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PubMed2000

Analytical reliability of mobile-phase recycling in liquid chromatography

Although it is not officially condoned, mobile-phase (MP) recycling has become a widespread practice that is not well documented in terms of its effects on sample quantification. MP was spiked with three different concentrations of two analytes, tartaric acid and sodium citrate, to simulate MP recycling. These MPs were used to analyze eight different concentrations of these analytes in standard solutions. When analyte concentration in the MP exceeds that in the sample, a vacancy (negative) peak is observed, and when its concentration in the MP is equal to that in the sample, no peak is observed for that analyte. The slopes of the linear regression lines for standards in MPs with different concentrations of analyte did not change, although the gamma-intercept values decrease with increasing concentration of analyte in the MP. These results show that the concentration of analytes in recycled MP can be determined by comparing the absolute value of the gamma-intercept of the linear regression line with the corresponding peak area from the linear regression line for clean (solute-free) MP, provided other chromatographic parameters do not change. Suggestions are made for determining when recycled MP should be discarded.

Journal Article↗
PubMed1994

Binding affinity and site selectivity of daunomycin analogues.

We have tested a series of daunomycin analogues for binding affinity to a group of oligonucleotides that contain binding sites specific for daunomycin and that were previously screened for relative binding affinity for daunomycin. The series of drugs differed from daunomycin in the sugar moiety, including substitution of a hydroxyl group for the charged amino group and replacement of the 2'-OH by an iodo substituent. Data were analyzed by Scatchard plots and association constants were estimated from the gamma-intercept at saturating levels of oligonucleotide. Because of the solubility problems associated with these compounds, Scatchard plots could not be extended to high levels of binding. A second method of analysis of the fluorescence data confirmed the semiquantitative association constants obtained from the intercepts of the Scatchard plots. The association constants were in the range of 10(5)-10(7) M-1. When compared with daunomycin, the compounds with hydroxyl substituted for the amino group in the sugar ring generally bound less well to the oligonucleotides, by factors of up to several hundred. Much of the binding lost upon removal of the charged amino group was restored, however, with compounds containing an iodo substituent on the sugar ring. Changing the iodo-substituted sugar from the natural L-form to the D-form diminished binding by 6-50-fold, depending on sequence. This result implies a stereospecific interaction of the natural sugar with the DNA chain. A positively cooperative curve was observed in the Scatchard plot for the D-form sugar.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Tubulin dimer dissociation and proteolytic accessibility.

The alpha and beta subunits of the tubulin dimer each possess a distal C-terminal subtilisin cleavage site which, when cleaved, releases an acidic, small peptide. In addition, each possesses an internal site, cleaved by trypsin in alpha and chymotrypsin in beta, which connects the amino and carboxyl structural domains. A model of the dimer is presented which suggests that the beta C-terminal subtilisin site may be more accessible in the monomer than in the dimer. Kinetics of cleavage at this site on the dimer yield straight-line plots of log (undigested fraction) versus time, from which pseudo-first-order rate constants are obtained. Temperature effects on the rate constant are due to changes in the activity of subtilisin, not to temperature-induced unfolding around this site. The rate constant is proportional to the subtilisin/tubulin ratio, whether this is varied by changing the concentration of subtilisin or of tubulin. However, if the rate constant increases due to decreasing tubulin concentration, the extrapolated zero time intercept decreases. The decrease in zero time intercept is interpreted as being due to the appearance of a rapidly digested fraction upon dilution of tubulin. The increase observed in this fast fraction with dilution of tubulin is fully reversible upon reconcentration. It is suggested that this fast fraction represents monomeric beta-tubulin and the concentration dependence of this fast fraction indicates a dissociation constant of about 1.5 X 10(-7) M.

Animals↗
PubMed1980

Studies on the mechanism of adenosine 5'-monophosphate inhibition of bovine liver fructose 1,6-bisphosphatase.

