Assessment of drug content uniformity of atropine sulfate triturate by liquid chromatography-tandem mass spectrometry, X-ray powder diffraction, and Raman chemical imaging.

Kei Moriyama,Natsuki Uozumi,Kazunobu Takayanagi,Kenichi Shimada,Akiko Okuda,Mayumi Yamashita,Yoichiro Takami,Takehito Kamei,Takashi Egawa,Rie Yokomizo

doi:10.1186/s40780-016-0038-7

Kei Moriyama, Natsuki Uozumi + Show 8 more

Open Access

https://doi.org/10.1186/s40780-016-0038-7

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Abstract

BackgroundAtropine sulfate is an anticholinergic agent for treatment of hypertrophic pyloric stenosis and is orally administrated as a triturate with lactose hydrate. Because of the low safety margin of atropine sulfate, triturate uniformity is a key safety factor. In this study, we assessed the uniformity of atropine sulfate in 1000-fold triturates prepared by wet mixing and dry mixing methods and discussed the cause of the difference in uniformity between two preparation methods.MethodsA 1000-fold triturate of atropine sulfate with lactose hydrate was prepared by two different methods: wet mixing and dry mixing. The wet mixing was performed according to Kurashiki Central Hospital protocol and the dry mixing was a simple physical mixing by a rocking mixer. The uniformity of atropine sulfate content in aliquots of a 1000-fold triturate with lactate hydrate was assessed by liquid chromatography–tandem mass spectrometry (LC–MS/MS) quantification. Solid-state analyses of the triturates by Raman chemical imaging and X-ray powder diffraction (XRPD) were performed to investigate the difference in uniformity.ResultsThe LC–MS/MS quantification showed that the uniformity of atropine sulfate in the 1000-fold triturate was excellent for wet mixing but was significantly variable for dry mixing. On the basis of the Raman chemical imaging and XRPD analyses, it was indicated that an amorphous thin film of atropine sulfate coated the surfaces of the lactose hydrate particles during wet mixing and contributed to the uniformity of the triturate. In contrast, clusters of the crystalline atropine sulfate were found in the dry mixing samples.ConclusionThe results showed that better atropine sulfate triturate uniformity was achieved using the wet mixing method rather than the dry method and the cause of the uniformity difference between two mixing methods was indicated by the multilateral assessment.

Highlights

Atropine sulfate is an anticholinergic agent for treatment of hypertrophic pyloric stenosis and is orally administrated as a triturate with lactose hydrate
Atropine sulfate was rarely detected by Raman chemical imaging in a 10 mm × 10 mm area of triturates prepared by the wet mixing method (Fig. 2a–c)
In this study, we found that much higher uniformity of atropine sulfate in the triturate was achieved using the wet mixing preparation method of Kurashiki Central Hospital than using the dry mixing method

Summary

Introduction

Atropine sulfate is an anticholinergic agent for treatment of hypertrophic pyloric stenosis and is orally administrated as a triturate with lactose hydrate. Atropine sulfate is an anticholinergic alkaloid that has been used to prevent muscarinic effects of anticholinesterases in adults [1] It has been used in an oral dosage form for treatment of infant hypertrophic pyloric stenosis [2]. Because of the large particle size of the crystalline atropine sulfate, it is believed that simple dry mixing with lactose hydrate causes poor uniformity of atropine sulfate in the triturate, and wide variation in the amount of drug that is dosed. To overcome this problem, some institutions including Kurashiki Central Hospital prepare the triturate using a wet mixing method: the crystalline atropine sulfate is dissolved in water followed by mixing of the solution with lactose hydrate and drying

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