TY - JOUR
AU - Zhao,, Fang
AB - Abstract Purpose The long-term stability of levetiracetam solution in oral syringes was investigated in order to define a suitable beyond-use date and demonstrate the feasibility of storing prepared syringes for extended periods as an alternative to commercial levetiracetam unit dose cups. Methods Levetiracetam oral solution (100 mg/mL) was drawn into 1- and 10-mL amber polypropylene oral syringes. Triplicate samples of the syringe preparations were stored at refrigeration (2–8 °C) or room temperature (20–25 °C) and evaluated at monthly intervals for up to six months. At each time point, the samples were visually inspected and levetiracetam stability was assessed via pH measurement and high-performance liquid chromatography (HPLC). A short-term forced degradation study was conducted to confirm that the HPLC assay method was stability indicating. Results Over the six-month storage period, there was no significant change in either the visual appearance or pH of any of the levetiracetam samples. The results of serial HPLC assessment indicated that at least 97% of the initial levetiracetam concentration was retained in all samples of 1- and 10-mL oral syringes at both refrigeration and room temperature. Although this study was conducted using a generic product, the stability data obtained may be applied in repackaging decisions regarding other generic formulations of levetiracetam with similar excipient compositions. Conclusion Commercial levetiracetam 100-mg/mL oral solution was stable for up to six months in amber polypropylene oral syringes stored at both refrigeration and room temperature conditions. Levetiracetam is an anticonvulsant used as an adjunctive therapy in the treatment of partial-onset seizures, myoclonic seizures, primary generalized tonic–clonic seizures, and idiopathic generalized epilepsy in both adults and children.1 Levetiracetam oral solution (100 mg/mL) is available commercially for patients with difficulty swallowing tablets.1 This solution is frequently prescribed in hospitals, which prompts the need to repackage the product into oral plastic syringes to facilitate dispensing and dosing. Unfortunately, there are no published data concerning the stability of the commercial levetiracetam oral solution in commonly used oral plastic syringes. The purpose of the study described here was to evaluate the long-term stability of levetiracetam oral solution (100 mg/mL) in oral plastic syringes for up to six months. The 1- and 10-mL syringe volumes were selected in order to bracket the typical dose range of levetiracetam oral solution.1 The 1-mL syringe represented the worst-case scenario for the ratio of surface area to volume. Both refrigeration and room temperature storage conditions were included in this study to provide options and flexibility for the pharmacy. It is worth mentioning that a few manufacturers market the levetiracetam solution in unit dose cups. These unit dose cups provide convenience in dispensing, but dose delivery via cups is not as accurate as can be achieved with the oral syringes; it is common for a substantial volume of solution to be retained in the cup after oral administration. Accurate dose delivery—always important with the use of any medication—is critical to ensure optimal anticonvulsant therapy with levetiracetam. In addition, the oral syringes can be used to deliver pediatric doses that are below those contained in the lowest-volume unit dose cups available. Finally, with the ever-changing landscape of actual and threatened drug shortages, institutional pharmacies are frequently called on to create temporary supplies of repackaged medications. With the accuracy and broad