Inhibition by adenosine 5'-monophosphate (AMP) of the forward reaction of fructose 1,6-bisphosphatase (FBPase) has been studied by means of progress curve analysis. The full time course of the FBPase reaction was followed by coupling the reaction to the enzymes phosphoglucoisomerase and glucose-6-phosphate dehydrogenase. The data were analyzed by using three different methods of regression and these methods are compared. During these progress curve experiments, it was noticed that fructose 1,6-bisphosphate (Fru-P2) was not fully utilized in the presence of AMP. This anomaly could be best explained by proposing the formation of an AMP.Fur-P2 complex that was inactive with FBPase. Besides reducing the level of substrate available to FBPase, AMP caused slope-parabolic, intercept-parabolic noncompetitive inhibition with respect to Fru-P2. A kinetic model for AMP inhibition of the forward reaction of FBPase is presented. Initial rate kinetics were used to study the reverse reaction of FBPase; AMP was a slope-parabolic, intercept-parabolic noncompetitive inhibitor with respect to both fructose 6-phosphate and inorganic phosphate. Initial velocity experiments in which both fructose 6-phosphate and inorganic phosphate were varied were carried out in the absence and presence of AMP. The results of these experiments indicated to which reverse-reaction enzyme forms AMP was binding. The possible physiological significance of the AMP inhibition of FBPase and of the proposed AMP.Fru-P2 complex is discussed.

Adenosine Monophosphate↗
PubMed1977

D-Mannitol dehydrogenase from Absidia glauca. Steady-state kinetic properties and the inhibitory role of mannitol 1-phosphate.

Steady-state kinetic studies including initial velocity for mannitol oxidation and fructose reduction and product inhibition for mannitol oxidation using fructose and reduced nicotinamide adenine dinucleotide (NADH) are in accord with a reaction mechanism best described as ordered Bi-Bi with NAD+ and NADH designated as the first substrate, last product, respectively at pH 8.8. All replots of slopes and intercepts from product inhibition studies were linear. Dead-end inhibition studies using mannitol 1-phosphate gave slope-parabolic, intercept-linear noncompetitive inhibition for both NAD+ and mannitol as substrates. The dead-end inhibitor is capable of binding multiply to the E, EA, and EQ forms of the enzyme to an extent that is controlled by the concentration of substrates. The EQ complex is inferred to undergo a conformational change, E'Q equilibrium EQ, since (V1/E1) greater than (KiqV2)/(KqE1), and no evidence for dead-end complex formation with NADH can be adduced. This is interpreted to mean that the release of fructose from the central complex is faster than the isomerization of the E-NADH complex. When mannitol is saturating, the noncompetitive inhibition against NAD+, as the variable substrate, becomes parabolic uncompetitive. A replot of the slopes of the parabola against mannitol 1-phosphate remains concave upward. This situation could arise if the conformational change we infer in the EQ complex opens up additional sites on the protein which can interact with the dead-end inhibitor.

Fungi↗
PubMed1977

Pre-steady-state kinetics of intermediate formation in the deuteroferriheme-hydrogen peroxide system.

The pH dependence of formation of a peroxidatic intermediate from the reaction of deuteroferriheme with hydrogen peroxide has been determined for the region pH 8.7-10.1 from stopped-flow kinetic studies in which absorbancy changes are observed at heme monomer-dimer isosbestic points. Results are interpreted primarily in terms of the attainment of double "steady-state" concentrations of Michaelis-Menten complex I and peroxidatic intermediate I'. A linear correlation of observed first-order rate constants with alpha, the degree of dissociation of heme dimer, has been demonstrated and nonzero intercepts are obtained. Slopes and intercepts show a linear logarithmic dependence on pH which is interpreted in terms of HO2-participation both in the formation and subsequent (catalatic) decomposition of a peroxidatically active intermediate. General acid catalysis of intermediate formation is indicated from studies in phosphate, arsenate, and citrate buffer at pH 7.4-9.3. It is suggested that such catalysis may be responsible for anomalously high rates of H2O2 decomposition previously observed in phosphate buffer solution.

Deuteroporphyrins↗
PubMed2003

Reductive dechlorination of polychlorinated biphenyls: threshold concentration and dechlorination kinetics of individual congeners in Aroclor 1248.

