Stability of captopril in SyrSpend SF.

Captopril is an angiotensin-converting enzyme inhibitor available as a tablet. Patients who are unable to take tablets have led compounding pharmacies to seek alternative dosage forms including solutions and suspensions. The objective of this study was to determine the stability of captopril in sorbitol-free, alcohol-free SyrSpend SF suspending agent. The studied samples were compounded into a 0.8-mg/mL suspension and stored in low-actinic plastic bottles at temperatures between 2 degrees C to 8 degrees C. Six samples were assayed at each time point out to 32 days by a stability-indicating high-performance liquid chromatography method. The samples remained within 90% to 110% of the initial concentration throughout day 14 of the study. Based on the data collected, the beyond- use date of these preparations is 14 days when protected from light and refrigerated.

Prediction of photosensitivity of 1,4-dihydropyridine antihypertensives by quantitative structure-property relationship.

A quantitative structure-property relationships (QSPR) model, correlating the light sensitivity against theoretical molecular descriptors, was developed for a set of 1,4-dihydropyridine calcium channel antagonist drugs. These compounds are characterized by a high tendency to degradation when exposed to light, furnishing in the most of cases a related oxidation product from aromatization of the dihydropyridinic ring. Photodegradation was forced by exposing the drugs to a Xenon lamp, in accordance with the ICH international rules, and degradation kinetics was monitored by spectrophotometry. The photodegradation rates combined with a series of descriptors related to the chemical structures were computed by Partial Least Squares (PLS) multivariate analysis. An accurate selection of the variables, fitting at the best the PLS model, was performed. Two descriptors related to the substituent information on both the dihydropyridinic and benzenic rings and four molecular descriptors, were selected. The QSPR model was fully cross validated and then optimized with an external set of novel 1,4-dihydropyridine drugs, obtaining very satisfactory statistical results. The good agreement between predicted and measured photodegradation rate (R(2)=0.8727) demonstrated the high accuracy of the QSPR model in predicting the photosensitivity of the drugs belonging to this class. The model was finally proposed as an effective tool to design new congeneric molecules characterized by high photostability.

Surface treatment: a potential approach for enhancement of solid-state photostability.

The potentials of a simple surface treatment technique aiming at modifying solid-state properties with emphasis on photostability were investigated using methyldopa (MD), a photosensitive drug substance. MD was treated with a preselected solvent by stirring a drug suspension in the solvent in a predetermined solid/solvent ratio under controlled conditions. At the end of the solvent treatment period, MD powder was separated, dried and screened. Changes in the solid-state properties of surface-treated MD were monitored using flowability measurements, scanning electron microscopy, thermal analysis and dissolution rate. Further, photostability testing, according to the ICH guidelines, was conducted using compressed disks of MD treated with solvents in the absence and presence of antioxidants, namely ascorbic acid, butylated hydroxytoluene (BHT) and cysteine HCl. The color change (DeltaE) was determined according to the CIELAB system. Surface treatment of MD drug substance with ethanol, methanol and isopropanol resulted in a marked improvement in flowability which was associated with morphological crystalline changes. Treatment of MD with methanol provided free flowing spherical agglomerates. Disks of solvent-treated MD showed improved photostability which was further potentiated by the inclusion of antioxidants, although only traces of the antioxidant were retained in the treated powder. Tablets containing MD surface treated with methanol containing a mixture of 2% ascorbic acid and 0.2% BHT were prepared by direct compression using a simple formula. The tablets conformed to official requirements.

A new fluorescent assay for enalapril maleate.

A new spectrofluorimetric method for the enalapril maleate monitoring was studied. Enalapril maleate was found to be highly photolabile. This drug was evaluated according to photodegradation assay at pH 2.5 and 6. Enalapril maleate was exposed to UVA-UVB radiations. Under these specific conditions was found as degradation product, the diketopiperazine. The modification of the fluorescent properties of enalapril maleate in solution after exposure UV-radiation and the degradation mechanisms were studied. The photodegradation was followed by the developed spectrofluorimetric assay.

HPLC detection and quantification of radiolytic products of eight beta-blockers irradiated in the solid state and hypotheses on their origins.