application they afford, the oral syringes can provide a satisfactory substitute for the unit dose cups in case of shortages. Methods Stability study Commercially available levetiracetam 100-mg/mL oral solutiona was drawn into 1- and 10-mL amber polypropylene oral syringes.b A commonly used amber polypropylene oral syringe with a matching tip was chosen as the packaging device for the study. The syringe tips were capped immediately after filling. The filled syringes were stored at refrigeration (2–8 °C) and room temperature (20–25 °C) conditions. Triplicate samples were prepared for each syringe size, storage condition, and analysis time point. Stability evaluation was performed immediately after syringe preparation and at monthly intervals during six months of storage. At every time point, triplicate samples of 1- and 10-mL syringes representing both temperature conditions were pulled for evaluation. The entire content of each syringe sample was first expelled into a clear glass vial for visual inspection against a light background for clarity, color, precipitation, and microbial growth. The samples were then subjected to pH measurement.c Finally, a 200-μL aliquot from each sample was diluted with purified water in a 100-mL volumetric flask and analyzed by high-performance liquid chromatography (HPLC) for chemical stability (three injections were performed for each of the triplicate samples). HPLC analysis The HPLC analysis was performed using a Shimadzu instrument.d The chromatographic variables were adapted from a stability-indicating assay described by Saravanan et al.2 The HPLC columne was maintained at 30 °C. The mobile phase consisted of 0.1% aqueous phosphoric acid and acetonitrile at a volume-to-volume ratio of 85:15 (pH 2.10) with a flow rate of 1.0 mL/min. Each injection volume was 10 μL, and the UV detection wavelength was set at 205 nm. Under these conditions, the retention time of levetiracetam was approximately 5.4 minutes, as shown in Figure 1a. Figure 1 Open in new tabDownload slide Chromatograms of (a) levetiracetam standard solution 0.2 mg/mL in water, (b) levetiracetam solution 0.2 mg/mL in 0.5 N hydrogen chloride after 48 hours, and (c) levetiracetam solution 0.2 mg/mL in 0.5 N sodium hydroxide after 24 hours. UV = ultraviolet. Figure 1 Open in new tabDownload slide Chromatograms of (a) levetiracetam standard solution 0.2 mg/mL in water, (b) levetiracetam solution 0.2 mg/mL in 0.5 N hydrogen chloride after 48 hours, and (c) levetiracetam solution 0.2 mg/mL in 0.5 N sodium hydroxide after 24 hours. UV = ultraviolet. Standards of levetiracetam solutions of 0.05, 0.10, 0.15, 0.20, and 0.25 mg/mL were prepared for calibration purposes; this range of solutions encompassed the expected concentrations of the diluted stability samples. Because it was cost prohibitive to purchase levetiracetam as a pure drug substance, the standards were prepared by diluting the 100-mg/mL commercial oral solutiona with purified water; the same lot of levetiracetam oral solution was used to prepare the test samples. For practical purposes, it was assumed that the drug concentration of the lot of oral solution used was at the labeled claim of 100 mg/mL at the initiation of the study. Aliquots of the standard solutions were frozen for subsequent analysis at each time point in the study. It was also verified that there were no interfering excipients for the HPLC analysis (Figure 1a). A calibration curve was constructed by linear regression of the peak area of levetiracetam against levetiracetam concentration. The curve was found to be linear over the concentration range of the standards (r2 = 0.998). The standards were injected into the HPLC system three times at