Stability of Nitrofurantoin in Extemporaneously Compounded Suspensions: METHODS

Preparation of Suspensions

Nitrofurantoin suspensions (10 mg/mL) were prepared by crushing commercially available nitrofurantoin 50-mg tablets (Apotex Inc, Weston, Ontario, lot GE3153) and resuspending the powder in a 1:1 mixture of Ora-Sweet and Ora-Plus (Paddock Laboratories Inc, lots 4140869 and 4040385, respectively). Six replicates were prepared in separate 50-mL amber plastic prescription bottles (Richards Packaging Inc, RIGO Products Division, Gloucester, Ontario; polyvinyl chloride [recycle code 3]). Three of the bottles were stored at 4°C (refrigerated) and 3 at 25°C (room temperature). All bottles were exposed only to fluorescent light in the laboratory.

The physical appearance of the suspensions was evaluated qualitatively at the time of preparation and at weekly intervals up to 91 days. All suspensions were tested for odour and taste and were visually examined for changes in colour (against white and black back­grounds), viscosity, formation of precipitates, and ease of resuspension as samples were collected during the 91-day study period. Immediately after the physical observations were completed, each bottle was manually shaken for 10 s, and 2 samples were drawn. One sample (1.5-mL) was stored at -85°C until day 91, when a single batch analysis was performed by a stability- indicating high-performance liquid chromatography (HPLC) method developed in the authors’ laboratory. This method was similar to previously published methods. The second sample (also 1.5-mL) was allowed to equilibrate to room temperature, and the pH was then determined. The pH meter (model 8000, VWR Canlab, Mississauga, Ontario) was calibrated at the beginning of each testing session.
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Preparation of Stock and Standards

Stock solutions of nitrofurantoin at concentrations of 0.50, 1.00, 2.00, 3.00, and 4.00 mg/mL were prepared by diluting nitrofurantoin 4 mg/mL in HPLC-grade acetonitrile (Fisher Scientific, Richmond, British Columbia, lot 042332). The internal standard was furazolidone (Sigma-Aldrich Canada Ltd, Oakville, Ontario, lot 029H1117) at a concentration of 2.0 mg/mL in HPLC-grade acetonitrile. Standards were prepared by combining a 0.5-mL aliquot of each stock solution and a 0.5-mL aliquot of furazolidone 2.0 mg/mL. The final concentrations of nitrofurantoin in the samples injected onto the chromatograph were 0.25, 0.50, 1.00, 1.50, and 2.00 mg/mL. The final concentration of the internal standard was 1 mg/mL. These dilutions achieved optimal chromatographic characteristics. Before injection into the chromatographic system, all standards were passed through a 0.45-pm microfilter (Acrodisc GHP syringe filter, Gelman, Ann Arbor, Michigan, lot 40530) to prevent injection of impurities onto the column.

The HPLC instrumentation (model 2690, Waters Alliance Systems, Waters Ltd, Mississauga, Ontario) consisted of a delivery pump, an automatic injector equipped with a 200-pL injector, a YMC ODSA 4.0 ± 20 mm guard column (Waters Ltd, lot 4044110501), a YMC Pack ODS-AP 6.0 ± 250 mm column (Waters Ltd, lot 062506286W), and an ultraviolet detector set at 250 nm (model 2487 dual-wavelength absorbance detector, Waters Ltd). The mobile phase consisted of a 28:72 (v/v) mixture of acetonitrile and 10 mmol/L KH2PO4 salt buffer (Sigma-Aldrich Canada Ltd, lot 101K0025) at pH 3.0. All solvents were HPLC-grade and were filtered before use. The flow rate was set at 1.75 mL/min.
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A 5-point calibration curve was prepared, with a blank (acetonitrile only) at the beginning of each run, to ensure that there was no carry-over from one run to the next. The range of this calibration curve (0.25 to 2.00 mg/mL) encompassed the diluted (1.00 mg/mL) test concentration of nitrofurantoin. The calibration curve was generated by least-squares regression of the peak area ratio of nitrofurantoin to furazolidone and the concentration of each standard. The precision of the assay was evaluated by intraday and interday validation methods. Intraday variability was determined by running 0.50, 2.00, and 3.00 mg/mL stock solutions (diluted to standards of 0.25, 1.00, and 1.50 mg/mL) in quadruplicate throughout a single day, and interday variability was determined by running the same concentrations (as in the testing for intraday variability) in quadruplicate daily for 4 days. The means, standard deviations, and coefficients of variation were then calculated. The acceptable limit for the coefficients of variation was defined a priori as less than 10%.

Category: Main

Tags: nitrofurantoin, stability, suspension

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