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Detection and Identification of an Unknown Impurity in Ephedrine HCl 5 mg/mL Cyclic Olefin Syringes: Formulation Development

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Abstract

An unknown impurity was detected in in-house prepared ephedrine hydrochloride (HCl) 5 mg/mL prefilled sterilized syringes when applying a stability-indicating British Pharmacopoeia 2018 impurity method for ephedrine injection. Ultraviolet, chromatographic, mass spectral, and physicochemical methods were combined to identify the unknown impurity. The unknown impurity was identified as methcathinone, which is generated from ephedrine drug substance through an oxidation reaction. A formulation study, in which different process adjustments were tested, was carried out to reduce the amount of unknown impurity. Nitrogen gassing in combination with 0.05 M citrate buffer addition proved to be the most potent process adjustment in reducing methcathinone formation in ephedrine HCl 5 mg/mL prefilled sterilized syringes after 4 months of storage in the dark at room temperature (20 °C ± 5 °C). More detailed research on the long-term stability of the reformulated ephedrine HCl drug product is currently underway, with promising results for up to 9 months gathered already.

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Data Availability

The authors confirm that the data supporting the findings of this study are available within the article. Raw data are available from the corresponding author on request.

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Authors and Affiliations

  1. Unit of Pharmacotherapy, -Epidemiology, and -Economics, Groningen Research Institute of Pharmacy, University of Groningen, 9713 AV, Groningen, Groningen, the Netherlands

    Ellen A. Kok

  2. Department of Clinical Pharmacy, Isala Hospital, 8025 AB, Zwolle, Overijssel, the Netherlands

    Ellen A. Kok, Daphne den Besten-Bertholee, Stefan van Berkel & Karin H. M. Larmené-Beld

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  1. Ellen A. Kok
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  2. Daphne den Besten-Bertholee
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  3. Stefan van Berkel
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  4. Karin H. M. Larmené-Beld
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Contributions

Conceptualization, K.H.M.L.-B. and D.B.-B.; methodology, all; validation, D.B.-B. and S.B.; investigation, all; resources, K.H.M.L.-B. and D.B.-B.; data curation, S.B.; writing—original draft preparation, E.A.K.; writing—review and editing, all; visualization, E.A.K. and S.B.; supervision, K.H.M.L.-B. and D.B.-B.; project administration, K.H.M.L.-B., D.B.-B., and E.A.K. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Karin H. M. Larmené-Beld.

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Kok, E.A., den Besten-Bertholee, D., van Berkel, S. et al. Detection and Identification of an Unknown Impurity in Ephedrine HCl 5 mg/mL Cyclic Olefin Syringes: Formulation Development. AAPS PharmSciTech 24, 140 (2023). https://doi.org/10.1208/s12249-023-02602-y

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