each stability assessment time point to verify the precision of the method. The intraday and interday coefficients of variation were within 1.11%. Forced degradation A short-term forced degradation study of levetiracetam was conducted under extreme pH, light, and oxidative stress conditions. This study was intended to verify the ability of the HPLC assay to separate the potential degradation products from the parent drug. Levetiracetam solutions of 0.2 mg/mL were prepared in 0.5 N hydrogen chloride, 0.5 N sodium hydroxide, and 3% hydrogen peroxide. These samples were incubated at 60 °C for up to 72 hours. Three additional samples of 0.2-mg/mL levetiracetam solution in water were prepared and exposed to ultraviolet (UV) light (254 and 365 nm) and regular sunlight for over 72 hours. The UV light was generated by a standard handheld laboratory UV lamp.f Among these samples, notable degradation was observed in only the two samples stored under extreme pH conditions. As shown in Figure 1, the degradation products were well separated from the parent molecule by the HPLC method, and no interfering peaks were observed. Therefore, the HPLC method was considered as stability indicating and suitable for the stability evaluation of levetiracetam oral solution in the repackaged syringes. Results and discussion United States Pharmacopeia general chapter 1136 provides guidance on noncommercial repackaging of nonsterile liquid dosage forms into unit dose containers.3 According to this guidance, the manufacturer’s expiration date applies to the original container-closure system and is not intended to apply to the repackaged product. A suitable beyond-use date (BUD) should be selected according to the nature of the drug, the container, and the storage condition, in addition to the packaging and expiration information in the manufacturer’s product labeling.3 Levetiracetam is a relatively simple molecule with only two main functional groups, a five-membered lactam ring and a terminal amide.1 Based on the physicochemical properties and the formulation ingredients described in the commercial product package insert,1 the repackaging of levetiracetam oral solution in syringes is not expected to significantly alter the physical and chemical stabilities of the product over the desired six-month BUD (not to exceed the original manufacturer’s expiration date). The solution product also contains paraben preservatives,1 which should prevent microbial growth even after repackaging. However, due to the high ratio of surface area to volume of the syringe sample and the plastic from which the oral syringes are made, there are several stability concerns. For example, there might be drug loss due to adsorption to the syringe and leaching from the syringe into the drug solution. In comparison to the original bottle, the thin plastic syringe barrel and weak closures may lead to water loss or increased exposure to oxygen over long-term storage. At the initiation of the stability study, the levetiracetam 100-mg/mL oral solution appeared as a clear and colorless liquid. The initial sample pH and concentration values are reported in Tables 1 and 2. Over the six months of storage at refrigeration (2–8 °C) or room temperature (20–25 °C), all samples remained clear, colorless, and free of visible precipitation or microbial growth. No significant change in the pH of any samples was observed (Table 1). The stability-indicating HPLC analysis also confirmed that all samples retained 97–108% of the initial drug concentration, with no new peaks observed (Table 2). Overall, the levetiracetam 100-mg/mL oral solution was found to be stable in amber polypropylene oral syringes under the evaluated