004

Soluble fibrin augments spreading of fibroblasts by providing RGD sequences of fibrinogen in soluble fibrin.

We previously reported that fibroblasts were found to spread far more avidly on NaBr-solubilized fibrin monomer (FM) monolayers than on immobilized fibrinogen (Fbg), indicating that removal of fibrinopeptides by thrombin is a prerequisite for the fibrin-mediated augmentation of cell spreading [J. Biol. Chem. 272 (1997) 8824-8829]. Soluble fibrin (SF), a 1:2 complex of fibrin-monomer and fibrinogen, is known to be present in the circulating blood under the pathological condition in which blood coagulation is activated. However, its physiological roles are still incompletely known. Fibroblasts spread on immobilized purified soluble fibrin. Cells spreading on immobilized soluble fibrin were blocked by the exogenous addition of soluble fibrin and glycine-arginine-glycine-aspartic acid-serine-phenylalanine (GRGDSP)-synthetic peptide but not by the addition of fibrinogen or fibrin monomer. However, cell spreading activity was decreased in the surfaces coated with fragment X, whose Aalpha-chains lack carboxyl-terminal segments including arginine-glycine-aspartic acid (RGD)-2 domain, fibrin monomer complexes. It suggests that the RGD-2 domain of fibrinogen after being complexed with fibrin monomer plays a pivotal role for soluble fibrin-dependent cell spreading. Soluble fibrin in plasma derived from the patients of disseminated intravascular coagulation (DIC) was immuno-purified using the monoclonal antibody (mAb) which specifically recognizes the Ca(++)-dependent conformer of fibrinogen. The purified soluble fibrin consisted of desAA-fibrin monomer and two fibrinogen molecules and did show the cell spreading activity. Thus, soluble fibrin in plasma plays a role as the modulator of thrombogenic process in vivo.

Cell Adhesion↗
PubMed1994

Predicting the solubility of drugs in solvent mixtures: multiple solubility maxima and the chameleonic effect.

An approach to reproduce the solubility profile of a drug in several solvent mixtures showing two solubility maxima is proposed in this work. The solubility of sulphamethoxypyridazine was determined at 25 degrees C in several mixtures of varying polarity (hexane:ethyl acetate, ethyl acetate:ethanol and ethanol:water). Sulphamethoxypyridazine was chosen as a model drug because of its proton-donor and proton-acceptor properties. A plot of the mole fraction of the drug vs the solubility parameter of the solvent mixtures shows two solubility peaks. The two peaks found for sulphamethoxypyridazine demonstrate the chameleonic effect as described by Hoy and suggest that the solute-solvent interaction does not vary uniformly from one mixture to another. The different behaviour of the drug in mixtures of two proton-donor and proton-acceptor solvents (alcohol and water), and in mixtures of one proton acceptor (ethyl acetate) and one proton donor-proton acceptor (ethanol) is rationalized in terms of differences in the proton donor-acceptor ability of the solvent mixtures. An approach based on the acidic and basic partial solubility parameters together with the Hildebrand solubility parameter of the solvent mixtures is developed to reproduce the experimental results quantitatively. The equation predicts the two solubility maxima as found experimentally, and the calculated values closely correspond to the experimental values through the range composition of the solvent mixtures. These results show that the chameleonic effect can be described in a quantitative way in terms of Lewis acid-base interactions; this approach can assist the product formulator to choose the proper solvent mixture for a new drug.

Acetates↗
PubMed2006

Soluble Epstein-Barr virus glycoproteins gH, gL, and gp42 form a 1:1:1 stable complex that acts like soluble gp42 in B-cell fusion but not in epithelial cell fusion.

Epstein-Barr virus (EBV) is a herpesvirus that infects cells by fusing its lipid envelope with the target cell membrane. The fusion process requires the actions of viral glycoproteins gH, gL, and gB for entry into epithelial cells and additionally requires gp42 for entry into B cells. To further study the roles of these membrane-associated glycoproteins, purified soluble forms of gp42, gH, and gL were expressed that lack the membrane-spanning regions. The soluble gH/gL protein complex binds to soluble gp42 with high affinity, forming a stable heterotrimer with 1:1:1 stoichiometry, and this complex is not formed by an N-terminally truncated variant of gp42. The effects of adding soluble gp42, gH/gL, and gH/gL/gp42 were examined with a virus-free cell-cell fusion assay. The results demonstrate that, in contrast to gp42, membrane fusion does not proceed with secreted gH/gL. The addition of soluble gH/gL does not inhibit or enhance B-cell or epithelial cell fusion when membrane-bound gH/gL, gB, and gp42 are present. However, the soluble gH/gL/gp42 complex does activate membrane fusion with B cells, similarly to soluble gp42, but it does not inhibit fusion with epithelial cells, as observed for gp42 alone. A gp42 peptide, derived from an N-terminal segment involved in gH/gL interactions, binds to soluble gH/gL and inhibits EBV-mediated epithelial cell fusion, mimicking gp42. These observations reveal distinct functional requirements for gH/gL and gp42 complexes in EBV-mediated membrane fusion.