PURPOSE: The radiolytic products of eight beta-blockers were studied in order to understand the mechanisms of irradiation of drugs in the solid state. METHODS: The drugs were analyzed by high-performance liquid chromatography coupled to a diode array detector in order to observe the degradation of the main compound after irradiation and in order to study the nonvolatile final products on more concentrated solutions of irradiated drugs. RESULTS: The first test assessed that the main compound was not significantly degraded after gamma irradiation for any of the eight beta-blockers. A more complete study, which consisted on separating the nonvolatile products and on quantifying them, indicated first that the radiolytic products could reach the number of 14 and moreover that some could exceed the 0.1% threshold at 30 kGy. Eventually, radiolytic yields were compared with radical yields previously determined. CONCLUSIONS: The sensitivity of the first test can be discussed. It seems that, to study the feasibility of the radiosterilization, a complete study of the products of degradation is needed. Moreover, no correlation between radical and final products could be established, which denies that the former would be the precursors of the latter.

Electron paramagnetic resonance of some gamma-irradiated drugs.

Some drugs, used mainly in treatment of some neurological diseases and hypertension were exposed to gamma-irradiation, and the samples were investigated by electron paramagnetic resonance (EPR). The observed spectra were interpreted in terms of some type of alkyl and amine radical fragments. The spectra were computer simulated and the g values of the radicals and the hyperfine structure constants of the free electron with nearby protons were determined. The species were found to be stable at room temperature for more than a year. The samples were found to display no EPR signal without irradiation.

Effect of temperature and light on the stability of latanoprost and its clinical relevance.

PURPOSE: To examine the effect of controlled heat and ultraviolet exposures on the stability of latanoprost (Xalatan, Pharmacia & Upjohn, Kalamazoo, MI) using high-performance liquid chromatography to derive practical recommendations for patients regarding its use and storage. METHODS: Using serial dilution of a latanoprost stock solution, varying concentrations were prepared to obtain a standard curve. The accuracy and precision of the high-performance liquid chromatography assay conditions were validated using between-day and within-day studies. The original latanoprost containers were stored at 4, 25, 50, and 70 degrees C, and the concentration of latanoprost remaining was measured by high-performance liquid chromatography at different times for up to 1 month. In addition, the original latanoprost containers were exposed to known amounts of ultraviolet A and B radiation for 4 hours, and the concentration of latanoprost was measured at 1-hour intervals using high-performance liquid chromatography. RESULTS: The increased temperature studies showed that latanoprost remained stable at 4 and 25 degrees C for the 30-day study duration. Analysis of concentration versus time curves for 50 and 70 degrees C yielded a t90 (time for 10% degradation) of 8.25 and 1.32 days, respectively. Ultraviolet B radiation caused a rapid degradation of latanoprost, whereas ultraviolet A radiation was less effective in causing the degradation of latanoprost. CONCLUSIONS: Latanoprost exhibits thermal and solar instability and should ideally be stored below room temperature and in the dark. The importance of these storage conditions should be conveyed clearly to the patient.

Increased phototoxicity of hydrochlorothiazide by photodegradation.

The photodegradation products of hydrochlorothiazide produced by ultraviolet (UV) radiation were investigated for their phototoxicity utilizing the photohemolysis and Candida albicans tests. Hydrochlorothiazide was irradiated for 30, 60, 90 and 120 min with a 250 W xenon arc lamp using a WG295 cut-off filter. Irradiation of hydrochlorothiazide resulted in the gradual decrease of all three absorption bands (225, 270 and 320 nm), the blue shift of the 225 nm band, and the appearance of a new band around 290 nm. Since previous results demonstrated that photosubstitution of chloride could occur, the main product of this photolysis most likely is ethoxyhydrochlorothiazide. The photohemolysis test revealed a significant increase in photohemolysis observed in the photodegradation products produced after 60, 90 and 120 min of UV irradiation. This increase in hemolysis value directly correlated with the UV-irradiation time. However, there was no significant phototoxic killing of yeast in the Candida albicans test. This suggests photodegradation products of hydrochlorothiazide may play an important role in phototoxicity by acting on the cell membrane, but not on DNA. Considering the high in vitro phototoxicity observed in bendroflumethiazide and the data presented here, substitution of chloride seems to be responsible for the increased phototoxicity of hydrochlorothiazide.