conditions. Table 2 HPLC Data on Stability of Levetiracetam Oral Solution Stored in Polypropylene Syringes (n = 3)a Storage Temperature and Syringe Size Mean ± S.D. Initial Drug Concentration (mg/mL) Mean ± S.D. Initial Drug Concentration Remaining (%) 1 mo 2 mo 3 mo 4 mo 5 mo 6 mo 2–8 °C, 1 mL 97.8 ± 0.9 102.7 ± 0.2 102.9 ± 1.0 106.2 ± 2.2 102.8 ± 0.1 103.4 ± 0.5 105.2 ± 0.8 20–25 °C, 1 mL 97.8 ± 0.9 103.2 ± 0.4 105.1 ± 0.3 107.8 ± 0.5 105.9 ± 0.7 105.3 ± 0.2 104.3 ± 0.6 2–8 °C, 10 mL 101.1 ± 1.4 99.1 ± 0.4 101.0 ± 2.9 104.2 ± 1.0 100.6 ± 1.0 101.7 ± 1.5 98.6 ± 1.3 20–25 °C, 10 mL 101.1 ± 1.4 99.1 ± 0.9 100.8 ± 0.9 103.0 ± 1.2 102.2 ± 1.1 102.3 ± 1.4 101.0 ± 1.3 Storage Temperature and Syringe Size Mean ± S.D. Initial Drug Concentration (mg/mL) Mean ± S.D. Initial Drug Concentration Remaining (%) 1 mo 2 mo 3 mo 4 mo 5 mo 6 mo 2–8 °C, 1 mL 97.8 ± 0.9 102.7 ± 0.2 102.9 ± 1.0 106.2 ± 2.2 102.8 ± 0.1 103.4 ± 0.5 105.2 ± 0.8 20–25 °C, 1 mL 97.8 ± 0.9 103.2 ± 0.4 105.1 ± 0.3 107.8 ± 0.5 105.9 ± 0.7 105.3 ± 0.2 104.3 ± 0.6 2–8 °C, 10 mL 101.1 ± 1.4 99.1 ± 0.4 101.0 ± 2.9 104.2 ± 1.0 100.6 ± 1.0 101.7 ± 1.5 98.6 ± 1.3 20–25 °C, 10 mL 101.1 ± 1.4 99.1 ± 0.9 100.8 ± 0.9 103.0 ± 1.2 102.2 ± 1.1 102.3 ± 1.4 101.0 ± 1.3 a HPLC = high-performance liquid chromatography. Open in new tab Table 2 HPLC Data on Stability of Levetiracetam Oral Solution Stored in Polypropylene Syringes (n = 3)a Storage Temperature and Syringe Size Mean ± S.D. Initial Drug Concentration (mg/mL) Mean ± S.D. Initial Drug Concentration Remaining (%) 1 mo 2 mo 3 mo 4 mo 5 mo 6 mo 2–8 °C, 1 mL 97.8 ± 0.9 102.7 ± 0.2 102.9 ± 1.0 106.2 ± 2.2 102.8 ± 0.1 103.4 ± 0.5 105.2 ± 0.8 20–25 °C, 1 mL 97.8 ± 0.9 103.2 ± 0.4 105.1 ± 0.3 107.8 ± 0.5 105.9 ± 0.7 105.3 ± 0.2 104.3 ± 0.6 2–8 °C, 10 mL 101.1 ± 1.4 99.1 ± 0.4 101.0 ± 2.9 104.2 ± 1.0 100.6 ± 1.0 101.7 ± 1.5 98.6 ± 1.3 20–25 °C, 10 mL 101.1 ± 1.4 99.1 ± 0.9 100.8 ± 0.9 103.0 ± 1.2 102.2 ± 1.1 102.3 ± 1.4 101.0 ± 1.3 Storage Temperature and Syringe Size Mean ± S.D. Initial Drug Concentration (mg/mL) Mean ± S.D. Initial Drug Concentration Remaining (%) 1 mo 2 mo 3 mo 4 mo 5 mo 6 mo 2–8 °C, 1 mL 97.8 ± 0.9 102.7 ± 0.2 102.9 ± 1.0 106.2 ± 2.2 102.8 ± 0.1 103.4 ± 0.5 105.2 ± 0.8 20–25 °C, 1 mL 97.8 ± 0.9 103.2 ± 0.4 105.1 ± 0.3 107.8 ± 0.5 105.9 ± 0.7 105.3 ± 0.2 104.3 ± 0.6 2–8 °C, 10 mL 101.1 ± 1.4 99.1 ± 0.4 101.0 ± 2.9 104.2 ± 1.0 100.6 ± 1.0 101.7 ± 1.5 98.6 ± 1.3 20–25 °C, 10 mL 101.1 ± 1.4 99.1 ± 0.9 100.8 ± 0.9 103.0 ± 1.2 102.2 ± 1.1 102.3 ± 1.4 101.0 ± 1.3 a HPLC = high-performance liquid chromatography. Open in new tab Table 1 pH Stability of Levetiracetam Oral Solution Stored in Polypropylene Syringes (n = 3) Storage Temperature and Syringe Size Mean ± S.D. pH Initial 1 mo 2 mo 3 mo 4 mo 5 mo 6 mo  2–8 °C, 1 mL 5.50 ± 0.00 5.57 ± 0.03 5.61 ± 0.01 5.54 ± 0.01 5.47 ± 0.02 5.49 ± 0.01 5.53 ± 0.02  20–25 °C, 1 mL 5.50 ± 0.00 5.57 ± 0.01 5.64 ± 0.02 5.52 ± 0.00 5.46 ± 0.01 5.48 ± 0.00 5.55 ± 0.01  2–8 °C, 10 mL 5.50 ± 0.00 5.57 ± 0.01 5.57 ± 0.02 5.51 ± 0.01 5.46 ± 0.01 5.51 ± 0.01 5.57 ± 0.01  20–25 °C, 10 mL 5.50 ± 0.00 5.55 ± 0.01 5.63 ± 0.02 5.53 ± 0.01 5.45 ± 0.01 5.47 ± 0.00 5.55 ± 0.01 Storage Temperature and Syringe Size Mean ± S.D. pH Initial 1 mo 2 mo 3 mo 4 mo 5 mo 6 mo  2–8 °C, 1 mL 5.50 ± 0.00 5.57 ± 0.03 5.61 ± 0.01 5.54 ± 0.01 5.47 ± 0.02 5.49 ± 0.01 5.53 ± 0.02  20–25 °C, 1 mL 5.50 ± 0.00 5.57 ± 0.01 5.64 ± 0.02 5.52 ± 0.00 5.46 ± 0.01 5.48 ± 0.00 5.55 ± 0.01  2–8 °C, 10 mL 5.50 ± 0.00 5.57 ± 0.01 5.57 ± 0.02 5.51 ± 0.01 5.46 ± 0.01 5.51 ± 0.01 5.57 ± 0.01  20–25 °C, 10 mL 5.50 ± 0.00 5.55 ± 0.01 5.63 ± 0.02 5.53 ± 0.01 5.45 ± 0.01 5.47 ± 0.00 5.55 ± 0.01 Open in new tab Table 1 pH Stability of Levetiracetam Oral Solution Stored in