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华法林钠片的结构变化对溶出度及仿制药替代潜在安全性的影响

Structural Changes of Sodium Warfarin in Tablets Affecting the Dissolution Profiles and Potential Safety of Generic Substitution.

作者信息

Muselík Jan, Urbanova Martina, Bartoníčková Eva, Palovčík Jakub, Vetchý David, Czernek Jiří, Janisova Larisa, Velychkivska Nadiia, Franc Aleš, Brus Jiří

机构信息

Department of Pharmaceutical Technology, Faculty of Pharmacy, Masaryk University, Palackého třída 1946/1, 612 00 Brno, Czech Republic.

Department of NMR Spectroscopy, Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovsky sq. 2, 162 06 Prague 6, Czech Republic.

出版信息

Pharmaceutics. 2021 Aug 30;13(9):1364. doi: 10.3390/pharmaceutics13091364.

DOI:10.3390/pharmaceutics13091364
PMID:34575440
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8470675/
Abstract

At present, the risk of generic substitutions in warfarin tablets is still being discussed. The aim of this study was to assess whether API interactions with commonly used excipients may affect the safety of generic replacement of warfarin sodium tablets. These interactions were observed during an accelerated stability study, and the effect of the warfarin solid phase (crystalline/amorphous form) as well as the API particle size distribution was studied. Commercial tablets and prepared tablets containing crystalline warfarin or amorphous warfarin were used. In addition, binary mixtures of warfarin with various excipients were prepared. The structural changes before and after the stability study were monitored by dissolution test in different media, solid-state NMR spectroscopy and Raman microscopy. During the stability study, the conversion of the sodium in warfarin to its acid form was demonstrated by some excipients (e.g., calcium phosphate). This change in the solid phase of warfarin leads to significant changes in dissolution, especially with the different particle sizes of the APIs in the tablet. Thus, the choice of suitable excipients and particle sizes are critical factors influencing the safety of generic warfarin sodium tablets.

摘要

目前，华法林片剂中通用名替换的风险仍在讨论中。本研究的目的是评估活性药物成分（API）与常用辅料的相互作用是否会影响华法林钠片通用名替换的安全性。这些相互作用是在加速稳定性研究中观察到的，同时研究了华法林固相（结晶/无定形形式）以及API粒度分布的影响。使用了含有结晶型华法林或无定形华法林的市售片剂和自制片剂。此外，还制备了华法林与各种辅料的二元混合物。通过在不同介质中的溶出度试验、固态核磁共振光谱和拉曼显微镜监测稳定性研究前后的结构变化。在稳定性研究期间，一些辅料（如磷酸钙）证明了华法林中的钠向其酸形式的转化。华法林固相的这种变化导致溶出度发生显著变化，尤其是片剂中不同粒度的API。因此，选择合适的辅料和粒度是影响通用名华法林钠片安全性的关键因素。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c57/8470675/60df2c8dcf6e/pharmaceutics-13-01364-g011.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c57/8470675/2a1a9a310b40/pharmaceutics-13-01364-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c57/8470675/21fa7c8e1913/pharmaceutics-13-01364-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c57/8470675/60df2c8dcf6e/pharmaceutics-13-01364-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c57/8470675/31ddfcf38df9/pharmaceutics-13-01364-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c57/8470675/661f73ffce94/pharmaceutics-13-01364-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c57/8470675/7fca1d4d11ad/pharmaceutics-13-01364-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c57/8470675/b5d896ba5939/pharmaceutics-13-01364-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c57/8470675/8f4b40023f94/pharmaceutics-13-01364-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c57/8470675/c1d956f4196c/pharmaceutics-13-01364-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c57/8470675/2a1a9a310b40/pharmaceutics-13-01364-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c57/8470675/21fa7c8e1913/pharmaceutics-13-01364-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c57/8470675/e424124c80d8/pharmaceutics-13-01364-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c57/8470675/da9890b5dbae/pharmaceutics-13-01364-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c57/8470675/b495f7e64318/pharmaceutics-13-01364-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c57/8470675/60df2c8dcf6e/pharmaceutics-13-01364-g011.jpg

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