Reductive dechlorination of individual PCB congeners in Aroclor 1248 was investigated using sediment microorganisms from the St. Lawrence River (NY). No dechlorination was observed at Aroclor concentrations below 40 ppm [137 nmol (g of sediment)(-1)]. Above this threshold, congeners could be divided into three categories: group A, congeners that dechlorinated above 40 ppm; group B, congeners that dechlorinated only at high concentrations above 60 ppm [206 nmol (g of sediment)(-1)]; and group C, lower chlorinated congeners that increased in concentration. The dechlorination rate of congeners in groups A and B was a linear function of their initial sediment concentration. For group A congeners, the concentration intercepts of this linear function were the same as their concentrations in the Aroclor at the threshold concentration, and these therefore represented the threshold values. However, the intercepts of group B congeners were significantly higher than their levels at the threshold Aroclor concentration and were equivalent to their concentrations in Aroclor 1248 at about 75 ppm [258 nmol (g of sediment)(-1)]. The final concentrations of group A and group B congeners at the end of dechlorination were the same, regardless of their initial concentrations. These final concentrations were significantly lower than their threshold values. The accumulation rate of group C congeners was a linear function of their initial concentrations, and the total accumulation was greater at higher Aroclor concentrations in sediments.

Aroclors↗
PubMed2006

Magnitude and directional measures of water and Cr(VI) fluxes by passive flux meter.

A new configuration of the passive fluxmeter (PFM) is presented that provides for simultaneous measurements of both the magnitude and the direction of ambient groundwater specific discharge qo and Cr(VI) mass flux J(Cr). The PFM is configured as a cylindrical unit with an interior divided into a center section and three outer sectors, each packed with a granular anion exchange resin having high sorption capacity for the Cr(VI) oxyanions CrO4(2-) and HCrO4-. The sorbent in the center section is preloaded with benzoate as the "resident" tracer. Laboratory experiments were conducted in which PFMs were placed in porous packed bed columns, through which was passed a measured volume of synthetic groundwater containing Cr(VI). During the deployment period, some of the resident tracer is depleted while the Cr(VI) is sorbed. The resin was then removed from the four sectors separately and extracted to determine the "captured" mass of Cr(VI) and the residual mass of the resident tracer in each. Cumulative specific discharge, q0t, values were assessed using the residual mass of benzoate retained in the center section. The direction of this discharge theta was ascertained from the mass distribution of benzoate intercepted and retained in the outer three sections of the PFM. Cumulative chromium fluxes, J(Cr)t, were quantified using the total Cr(VI) mass intercepted and retained on the PFM. Experiments produced an average measurement error for direction theta of 3 degrees +/- 14 degrees, while the average measurement errors for q0 and J(Cr) were, respectively, -8% +/- 15% and -12% +/- 23%. Results demonstrate the potential utility of the new PFM configuration for characterizing groundwater and contaminant fluxes.

Chromium↗
PubMed2001

Mechanism of beta-hydrogen elimination from square planar iridium(I) alkoxide complexes with labile dative ligands.

Mechanistic studies were conducted on beta-hydrogen elimination from complexes of the general formula [Ir(CO)(PPh(3))(2)(OR)], which are square planar alkoxo complexes with labile ligands. The dependence of rate, isotope effect, and alkoxide racemization on phosphine concentration revealed unusually detailed information on the reaction pathway. The alkoxo complexes were remarkably stable, including those with a variety of electronically and sterically distinct groups at the beta-carbon. These complexes were much more stable than the corresponding alkyl complexes. Thermolysis of these complexes in the presence of PPh(3) yielded the iridium hydride [Ir(CO)(PPh(3))(3)H] and the corresponding aldehyde or ketone with rate constants that were affected little by the groups at the beta-carbon. The reactions were first order in iridium complexes. At low [PPh(3)], the reaction rate was nearly zero order in PPh(3), but reactions at high [PPh(3)] revealed an inverse dependence of reaction rate on PPh(3). The rate constants were similar in toluene, THF, and chlorobenzene. The y-intercept of a 1/k(obs) vs [PPh(3)] plot displayed a primary isotope effect, indicating that the y-intercept did not simply correspond to phosphine dissociation. These data and a dependence of alkoxide racemization on [PPh(3)] showed that the elementary beta-hydrogen elimination step was reversible. A mechanism involving reversible beta-hydrogen elimination followed by associative displacement of the coordinated ketone or aldehyde by PPh(3) was consistent with all of our data. This mechanism stands in contrast with the pathways proposed recently for alkoxide beta-hydrogen elimination involving direct elimination, protic catalysts, or binuclear mechanisms and shows that alkoxide elimination can follow pathways similar to those for beta-hydrogen elimination from alkyl complexes.

