The Effects of Heat Degradation Determined by HPLC on Mail-Order Delivered Levothyroxine Tablets, Epinephrine-Pen, and Timolol Drops

Abstract

Objectives: The purpose/objective of this study is to determine the effects of heat exposure, on the levels of active ingredient in three selected medications with narrow therapeutic indices: levothyroxine, epinephrine, and timolol. Methods: In order to complete the study, a variety of methods were carried out to simulate the desired and appropriate environmental conditions. The drug selection was based on the medications pharmacokinetic properties. Levothyroxine was considered ideal to include in the study due to the medication's short shelf life and narrow therapeutic window. Epinephrine was selected since it is a life-saving medication, which has been reported to degrade to a significant extent under extreme heat. Timolol was chosen since its liquid formulation can be unstable when exposed to extreme heat. Epi- Pen ®, levothyroxine 150 mcg, and timolol 0.5% were mailed from Phoenix on 7/12/06, via FedEx in order to simulate the mail order prescription delivery process. Alternatively, other samples of the medications were also placed at room temperature and a variety of heat and humidity conditions. The temperature and relative humidity profiles for the mail order drugs were monitored by a temperature and RH device. Three different assessments were made for each drug. Within each assessment, three analyses were conducted on that same sample. For the timolol drops, each 5ml (??)bottle was assayed three times in addition to baseline measurements. Likewise, the levothyroxine tablets and epinephrine injections each were analyzed three times from the same sample, from three different lots. In addition, we also examined the degredation of these three drugs when subjected to constant temperature exposure of 37, 45, 45 with RH, and 55 degrees Celsius in a lab oven. Samples were collected after 1-. 4-, and 7-days of heat exposure in both the mail box and the oven; 7/14/06, 7/17/06, and 7/20/06, respectively. Each medication was analyzed by its respective high-performance liquid chromatography (HPLC) method. The amount of drug taken for each sample was 0.5mL of epinephrine, 10 tablets of levothyroxine, and 0.5mL of timolol were used in the preparation for HPLC analysis. Results: The temperature and RH profile were recorded and graphed. The temperature measured in the mail box ranged from ~75 degreees Fahrenheit to ~140 degrees Fahrenheit. Based on the extrapolation to the baseline, the amount of drug measured on days 1, 4, and 7 were the following: 1) Levothyroxine: 123.66 mcg, 118.61mcg, and 119.3 mcg, respectively; 2) EpiPen: 1121.48 mcg/ml, 1215.52 mcg/ml, and 1167.22 mcg/ml, respectively; 3) timolol: 6766.30 mcg/ml, 6659.52 mcg/ml, and 6508.48 mcg/ml, respectively. Conclusions: The medications studied were exposed to temperatures above the manufacturer’s recommended storage conditions for the majority of the time. Despite being out of opitmal conditions, the results indicated that all three drugs did not have significant degradation.