Use of stable isotopes for evaluation of drug delivery systems: comparison of ibuprofen release in vivo and in vitro from two biphasic release formulations utilizing different rate-controlling polymers.

Certain delivery systems are intended to release the active ingredient in different phases to obtain the desired therapeutic effect. For these formulations, such as a bilayer tablet, it is desirable to distinguish and measure the release of drug from the different phases simultaneously. Mass spectrometric methods were developed to measure three ibuprofen isotopomers in serum and two in dissolution fluid. The analytical methods were linear (r > or = 0.992) over the concentration range of interest and recovery was greater than 99.2% for all isotopomers. Coadministration of [2H0]ibuprofen, [2H4]ibuprofen, and [2H7]ibuprofen to male beagles demonstrated that the isotopomers were bioequivalent and verified the absence of any kinetic isotope effect due to deuterium incorporation (p = 0.286). These methods were then used to evaluate a bilayer tablet formulation composed of an immediate release layer of 100 mg [2H4]ibuprofen and a sustained release layer with a drug load of 300 mg [2H0]ibuprofen. Two different rate-controlling polymer matrices that provided similar in vitro dissolution profiles were compared in the sustained release phase, while the immediate release formulation remained the same. In male beagles, the HPMC matrix delivered a significantly greater amount of ibuprofen (p < 0.05). The AUC was threefold greater for HPMC (1067 +/- 437 nmole*h/ml) versus EUDRAGIT (320 +/- 51), and Cmax was nearly four times greater (145 +/- 62.1 nmole/ml for HPMC versus 37.9 +/- 14.4 for EUDRAGIT).(ABSTRACT TRUNCATED AT 250 WORDS)

Investigation of the relationship between melting-related parameters and in vitro drug release from vaginal suppositories.

The effect of temperature on drug release from meteneprost potassium vaginal suppositories was investigated using a dissolution test based on the USP I apparatus. Comparison of the dissolution results with the DSC melting behaviour revealed that drug release was extremely slow until melting of the suppository was essentially complete. The melting behaviour of the meteneprost potassium suppositories was also varied by preparing suppositories from bases with higher and broader melting ranges. The observed dissolution behaviour (at 37 degrees C) confirmed that drug release increased as the melting temperature of a particular suppository decreased. Differential scanning calorimetry, viscosity and dilatometry methods were used to characterize the suppository melting process. The effects of suppository melting range, melt temperature and composition were investigated with respect to in vitro drug release. Methodology for the HPLC determination of meteneprost in suppositories and in dissolution media are also reported.

Development of capillary gas chromatographic-mass spectrometric methodology for the simultaneous determination of ibuprofen and [ar-2H4]ibuprofen in serum: demonstration of kinetic equivalence in the beagle.

A capillary gas chromatographic-mass spectrometric method for the determination of ibuprofen and tetra-deuterated ibuprofen in serum is described. Ibuprofen, [ar-2H4]ibuprofen and the internal standard, [ar-2H4,3,3,3-2H3]ibuprofen, are extracted (after acidification) from serum onto a cross-linked styrene divinyl benzene resin by an automated sample processor. After elution and evaporation of the organic phase, samples are reconstituted with solvent and analyzed without derivatization by capillary gas chromatography-mass spectrometry. This methodology was used to evaluate possible kinetic isotope effects after the coadministration of an equimolar mixture of ibuprofen and the deuterium-labeled covariant in the beagle. No significant differences in absorption or elimination were observed.

Quantitative determination of N-[trans-2-(dimethylamino)-cyclopentyl]-N-(3',4'-dichlorophenyl)propan amide, its 2H5-labeled analogue and their N-dealkylated metabolites in dog serum by capillary gas chromatography-mass spectrometry.

This paper describes the development of a capillary gas chromatographic--mass spectrometric method for the determination of N-[trans-2-(dimethylamino)cyclopentyl]-N-(3',4'-dichlorophenyl)propan amide and its metabolites in serum. The method utilizes an automated sample preparation whereby drug, metabolites and internal standard are extracted from polar serum components by adsorption chromatography onto an XAD-type resin. The N-demethylated metabolites are derivatized by acetylation prior to chromatography. Detection is by mass spectrometry with chemical ionization. This method was utilized to determine levels of unlabeled and pentadeuterated drug and their respective metabolites in canine serum after oral co-administration. No significant kinetic isotope effects were observed for either absorption or metabolism.

Drug release testing of a prostaglandin containing controlled-release vaginal device: development of a semi-automated method.

The effects of temperature, pH, and apparatus design on in vitro drug release from a controlled-release vaginal device containing the prostaglandin, carboprost methyl, were investigated and a semi-automated drug release test was developed based on these studies. Accelerated drug release testing was found not to be feasible due to an apparent change in the release mechanism observed at 60 degrees C. At temperatures between 30-50 degrees C, Arrhenius behavior was observed with an activation energy of 18 kcal/mol. Drug release from the device was found to be insensitive to changes in pH. A commercially available auto-sampler was modified to enable unattended sampling over a 24-h test period using a cumulative drug release test based on the USP apparatus 1. In vivo drug release from the devices was monitored by calculating the amount released in 24 h in vivo from the difference between initial drug content and residual drug content in devices returned from the clinic. Results obtained via the in vitro drug release test compare favorably with the in vivo release results.

High-performance liquid chromatography method for the separation of isomers of 9 beta-methylcarbacyclin (ciprostene) and the analysis of pharmaceutical samples.

An high-performance liquid chromatography method was developed that separates (5Z)-9 beta-methyl-6 alpha-carbaprostaglandin I2 (9 beta-methylcarbacyclin; ciprostene) from several closely related isomers: (i) a double bond isomer at C-5, (ii) an epimer at C-15, and (iii) combinations of i and ii. The method uses a Zorbax ODS column with a mobile phase consisting of acetonitrile-buffer pH 2.5 at a ratio of 45:55 for determination of purity and 40:60 for optimum separation of isomers. Detection is measurement of absorbance at 200 nm. Peak heights are measured relative to butylparaben which is used as an internal standard. The method is linear, free from interferences from degradation of ciprostene and has a relative standard deviation of 0.5-1% for solutions at 60 micrograms/ml. This assay has been applied to bulk powders and solutions of the drug. Stressed chemical stability studies have shown that the C-15 allylic secondary alcohol group undergoes epimerization under acidic conditions in solution and oxidation in the solid and solution state under thermal stress or in the presence of oxidants.