Journal Article↗
PubMed2002

Mössbauer quadrupole splittings and electronic structure in heme proteins and model systems: a density functional theory investigation.

We report the results of a series of density functional theory (DFT) calculations aimed at predicting the (57)Fe Mössbauer electric field gradient (EFG) tensors (quadrupole splittings and asymmetry parameters) and their orientations in S = 0, (1)/(2), 1, (3)/(2), 2, and (5)/(2) metalloproteins and/or model systems. Excellent results were found by using a Wachter's all electron basis set for iron, 6-311G for other heavy atoms, and 6-31G for hydrogen atoms, BPW91 and B3LYP exchange-correlation functionals, and spin-unrestricted methods for the paramagnetic systems. For the theory versus experiment correlation, we found R(2) = 0.975, slope = 0.99, intercept = -0.08 mm sec(-)(1), rmsd = 0.30 mm sec(-)(1) (N = 23 points) covering a DeltaE(Q) range of 5.63 mm s(-)(1) when using the BPW91 functional and R(2) = 0.978, slope = 1.12, intercept = -0.26 mm sec(-)(1), rmsd = 0.31 mm sec(-)(1) when using the B3LYP functional. DeltaE(Q) values in the following systems were successfully predicted: (1) ferric low-spin (S = (1)/(2)) systems, including one iron porphyrin with the usual (d(xy))(2)(d(xz)d(yz))(3) electronic configuration and two iron porphyrins with the more unusual (d(xz)d(yz))(4)(d(xy))(1) electronic configuration; (2) ferrous NO-heme model compounds (S = (1)/(2)); (3) ferrous intermediate spin (S = 1) tetraphenylporphinato iron(II); (4) a ferric intermediate spin (S = (3)/(2)) iron porphyrin; (5) ferrous high-spin (S = 2) deoxymyoglobin and deoxyhemoglobin; and (6) ferric high spin (S = (5)/(2)) metmyoglobin plus two five-coordinate and one six-coordinate iron porphyrins. In addition, seven diamagnetic (S = 0, d(6) and d(8)) systems studied previously were reinvestigated using the same functionals and basis set scheme as used for the paramagnetic systems. All computed asymmetry parameters were found to be in good agreement with the available experimental data as were the electric field gradient tensor orientations. In addition, we investigated the electronic structures of several systems, including the (d(xy))(2)(d(xz),d(yz))(3) and (d(xz),d(yz))(4)(d(xy))(1) [Fe(III)/porphyrinate](+) cations as well as the NO adduct of Fe(II)(octaethylporphinate), where interesting information on the spin density distributions can be readily obtained from the computed wave functions.

Hemeproteins↗
PubMed2003

Synthesis and characterization of potent bivalent amyloidosis inhibitors that bind prior to transthyretin tetramerization.

