Comparative Stability of Oral Vitamin K Solutions Stored in Refrigerated Amber Plastic Syringes

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Purpose: Vitamin K1 (phytonadione) is a fat-soluble vitamin and an essential cofactor for the synthesis of clotting factors II, VII, IX, X, protein C, and protein S. Vitamin K antagonists deplete vitamin K reserves effectively preventing the synthesis of these clotting factors leading to anticoagulation. Overly excessive anticoagulation, as evidenced by INRs greater than 5, may necessitate vitamin K for reversal of warfarin depending on bleeding risk factors. For elevated INR without bleeding, the oral route is preferred. Orally administered vitamin K1 tablets are only supplied by a single manufacturer, and only available as a 5 mg tablet. Concerns with availability of this tablet, lack of dosing options for treatment requiring less than 5 mg, and delivery options for patients unable to swallow whole tablets have prompted the exploration of alternative dosing strategies using the 10 mg/mL injectable emulsion compounded into an oral liquid. The possibility of storing the oral liquid in unit-doses adds a layer of convenience, and is common practice in many hospital pharmacies. In this project, we compared oral liquid vitamin K1 in sterile water for injection (SWFI) to oral liquid vitamin K1 in Ora-Sweet, simple syrup, cherry syrup, and Syrpalta stored in amber plastic oral syringes.

Methods: Batches of 1 mg/mL vitamin K1 were prepared in SWFI, Ora-Sweet, simple syrup, cherry syrup, and Syrpalta and drawn up by 1-mL aliquots into amber plastic oral syringes. Syringes were capped and stored in a laboratory refrigerator (4.9-5.4oC). for the duration of the study. On each study day (0, 1, 2, 4, 7, 14, 21, 30, 60, and 90), three syringes from each vehicle were removed, and the contents diluted with ethanol to achieve a 0.5 mg/mL assay concentration. Additionally, USP reference material was used on each study day to prepare a fresh 0.5 mg/mL reference solution. The samples and reference were analyzed using a previously validated HPLC-UV method. Results were compared using a 2-way ANOVA (p = 0.05) with post-hoc Tukey’s correction for multiple comparisons. Product stability was defined as 90-110% labeled amount.

Results: Of the vehicles tested, SWFI was the most suitable vehicle for longer-term storage of unit-dosed vitamin K1. The 1 mg/mL vitamin K1 in SWFI, when stored in amber plastic oral syringes, remains within the acceptable 90 – 110% range for 21 days. The Syrpalta preparation demonstrated the next highest BUD of 7 days, with one syringe (2 injections) falling outside the 90% potency at the 14 day time point. Cherry syrup allowed for very limited stability, with a BUD of 24 hours. By the 48-hour time point, two of the three samples were below the 90% potency cutoff. For the vitamin K oral solutions prepared in simple syrup and Ora-Sweet, the recovery of vitamin K was not within acceptable limits, even on the day of compounding. The initial recovery for vitamin K in simple syrup was only 86.8%. Similarly, the preparation in Ora-Sweet, was not at acceptable potency on the day of compounding, (92.7 ± 9.9%). While the average recovery in Ora-Sweet exceeded 90%, the variability between samples suggests a lack of homogeneous distribution of drug through the vehicle. Statistically significant differences were detected between the SWFI preparation and all other vehicles in a 2-way ANOVA with Tukey’s multiple comparison post-test (p-value of 0.05). This difference was most pronounced between SWFI and Ora-Sweet and SWFI and simple syrup (both p < 0.0001). Cherry syrup was also vastly different from SWFI (p = 0.0002), and the difference between SWFI and Syrpalta was less pronounced, yet still significant (p = 0.0442).

Conclusion: Vitamin K1 in sterile water and Syrpalta was stable for 21 days and 7 days, respectively, when stored in amber plastic syringes. Vitamin K1 in cherry syrup was only stable for 24 hours in the syringes. For vitamin K1 in Ora-Sweet and simple syrup, the within-day variability was very high due to limitations in drug dissolution; as such the average recovery was not consistently above 90%, even on the day of compounding. Statistically significant differences were detected between the SWFI formulation and all other vehicles. Several factors appear to affect the potency and stability of vitamin K1 in different vehicles. Because the stability of vitamin K1 oral solution differs between storage in amber glass bottles and oral syringes, vitamin K1 may have the potential to adsorb to polypropylene (PPE). The pH of the vehicle may contribute to degradation of vitamin K1, and the viscosity of the vehicle may affect the achievable potency of certain mixtures. The viscosity of the mixture also appears to affect maintenance of a homogenous mixture, but the presence of alcohol in the vehicle may help aid in solubilizing the vitamin K1 in Syrpalta. Vitamin K1 in SWFI appears to be the most suitable vehicle for longer-term storage of unit-dosed vitamin K, but Syrpalta and cherry syrup may also be appropriate for more immediate use.


Washington DC

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