Animals↗
PubMed2000

Multiple solubility maxima of oxolinic acid in mixed solvents and a new extension of Hildebrand solubility approach.

A new extension of the Hildebrand solubility approach which describes drug solubility in solvent mixtures showing multiple solubility peaks, the chameleonic effect, is proposed. The experimental solubilities of oxolinic acid were measured at 25 degrees C in solvent mixtures of ethanol-water and ethanol-ethyl acetate. A plot of the mole fraction of the drug against the solubility parameter (delta) of the solvent mixtures displays two peaks at delta = 30.78 MPa1/2 (80% v/v of ethanol in water) and at delta = 20.90 MPa1/2 (30% v/v of ethanol in ethyl acetate). The new extension proposed reproduces two solubility peaks. The thermograms of the solid phase before and after equilibration with the solvent mixtures did not show significant changes. The new extension was also tested with experimental data previously reported for drugs showing two solubility peaks of different height. The accuracy of other published models for describing two solubility maxima is also compared.

Algorithms↗
PubMed1982

Fractionation and quantitation of egg antigens from Schistosoma japonicum by the single-tube kinetic-dependent enzyme-linked immunosorbent assay (k-ELISA): higher antigenic activity in urea-soluble than in aqueous-soluble fractions.

To identify sources of high potency antigens for use in serodiagnosis, aqueous-soluble egg antigens from Schistosoma japonicum were extracted with Dulbecco's phosphate-buffered saline. Residual particulates were solubilized with Tris-buffered 8 M urea, yielding a urea-soluble egg antigen fraction. The urea-soluble fraction was further fractionated with Bio Gel A50m and QAE-Sephadex. All fractions were quantitatively assayed for their specific antigenic activities against serum specimens from infected rabbits by the single-tube enzyme-linked immunosorbent assay (k-ELISA). In antigen rate-limiting conditions, the urea-soluble particulate fractions were more antigenically active than the aqueous-soluble fraction. In antigen-excess and antibody-limiting assay conditions, the ideal conditions for serologic assays, the urea-derived antigens also showed superior activities against sera from infected humans. Analysis by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) on gradient gels revealed numerous low molecular weight protein bands in the aqueous-soluble fraction, whereas the urea-soluble fractions appeared to be much simpler with the majority of their proteins concentrated in one or two high molecular weight bands (greater than or equal to 200 kdaltons). Electro-transfer blots of the SDS-PAGE onto nitrocellulose papers and subsequent visualization of antigens by enzyme-linked immunoabsorbence confirmed these findings. The above data suggest that the urea-soluble fraction of S. japonicum eggs is antigenically active and has potential use in the development of a diagnostic reagent.

Animals↗
PubMed1994

Serum levels of interleukin 1-beta, tumor necrosis factor-alpha, soluble interleukin 2 receptor and soluble CD8 in seronegative spondylarthropathies.

Seronegative spondylarthropathies are disorders with the same predisposing antigen, namely HLA B27, a class I molecule of the HLA system. The mechanisms of the different diseases are unknown, and there is no proof of immune system participation. We have investigated patients with spondylarthropathies in order to search for an immunological component in the pathophysiology of these disorders, by measuring the serum level of two inflammatory cytokines--IL1 beta and TNF alpha--by a radioimmunological assay and the serum level of two soluble T cell activation markers--soluble IL2 receptor and soluble CD8--by an enzyme-linked immunosorbent assay. The choice of soluble CD8 can be explained by the strong link between HLA B27 and spondylarthropathies. Our series compared 24 patients to 24 healthy matched controls. A similar IL1 beta serum level was observed in both groups, while in the patients there was a nonsignificant increase in the TNF alpha level, a significant decrease in the soluble IL2 receptor level and a significant increase in the soluble CD8 serum level. The normal or moderately increased serum IL1 beta and TNF alpha levels in the disease group do not exclude a local role for these cytokines in the synovium or other inflammatory areas. However, we found a higher soluble CD8 serum level in the patient group. Most of these patients were in clinical exacerbation of their disease. As the serum level of soluble CD8 is well correlated with T CD8 lymphocyte activation, our data suggest that this lymphocyte subset is stimulated and consequently probably involved in seronegative spondylarthropathies.

Adult↗