(M1230-09-48) Role of Low Nitrite (LN) Excipients in Mitigating N-Nitrosamine Drug Substance-Related Impurity (NDSRI) Formation in Drug Products

Purpose: N-Nitrosamines, a class of chemical impurities and degradants, are a significant concern in the pharmaceutical industry. They arise from the reaction of endemic nitrites with vulnerable secondary amines that may be present in drug substances or other impurities left behind from the manufacturing process (Figure 1). N-Nitrosamines are either proven or highly suspected carcinogens. N-Nitrosamines found in drug products have thus become one of the fastest-growing causes of drug product recalls in the last decade. While the full scope of the dangers of these impurities is not fully understood, modes of control of their formation have become a focus of effort for pharmaceutical scientists. The primary control mode has so far included better purification of drug substances to remove vulnerable secondary amines' residual impurities. However, some drug substances contain the vulnerable secondary amine as part of the drug structure. In these cases, careful control of nitrite present in even a low-proportion excipient like crospovidone becomes a vital consideration.

Methods: Several formulations of Propranolol HCl 40 mg immediate-release tablets were manufactured to assess the efficacy of crospovidone type b ( < 15% on 63 µm screen), Polyplasdone™ XL-10 LN (nitrite < 100 ppb), and Ultra 10 (nitrite < 100 ppb, peroxide < 50 ppm) in mitigating the formation of N-Nitroso-propranolol (NNP) from Propranolol HCl. These formulations were compared against standard copovidone type b (Table 1). All tablets were characterized for dimensions, hardness, friability, and dissolution release profile. Dissolution testing was conducted in 900 mL of 0.1N HCl maintained at 37°C with USP Apparatus 1 (baskets) at 100 RPM with samples taken every 5 minutes up to 30 minutes, quantitation by UV detection at 289 nm. Tablets were stored at 40°C and 75%RH for 2 weeks and 1, 3, and 6 months in HIS sealed 60 cc HDPE bottles (to simulate aging up to 1.5 years) and tested for the presence of NNP, ensuring a comprehensive assessment of the potential impurity. NNP determination: Samples and standards were prepared in 15:85 water: methanol. LC/MS/MS was performed on an Agilent 6420 QQQ LC/MS with 1260 Infinity Binary Modular HPLC and MassHunter software.

Results: All tablet formulations were comparable in hardness, friability, disintegration time, and dissolution release profile. All tablets initially contained 0.3-0.4 ng of NNP per mg of API. Without aging, some NNP was present in all formulations at about the same ng/mg of API level. During the aging study, however, it was evident that tight control of nitrites in even the low-weight ratio contributors to the formulation can significantly affect the amount of NDSRIs formed. In this instance, the only excipient variable was the type of crospovidone, which was only 5% of the total formulation. When the nitrite level is restricted to < 100 ppb in the starting excipient, as in the case of XL-10 LN and Ultra-10 grades, the NNP formation rate is significantly reduced (Figure 3).

Conclusion: Propranolol HCl Tablet formulations with LN, Ultra, or standard crospovidone grades show similar tablet properties and dissolution profiles. After 3 months at aggressive storage conditions, the LN grade contributed less than 1.0 ng of NNP formation to the total formulation content. This indicates that the LN grade is the best choice for the APIs containing secondary amines.

References: Alberto Berardi, M. J. (2023). Modeling the Impact of Excipients Selection on Nitrosamine Formation towards Risk Mitigation. Pharmaceutics, 1-15.
European Medicines Agency. (1 July 2024). Acceptable intakes (AIs) established for N-nitrosamines. Amsterdam: the agency of the European Union.
Food and Drug Administration. (3/5/2024). FDA Recommended AI Limits for Certain Hypothetical NDSRIs. Rockville, MD: FDA Dockets Management Staff (HFA-305).

Figure 1: Propranolol to N-nitroso-propranolol (NNP), Acceptable Intake (AI) limits: EMA1 and FDA2; 1500 ng/day

Table 1: Propranolol HCl Formulations

Figure 2. NNP Growth in Propranolol HCl 40 mg tablets (240mg as average maximum dosage) under accelerated aging conditions (6-month data pending)