The misfolding of transthyretin (TTR), including rate-limiting tetramer dissociation and partial monomer denaturation, is sufficient for TTR misassembly into amyloid and other abnormal quaternary structures associated with senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy. Monovalent small molecules that bind to one or both of the unoccupied thyroid hormone binding sites at the TTR quaternary structure interface stabilize the native state, raising the kinetic barrier for tetramer dissociation sufficiently that the rate of dissociation, and therefore amyloidosis, becomes slow. Bivalent amyloid inhibitors that bind to both binding sites simultaneously are reported herein. The candidate bivalent inhibitors are generally unable to bind to the native TTR tetramer and typically do not engage in monovalent binding owing to a strong inhibitor orientation preference. However, the TTR quaternary structure can assemble around several of the bivalent inhibitors if the inhibitor intercepts the protein before assembly occurs. Some of the wild-type TTR.bivalent inhibitor complexes prepared in this fashion retain a tetrameric structure when subjected to substantial denaturation stresses (8 M urea, 120 h). The best bivalent inhibitor reduced acid-mediated TTR (3.6 microM) amyloid fibril formation to 6% of that exhibited by TTR in the absence of inhibitor, a significant improvement over the approximately 30% observed for the best monovalent inhibitors (3.6 microM, 72 h). The apparent dissociation rate of the best bivalent inhibitor is effectively zero, consistent with the idea that TTR tetramer dissociation and inhibitor dissociation are linked-as a result of the inhibitor-templating tetramer assembly. X-ray cocrystal structures of two of the complexes demonstrate that the bivalent inhibitors simultaneously occupy both sites in TTR, consistent with the 1:1 binding stoichiometry derived from HPLC analysis. The purpose of this study was to demonstrate that bivalent inhibitors could be useful; what resulted are the best inhibitors produced to date. In this context, molecules capable of intercepting TTR during folding and assembly in the lumen of the endoplasmic reticulum would be of obvious interest.

Amyloid↗
PubMed2000

Comparison of enzyme-linked immunosorbent assay and gas chromatography procedures for the detection of cyanazine and metolachlor in surface water samples.

Enzyme-linked immunosorbent assay (ELISA) data from surface water reconnaissance were compared to data from samples analyzed by gas chromatography for the pesticide residues cyanazine (2-[[4-chloro-6-(ethylamino)-1,3,5-triazin-2-yl]amino]-2-methylpropanenitrile) and metolachlor (2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl)acetamide). When ELISA analyses were duplicated, cyanazine and metolachlor detection was found to have highly reproducible results; adjusted R2s were 0.97 and 0.94, respectively. When ELISA results for cyanazine were regressed against gas chromatography results, the models effectively predicted cyanazine concentrations from ELISA analyses (adjusted R2s ranging from 0.76 to 0.81). The intercepts and slopes for these models were not different from 0 and 1, respectively. This indicates that cyanazine analysis by ELISA is expected to give the same results as analysis by gas chromatography. However, regressing ELISA analyses for metolachlor against gas chromatography data provided more variable results (adjusted R2s ranged from 0.67 to 0.94). Regression models for metolachlor analyses had two of three intercepts that were not different from 0. Slopes for all metolachlor regression models were significantly different from 1. This indicates that as metolachlor concentrations increase, ELISA will over- or under-estimate metolachlor concentration, depending on the method of comparison. ELISA can be effectively used to detect cyanazine and metolachlor in surface water samples. However, when detections of metolachlor have significant consequences or implications it may be necessary to use other analytical methods.

Acetamides↗
PubMed1995

Mechanism of inhibition of poly(ADP-ribose) glycohydrolase by adenosine diphosphate (hydroxymethyl)pyrrolidinediol.

Adenosine diphosphate (hydroxymethyl)pyrrolidinediol (ADP-HPD), a nitrogen-in-the-ring analog of ADP-ribose, was recently shown to be a potent and specific inhibitor of poly(ADP-ribose) glycohydrolase. Analysis of the inhibition kinetics of the hydrolase by ADP-HPD using the method of Lineweaver and Burk yields a noncompetitive double-reciprocal plot. Both the intercept (1/V) versus [inhibitor] replot and the slope (Km/V) versus [inhibitor] replot are hyperbolic, indicating partial noncompetitive inhibition. Inhibitor dissociation constants Kii = 52 nM and Kis = 80 nM were determined for ADP-HPD by analysis of the intercept versus [inhibitor] and slope versus [inhibitor] replots. These results show that although ADP-HPD is extremely potent in inhibiting poly(ADP-ribose) glycohydrolase, its effectiveness is limited by its partial inhibition. ADP-HPD was significantly less potent as an inhibitor of the NAD glycohydrolase from Bungarus fasciatus venom. Analysis of the inhibition kinetics using the Lineweaver and Burk method indicated that ADP-HPD was a linear-competitive inhibitor of the NAD glycohydrolase with a Ki of 94 microM. The results indicate that at low concentration ADP-HPD will be a selective inhibitor of poly(ADP-ribose) glycohydrolase; however, complete inactivation of the activity will be difficult to obtain.