Polypropylene Syringes (n = 3) Storage Temperature and Syringe Size Mean ± S.D. pH Initial 1 mo 2 mo 3 mo 4 mo 5 mo 6 mo  2–8 °C, 1 mL 5.50 ± 0.00 5.57 ± 0.03 5.61 ± 0.01 5.54 ± 0.01 5.47 ± 0.02 5.49 ± 0.01 5.53 ± 0.02  20–25 °C, 1 mL 5.50 ± 0.00 5.57 ± 0.01 5.64 ± 0.02 5.52 ± 0.00 5.46 ± 0.01 5.48 ± 0.00 5.55 ± 0.01  2–8 °C, 10 mL 5.50 ± 0.00 5.57 ± 0.01 5.57 ± 0.02 5.51 ± 0.01 5.46 ± 0.01 5.51 ± 0.01 5.57 ± 0.01  20–25 °C, 10 mL 5.50 ± 0.00 5.55 ± 0.01 5.63 ± 0.02 5.53 ± 0.01 5.45 ± 0.01 5.47 ± 0.00 5.55 ± 0.01 Storage Temperature and Syringe Size Mean ± S.D. pH Initial 1 mo 2 mo 3 mo 4 mo 5 mo 6 mo  2–8 °C, 1 mL 5.50 ± 0.00 5.57 ± 0.03 5.61 ± 0.01 5.54 ± 0.01 5.47 ± 0.02 5.49 ± 0.01 5.53 ± 0.02  20–25 °C, 1 mL 5.50 ± 0.00 5.57 ± 0.01 5.64 ± 0.02 5.52 ± 0.00 5.46 ± 0.01 5.48 ± 0.00 5.55 ± 0.01  2–8 °C, 10 mL 5.50 ± 0.00 5.57 ± 0.01 5.57 ± 0.02 5.51 ± 0.01 5.46 ± 0.01 5.51 ± 0.01 5.57 ± 0.01  20–25 °C, 10 mL 5.50 ± 0.00 5.55 ± 0.01 5.63 ± 0.02 5.53 ± 0.01 5.45 ± 0.01 5.47 ± 0.00 5.55 ± 0.01 Open in new tab It is also important to note that the oral solution product was originally developed by Belgium-based UCB S.A. and approved by the Food and Drug Administration in 2003.4 Currently, the generic product is available through multiple sources,4 and most formulations contain excipients similar to those of the brand-name product.5 Therefore, the stability data generated in this study should be applicable to other generic products with similar excipient compositions. Conclusion Commercial levetiracetam 100-mg/mL oral solution was stable for up to six months in amber polypropylene oral syringes stored at both refrigeration and room temperature conditions. Footnotes The authors have declared no potential conflicts of interest. a Levetiracetam oral solution, 100 mg/mL. Morton Grove Pharmaceuticals, Inc., Morton Grove, IL, lot 31086A; NDC 60432-831-16. b Exacta-Med oral syringes with tips, Baxa Corporation, Englewood, CO. c SevenEasy pH meter, Mettler-Toledo Inc., Columbus, OH. d HPLC system, model 2010A, Shimadzu Scientific Instruments, Marlborough, MA. e HPLC column, ODS AQ, 5 μm, 250 × 4.6 mm, YMC America, Inc., Allentown, PA. f UV lamp, Spectroline model ENF-240C, Spectronics Corporation, Westbury, NY. References 1 Levetiracetam oral solution package insert . http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3edcaae5-81bb-4a18-8bfd-834835187b13 (accessed 2013 Jan 21). 2 Saravanan G Jyothi G Suresh Y et al. . LC method for determination of the stability of levetiracetam drug substance under stressing conditions . Chromatographia . 2008 ; 67 : 173 – 7 . Google Scholar Crossref Search ADS WorldCat 3 Packaging and repackaging—single-unit containers (general chapter 1136) . In: The United States pharmacopeia, 36th rev., and The national formulary , 19th ed. Rockville, MD : United States Pharmacopeial Convention ; 2013 : 844 – 50 . WorldCat COPAC 4 Food and Drug Administration . Orange book: approved drug products with therapeutic equivalence evaluation . www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=021505&TABLE1=OB_Rx (accessed 2013 Jan 28). 5 DailyMed, National Library of Medicine, National Institutes of Health . http://dailymed.nlm.nih.gov/daily med/search.cfm?startswith=levetiracetam&x=0&y=0 (accessed 2013 Jan 17). Copyright © 2014 by the American Society of Health-System Pharmacists, Inc. All rights reserved.
TI - Stability of levetiracetam oral solution repackaged in oral plastic syringes
JF - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp130189
DA - 2014-02-01
UR - https://www.deepdyve.com/lp/oxford-university-press/stability-of-levetiracetam-oral-solution-repackaged-in-oral-plastic-RxrwozkyPd
SP - 219
VL - 71
IS - 3
DP - DeepDyve
ER -