Recrystallization can stop nitrosamine formation in ranitidine hydrochloride

Abstract

Nitrosamines were first identified in the 1950s as carcinogenic contaminants in food, tobacco, and industrial chemicals. Among them, N-nitrosodimethylamine (NDMA) is particularly dangerous due to its high carcinogenicity and frequent occurrence in drugs, such as ranitidine hydrochloride. Recent studies indicate that NDMA formation in solid-state ranitidine hydrochloride is driven by solid-state reactive species (SSRS), such as crystal defects, amorphous regions, and other high-energy sites within the drug crystal. In this paper, we demonstrate that NDMA formation in ranitidine hydrochloride can be essentially stopped by reducing the presence of SSRS in the drug substance through recrystallization. Well-controlled recrystallized ranitidine hydrochloride that resulted in high-quality crystals exhibited significantly lower NDMA formation compared to as-received material when stored at 60 °C and <2% relative humidity. Cryoground samples showed substantially increased reactivity, whereas subsequent well-controlled recrystallization restored stability, confirming the critical role of crystal quality. In contrast, poorly controlled recrystallization produced low-quality crystals with elevated SSRS, leading to higher degradation rates. These results eventually motivated us to test the role of oxygen in the degradation process for ranitidine hydrochloride. Cryoground ranitidine hydrochloride samples exhibited minimal reactivity under vacuum or nitrogen, elevated reactivity in air (∼21% oxygen), and the highest nitrosamine formation in an oxygen-rich environment. These results suggest that well-controlled crystallization that produced high-quality crystals may be an extremely effective method to inhibit nitrosamine formation, as SSRS are needed to promote reactivity, and could be an alternative and/or complementary approach to the current strategy of adding antioxidants and/or pH modification to formulations to minimize nitrosamine formation.

Introduction

Nitrosamines were first identified in the 1950s as carcinogenic contaminants in food, tobacco, and industrial chemicals, prompting initial investigation into their widespread presence in the environment and potential health risks.1, 2, 3, 4, 5 While these concerns have existed for decades, attention to nitrosamines has been renewed in recent years due to their detection in pharmaceutical products and their degradants. Nitrosamines found in pharmaceutical products are typically formed by the reaction between secondary or tertiary amines and nitrosating agents, such as sodium nitrite, a common impurity found in excipients and introduced during the manufacturing process.6, 7, 8, 9

N-nitrosodimethylamine (NDMA) has emerged as a nitrosamine of particular concern in the pharmaceutical industry due to its potent carcinogenicity and frequent detection in pharmaceutical products. The daily intake limit of NDMA is 96 ng/day or 0.32 ppm/day for ranitidine.10 The presence of NDMA in pharmaceutical products first drew attention in 2018, when it was detected in batches of valsartan, an angiotensin II report blocker (ARB), manufactured by Teva Pharmaceutical Industries.11 The source of the nitrosamine impurities was found in the drug substances that were manufactured by Zhejiang Huahai Pharmaceuticals (ZHP).12 Additional research indicated that NDMA was present in other ARBs such as losartan and irbesartan.13,14 In 2019, Emery Pharma conducted an independent investigation into the stability of ranitidine hydrochloride (commercial name Zantac) and found NDMA could be formed during storage of the ranitidine hydrochloride dosage forms after only a few days at 60 °C, and reported their results to the Food and Drug Administration. The results were particularly concerning because they challenged the existing assumption that nitrosamine contamination was primarily formed during drug synthesis and was stable thereafter.7

There have been several investigations into the cause of nitrosamine formation during stability studies of ranitidine hydrochloride. King et al. studied the stability of ranitidine hydrochloride in samples produced by two suppliers using three different crystallization methods. Two of the crystallization methods produced ranitidine hydrochloride that were relatively stable on storage, whereas a third method produced ranitidine hydrochloride that degraded ∼25× faster than samples produced using the other two methods. No specific analytical technique could identify differences between the samples, although scanning electron microscopy did reveal features that distinguished the stable from the unstable samples, specifically that columnar crystals were observed in the most stable samples, whereas spherical particulates were associated with samples showing a faster reaction rate.15 Harmon has also suggested that oxygen plays a key role in the degradation of ranitidine hydrochloride to form NDMA, and suggested that oxygen scavengers could be an effective mechanism for inhibiting NDMA formation.16

The current recommended strategy for reducing nitrosamine formation in products is to add antioxidants and/or pH modifiers to the formulation and to minimize the presence of nitrosating agents in excipients that may react with the drug substance that contains reactive amines.17, 18, 19, 20 While this strategy may be effective at minimizing nitrosamine formation, it requires adding components that may be problematic for the formulation and may require reformulating existing products to reduce nitrosamine formation. Other studies have suggested that nitrite levels in excipients influence nitrosamine formation. Reducing nitrite levels in excipients may therefore be a potential mitigation strategy.21, 22, 23 It should be noted that the FDA recently approved a reformulated ranitidine HCl product.24

We have recently shown that the degradation of ranitidine hydrochloride in the solid state is driven by the presence of solid-state reactive species (SSRS).25 SSRSs include crystal defects, amorphous regions, and other sites of degradation in a crystalline material. A ranitidine hydrochloride sample that was unreactive in the solid state was cryoground for 5–30 min, followed by storage for 16–24 days at 60 °C and <2% relative humidity. Ranitidine hydrochloride formed < 5 lt; 5 ppm of NDMA in either the unground drug substance or in tablets made from unground material, whereas ranitidine hydrochloride that was cryoground for 30 min formed ∼300 ppm and ∼900 ppm NDMA in the drug substance and drug product, respectively. Our results clearly showed that SSRSs were the cause of NDMA formation from ranitidine hydrochloride, but did not identify a mitigation strategy to inhibit degradation. In this paper, we show that it is possible to essentially stop the formation of NDMA from ranitidine hydrochloride by reducing the presence of SSRSs in the drug substance through seeded controlled recrystallizations.

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Materials

Ranitidine Hydrochloride (RAN, Sigma-Aldrich, St. Louis, MO, U.S.A), N-Nitrosodimethylamine (NDMA, Spex CertiPrep, Cranbury, NJ, U.S.A), Sucrose Anhydrous (Suc, Sigma-Aldrich, St. Louis, MO, U.S.A), Magnesium Stearate (MgSt, Spectrum, New Brunswick, NJ, U.S.A), Methanol (MeOH, Thermo-Fisher, Waltham, MA, U.S.A), and Toluene (Tol, Thermo-Fisher, Waltham, MA, U.S.A) were used as received.