Adenosine Diphosphate↗
PubMed2005

Generation and characterization of highly strained dibenzotetrakisdehydro[12]- and dibenzopentakisdehydro[14]annulenes.

To generate dibenzotetrakisdehydro[12]- and dibenzopentakisdehydro[14]annulenes ([12]- and [14]DBAs) having a highly deformed triyne moiety, [4.3.2]propellatriene-anneleted dehydro[12]- and dehydro[14]annulenes were prepared as their precursors. UV irradiation of the precursors resulted in the photochemical [2 + 2] cycloreversion to generate the strained [12]- and [14]DBAs, respectively. The [12]DBA was not detected by 1H NMR spectroscopy, but it was intercepted as Diels-Alder adducts in solution, suggesting its intermediacy. Its spectroscopic characterization was successfully carried out by UV-vis spectroscopy in a 2-methyltetrahydrofuran (MTHF) glass matrix at 77 K and by FT-IR spectroscopy in an argon matrix at 20 K. On the other hand, the [14]DBA was stable enough for observation by 1H and 13C NMR spectra in solution, though it was not isolated because of the low efficiency of the cycloreversion. The [14]DBA was also characterized by interception as Diels-Alder adducts in solution and by UV-vis spectroscopy in a MTHF glass matrix at 77 K. The kinetic stabilities of the DBAs are compared with the related dehydrobenzoannulenes with respect to the topology of the pi-systems. In addition, the tropicity of the [14]DBA is discussed based on its experimental and theoretical 1H NMR chemical shifts.

Cold Temperature↗
PubMed1996

Tandem Pummerer-Diels-Alder Reaction Sequence. A Novel Cascade Process for the Preparation of 1-Arylnaphthalene Lignans.

The alpha-thiocarbocation generated from the Pummerer reaction of an o-benzoyl-substituted sulfoxide is intercepted by the adjacent keto group to produce an alpha-thio isobenzofuran as a transient intermediate which undergoes a subsequent Diels-Alder cycloaddition with added dienophiles. Acid-catalyzed ring-opening of the cycloadduct followed by aromatization gave an arylnaphthalene derivative. With acetylenic dienophiles, the tandem cyclization-cycloaddition sequence provided tetralones which result from a pinacol-type rearrangement of the primary cycloadducts. The versatility of the approach is highlighted through the synthesis of taiwanin C and E and justicidin E. The alpha-thiocarbocation generated from the Pummerer reaction of benzo[1,3]dioxol-5-yl-[6-[(ethylsulfinyl)methyl]benzo[1,3]dioxol-5-yl)methanone is intercepted by the adjacent keto group to produce an alpha-thioisobenzofuran as a transient intermediate which undergoes a subsequent Diels-Alder cycloaddition with dimethyl maleate. The initially formed Diels-Alder cycloadduct was readily converted to 5-benzo[1,3]dioxol-5-yl-8-(ethylthio)naphtho[2,3-d][1,3]dioxole-6,7-dicarboxylic acid dimethyl ester by loss of water on treatment with p-toluenesulfonic acid. Desulfurization of the thionaphthalene with Ra/Ni followed by hydrolysis of the less hindered methyl ester afforded 5-benzo[1,3]dioxol-5-ylnaphtho[2,3-d][1,3]dioxole-6,7-dicarboxylic acid 6-methyl ester which was further transformed into taiwanin C and justicidin E in good yield. Oxidation of the initial Diels-Alder cycloadduct with NaIO(4) in the presence of RuCl(3) followed by extrusion of ethyl sulfinate gave a naphthol derivative which can be converted into taiwanin E.

