Formulation and Delivery

Mitigating Nitrosamine Risk in Secondary Amine Drugs: A Formulation Case Study Using Low-Nitrite Microcrystalline Cellulose (MCC)

Partner Presentation Speaker(s)

• RM

  Raxit Mehta

  Technical Director
  Asahi Kasei America
  Chalfont, Pennsylvania
• SN

  Srinesh Naidu, MS

  Senior Scientist
  MSN Pharmaceuticals Inc.,
  Piscataway, New Jersey

Description: As per literature, drugs containing secondary amines are more susceptible to the formation of nitrosamine impurities. Among various mitigation strategies, the use of low-nitrite excipients—such as microcrystalline cellulose (MCC)—has emerged as a viable and effective approach to reduce nitrosamine levels. This case study focuses on hypertension drug containing secondary amine. Upon submission of ANDA, the FDA required a demonstration of control over nitrosamine levels detected in the drug product.

To address this, a reformulation strategy was implemented using low-nitrite MCC to reduce nitrosamine content below the acceptable intake (AI) threshold. Comprehensive evaluations were conducted on tablet characteristics, bulk and tap density, Hausner’s ratio, Carr’s index, drug release profiles, and nitrosamine levels post-reformulation. The switch to low-nitrite MCC resulted in a 40% reduction in nitrosamine impurities, successfully bringing them below the recommended AI limit.