Alan S. Carlin

Comparative stability of repackaged metoprolol tartrate tablets.

The stability of metoprolol tartrate tablets packaged in original high density polyethylene containers and repackaged in USP Class A unit-dose blister packs was investigated. Studies were conducted at 25 degrees C/60% relative humidity (RH) for 52 weeks and at 40 degrees C/75% RH for 13 weeks. The potency, dissolution, water content, loss on drying and hardness of the drug products were analyzed. Results indicated no differences in the stability between the tablets in both packages stored under 25 degrees C/60% RH. No difference in potency was found in both packages under either condition. However, a significant weight increase due to moisture uptake was observed for the repackaged tablets stored under 40 degrees C/75% RH. The weight increase was accompanied by a decrease in tablet hardness (6.5-0 kp) and a increase in dissolution rate (51-92%) in 5 min. Near-infrared (NIR) chemical imaging also monitored moisture uptake of the tablet non-invasively through the package. The observed changes in product stability may adversely affect the products bioavailability profile, even though the potency of the active drug remained within USP specification range of 90-110%. Study results suggest product quality can be negatively impacted even when using USP Class A repackaging materials.

Assay for valproic acid and its E-Δ2 metabolite in rat plasma by capillary gas chromatography without prior derivatization

A new and improved gas chromatographic assay method for valproic acid and a metabolite, E-delta2 valproic acid, in rat plasma has been developed. The assay has sufficient sensitivity to measure free levels of the parent drug and metabolite. By employing a Stabilwax-DA capillary column, symmetrical chromatographic peaks were obtained without the need for prior derivatization. Standard curves for valproic acid were linear from 0.1 to 640 microg/ml. Standard curves for the metabolite were linear from 0.1 to 556 microg/ml.

Comparative stability study of unit-dose repackaged furosemide tablets

The stability of a 40 mg furosemide tablet drug product repackaged in a unit-dose USP class A blister pack and the identical product in its original container made of HDPE material was studied under ICH long-term conditions of 25°C and relative humidity (RH) of 60% and accelerated stressed conditions of 40°C and 75% RH. Samples from original and repackaged drug products were periodically removed from storage conditions and subjected to pharmaceutical and spectroscopic analysis. Results indicate the potency 91.5 ± 0.9% of the tablet strength for the original packaging drug product vs 91.6 ± 4.0% for the repackaged product are statistically similar for long-term and accelerated stress conditions. Tablet hardness (6.0 ± 0.3 KP) and loss on drying (3.2%) was the same for original and repackaged drug products under both stressed conditions indicating similar moisture sorption behavior. Non-invasive spectroscopic techniques did not show any differences in moisture content. Dissolution and TGA results were similar for all study samples. In conclusion, contrary to a previous FDA repackaging study for tablets with hygroscopic excipients, the product quality attributes of furosemide tablets formulated with low sorption excipients were not affected by repackaging, under the specific stress conditions of this study.

Determination of khellin in serum by gas chromatography.

A rapid gas chromatographic assay has been developed for the separation and determination of khellin in human serum. Using a DB-17 capillary column and a simple chloroform extraction, khellin and an internal standard, trioxsalen, were separated from endogenous substances without further clean-up. Spiked serum samples in the range 0.11-1.1 micrograms/ml were assayed and a linear calibration curve obtained.

Cutaneous metabolism of nitroglycerin in viable rat skin in vitro

Abstract Percutaneous penetration and metabolism of nitroglycerin (GTN) in vitro were compared in viable rat skin (perfused with minimal essential medium (MEM)) and nonviable rat skin (perfused with phosphate-buffered saline (PBSA)) in flow-through diffusion cells. The fraction of nitrates penetrating as dinitrate metabolites was significantly greater in MEM-perfused skin than in PBSA-perfused skin, while the fraction of nitrates penetrating as GTN was significantly less. Moreover, differences between MEM and PBSA in the fraction of absorbed nitrates present as GTN coincided in time with the loss of metabolizing capacity in PBSA-perfused skin, supporting the notion that it was the loss of metabolic capacity which led to an increase in GTN penetration. Over the 24 h experimental period, 29% of the GTN penetrating the MEM-perfused skin was metabolized and 71% of the absorbed dose was present as GTN, whereas only 14% of GTN penetrating PBSA-perfused skin was metabolized and 86% of the absorbed dose was present as GTN. These results demonstrate that metabolic viability of skin in vitro can affect not only the degree of cutaneous metabolism of penetrating compounds but also their rates of penetration

Controlled initial surge despite high drug fraction and high solubility

Abstract Potential connections between release profiles and solvent evaporation rates alongside polymer chemistry were elucidated for the release of tetracycline hydrochloride from two different poly (d, l-lactide-co-glycolide) (PLGA) film matrices containing high drug fractions (50%, 30%, and 15%), and prepared at two distinct solvent evaporation rates. At highest tetracycline concentrations (50%), (i) the early release rates were ≤0.5 μg/min in all cases; (ii) release was linear from systems fabricated with lower lactic content and slower solvent evaporation rate and bimodal from systems fabricated with higher lactic content and faster evaporation rate; (iii) surface fractions covered by the drug were similar at both evaporation rates for 85:15 PLGA but very different for 50:50 PLGA, leading to unexpectedly reduced early release from 50:50 PLGA than from 85:15 PLGA when both the matrices were fabricated using a slower evaporation rate. These features remained unaffected in case of low drug concentration. Results suggested that during the formation of the drug-polymer microstructure, the combined effect of polymer chemistry and solvent evaporation rate sets apart the surface characteristics and the initial release profiles of systems containing high drug fraction, and an appropriate combination of these parameters may be utilized to control the early stage of drug release.