Journal Article↗
PubMed1997

The Direct Alkylation of pi-Rich, Acid-Sensitive Heterocyclic Compounds via Essentially Free Carbocations(1).

Alkylation of pi-rich heteroaromatics such as pyrroles and furans by the standard Friedel-Crafts approach is impractical because the acid catalysts employed (Brønsted or Lewis) induce polyalkylation, ring opening, and polymerization. The present study describes the facile benzylation of pi-excessive heteroaromatics using the nitrosoamide approach, which generates nitrogen-separated carbocation-counterion ion-pairs as the alkylating agent with no catalyst being required. N-Nitrosoamides are favorable sources of carbocations because of the following variables: mildness of the conditions required to generate cations, high reactivity of the unsolvated carbocations formed, solubility of the precursors in a wide range of solvents, homogeneity of the reactions, wide range of decomposition temperatures possible, straightforward chemistry, and excellent product balance. The majority of the cations that are generated in pyrrole (80%) are intercepted by the solvent, and only 20% are intercepted by the counterion; this result provides support for the intermediacy of nitrogen-separated ion-pairs in deamination. A nucleophilicity scale is presented for reactions of selected nucleophiles with essentially free carbocations.

Journal Article↗
PubMed1997

Chemical release from topical formulations across synthetic membranes: infinite dose.

Drug release rates from topical preparations are sometimes measured by monitoring the cumulative mass of drug appearing in a receptor solution (MR). If the topical formulation and receptor solution are in direct contact, then MR increases linearly with square root of t. When a synthetic membrane is placed between the topical formulation and receptor solution, drug appearance in the receptor solution is delayed and MR is not immediately linear in square root of t. As a result, linear regressions of MR with square root of t produce positive values for the square root of t-intercept. Here, we mathematically model chemical release from an infinite-dose, topical formulation across synthetic membrane to quanitiatively determine the physical meaning of the square root of t-intercept. To correctly determine drug diffusivity in the topical formulation, the experiment must be conducted long enough that MR is linear in square root of t. Theoretically based procedures are presented for testing which data should not be used in linear regression of MR with square root of t. Theoretical predictions are compared with previously published experimental results for ethyl salicylate across a poly(dimethylsiloxane) (Silastic) membrane and for hydrocortisone across several different synthetic membranes.

Administration, Topical↗
PubMed2006

Role of linear charge density and counterion quality in thermodynamic properties of strong acid type polyelectrolytes: divalent transition metal cations.

Thermodynamic properties of aqueous solutions of poly[(vinyl alcohol)-co-(vinyl sulfate)] (PVAS) copolymer polyelectrolytes with divalent transition metal (Co(II), Ni(II), and Cu(II)) counterions have been determined by the gel deswelling method in the concentration range of 0.0005-0.12 mol of counterion/kg of water (0.09-9 w/w% of the polymer). The influence of the chemical nature of the counterion as well as the effect of the composition of the copolymer from small to medium linear charge density have been systematically studied. Solvent activity, reduced osmotic pressure, the Flory-Huggins pair interaction parameter, rational osmotic coefficients, and degrees of dissociation were calculated from the measured data. No difference could have been observed between the three counterions. Reduced osmotic pressure curves are found to be convex from above, as for Na+ counterions studied previously, which is contrary to the usual behavior of neutral polymers. Intercepts are increasing, and the calculated apparent molar masses and degrees of dissociation at infinite dilution are decreasing with increasing linear charge density of the polyelectrolytes. The pair interaction parameters show a considerable negative deviation from linearity, except for the high volume fraction region. From the differences, concentration dependence of degrees of dissociation could have been calculated. The values at infinite dilution are in good agreement with those obtained from the intercepts of the reduced osmotic pressure curves. Degrees of dissociation seem to decrease approximately linearly with increasing concentration and reach zero at finite concentrations. Rational osmotic coefficients have been calculated in three different ways, both regarding and neglecting the change in the degrees of dissociation.

Acids↗