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Extemporaneous Formulation and Stability Testing of Mexiletine HCl Solution

Author(s):  Alexander Kenneth S, Kaushik Sarita

Issue:  Mar/Apr 2004 - Overview of USP Chapter <797>
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Abstract:  Mexiletine hydrochloride is an orally active class I antiarrythmic agent. An extemporaneous solution of mexiletine hydrochloride was prepared for this study. Water was chosen as the vehicle due to the high solubility of the drug in water. Sorbitol, simple syrup and raspberry syrup were used as sweeteners in an attempt to mask the bitter taste of the drug. The solution was analyzed over 91 days of storage at five temperatures, ie, 4, 30, 40, 50 and 60°C. The sample was analyzed at 2, 6, 24 and 48 hours and then at 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 and 91 days at each designated temperature. The peak area for the mexiletine hydrochloride peak at time t = 0 was taken as 100%; and, accordingly, the percentages of intact drug remaining at each interval were calculated. The log percentage of the drug remaining was plotted against time (in days) at each temperature. The first-order constants for mexiletine hydrochloride at 4, 30, 40, 50 and 60°C were calculated to be -0.0007, -0.0009, -0.0010, -0.0011 and -0.0013, respectively. The Arrhenius plot was obtained by plotting the first-order degradation constants against the reciprocal of the absolute temperatures. The first-order degradation constant for mexiletine hydrochloride at 25°C was found to be 9.053 × 10-4(day-1). The energy of activation for the reaction was calculated to be -8663.88 J/mole. The shelf lives of the formulation at 4 and 25°C were found to be 173.3 and 115.5 days, respectively.

An attempt was made to identify and characterize any degradation products using the high-performance liquid chromatographic-mass spectrometry technique, as none of the degradation products were detected by ultraviolet analysis. However, this attempt was unsuccessful due to coating of the injection port with the sample, which might be due to crystallization of any of the excipients of the formulation under high temperatures. A degradation mechanism has been hypothesized based on either acid or base attack on the parent compound. The products from this degradation are presented.

Related Keywords: Alexander, Kenneth S, PhD, RPh, Kaushik, Sarita, Mexiletine hydrochloride solution, extemporaneous formulation of, Mexiletine hydrochloride solution, stability testing of


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