Understanding drug release from poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) gels.

Experimental and mathematical studies were performed to understand the release mechanism of small molecular weight compounds from poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) polymer gels (trademarked Pluronic by BASF Corp.) of various concentrations. Studies of the diffusion coefficient of solutes in the polymer gels were performed using a novel technique to predict movement of drugs within the gel as release occurs. Studies were also performed to determine the diffusion coefficient of water in the polymer gel, as it is this parameter that controls the dissolution rate of the polymer, and in turn, the drug release rate. A model was formulated and solved numerically to determine the controlling release mechanism. By parameter modification, this algorithm for determining the overall mass of drug released from a drug loaded gel can be used for a number of drugs and for a wide range of initial polymer concentrations. Drug release data were obtained with a novel experimental setup and were used to verify the accuracy of the overall solution of the model. The results of the model indicate that although the rate of polymer dissolution ultimately controls the drug release, about 5% of the release is due to diffusion at the gel/liquid interface, giving rise to a slightly non-linear release. It was also found that agitation speed greatly affects the dissolution rates of these polymer gels.

Liposphere based lipoprotein-mimetic delivery system for 6-mercaptopurine.

Long-circulating lipospheres containing 6-mercaptopurine (6-MP) were prepared by solidification of warm microemulsion at low temperature. Palmitoyl PEG was incorporated in the system to confer stealth-type nature. The size of lipospheres was in the range of 60-70 nm and was inversely proportional to sonication time. The size range was attained after 8 h. of sonication. The entrapped 6-MP contained 0.12 mmol/mole of lipid. The coating efficiency of 63-71% was attained. The zeta potential substantially decreased after PEG coating, however, the lipospheres were stable due to steric repulsion and exhibited no aggregation. The release of 6-MP was found to be 18-25% of administered dose in 24 h. and followed a mixed profile for stealth lipospheres. The percent dose remaining in plasma was found to be high even after 24 h as compared to control, indicating an increase in circulation time of lipospheres. Tissue accumulation of drug correlated with the pharmacokinetic behavior of lipospheres. The system seems to be an ideal carrier for anticancer drug delivery.

Gelation of Pluronic F127-polyethylene glycol mixtures: relationship to PEG molecular weight.

The formation and melting of Pluronic F127 gels in the presence of polyethylene glycols (PEGs) has been studied. All the PEGs studied raised T1 and lowered T2 of 20% F127 gels; this effect was proportional to PEG concentration. At a certain critical "no-gel" concentration of PEG (Cng), F127 lost its ability to form gels. Cng was found to be inversely proportional to PEG molecular weight. An empirical relationship between Cng and PEG molecular weight was obtained which can be used to predict effects of PEGs of any molecular weight on F127 gelation.

Effect of pH and temperature on the solubility of a surface active carboxylic acid.

We have examined the effect of pH and temperature on the solubility of 3-(4-heptylbenzoyl) benzoic acid (1), a surface active carboxylic acid with a pKa of 4.83 and a critical micelle concentration (cmc) of 4 X 10(-4) M. Our results show that below a pH of 7.0 and a temperature of 50 degrees C, the solubility of 1 is less than the cmc; under these conditions, 1 behaves like a typical weak acid. Above pH 7.0, the solubility can equal or exceed the cmc, depending on the temperature, and dramatic deviations from typical weak acid solubility behavior are observed. The temperatures at which the solubility becomes equal to the cmc at various pH values were determined; these temperatures are termed apparent Krafft Points (KPapp). The KPapp varies with pH; the higher the pH, the lower the KPapp. For example, the KPapp at pH 7.0 is 49 degrees C, and at pH 8.0 is less than 5 degrees C. We report the pH-temperature-solubility relationship for 1 and use it to construct simple phase diagrams.

The determination of microscopic ionization constants of a substituted piperazine using estimates from model compounds.

The microscopic ionization constants of 1-[3-(4-chlorophenyl) propyl] piperazine (I) were determined using piperazine (P) and 1,4-bis[3-(4-chlorophenyl)propyl] piperazine (II) as models for one of the ionizations. The macroscopic ionization constants for all three compounds were measured potentiometrically, and the micro constants of P and II, which are symmetrical molecules, were calculated from their macro constants. Only one micro constant of either P or II was suitable as a model for elucidating the micro constants of I.

Degradation of chlorthalidone in methanol: kinetics and stabilization.

The reaction of chlorthalidone with methanol to give the corresponding methyl ether was investigated. The kinetics are pseudo-first-order in chlorthalidone, but the observed pseudo-first-order rate constants show an unexpected dependence on the initial chlorthalidone concentration, attributable to the presence of trace catalytic impurities in commercial chlorthalidone. Evidence is presented to show that trace heavy metals are probably responsible for the primary catalytic effect. Trace quantities of acetic acid are also present and show a smaller secondary catalytic effect. Kinetics in the presence of added heavy metals and acetic acid were examined. EDTA and povidone reduce the degradation rate. Stabilization by EDTA is due to its ability to chelate heavy metals. Stabilization by povidone is also primarily due to its ability to complex heavy metals; complexation data of ferric and nickel ions with povidone and with 1-methyl-2-pyrrolidinone as a monomer model are presented. In addition, complexation constants were calculated for the interaction of povidone with chlorthalidone, which may also play a role in stabilization.

Kinetics and mechanism of hydroxy group acetylations catalyzed by N-methylimidazole.

The kinetics of acetylation of alcohols by acetyl chloride and acetic anhydride, with N-methylimidazole as the catalyst, were studied in acetonitrile solution at 25 degrees; some measurements were also made with 4-dimethylaminopyridine as the catalyst. The acetic anhydride-N-methylimidazole system proceeds entirely by a general base catalysis, whereas the acetyl chloride-N-methylimidazole system reacts entirely via a nucleophilic route, with the intermediate formation of the N-acylated catalyst. The reaction of this intermediate with the alcohol is general base catalyzed. The acetyl chloride-4-dimethylaminopyridine system also reacts via the nucleophilic route. In the acetic anhydride-4-dimethylaminopyridine system a small fraction of the intermediate was detected. The acetic anhydride-N-methylimidazole system was studied in n-propanol-acetonitrile solvent mixtures; no spectral evidence for intermediate formation was seen. However, the hydrolysis reaction in acetic anhydride-N-methylimidazole, studied over a wide range of water-acetonitrile mixtures, revealed a change in mechanism from general base in dry acetonitrile to a solely nucleophilic route at high water concentrations.