Defense Date

2014

Document Type

Thesis

Degree Name

Master of Science

Department

Chemistry

First Advisor

Scott Gronert

Abstract

Clenbuterol Hydrochloride is a bronchodilator marketed as Spirospent® for Human Pharmaceuticals and as Ventipulmin® for Veterinary Pharmaceuticals by Boehringer Ingelheim.1 This research investigates formation of the 4-amino-α,α-dihydroxy-3,5-dichloroacetophenone impurity (Dihydroxy Impurity) in the synthesis of Clenbuterol Hydrochloride. The Dihydroxy Impurity has increased three-fold since the process was transferred to Boehringer Ingelheim Chemicals, Inc. in 1999.1 The Dihydroxy Impurity is proposed to be produced during an amination/reduction step from a reaction of water with the starting material.2 Additionally, the Dihydroxy Impurity can be formed by the reaction of water with an impurity, 4-amino-α,α-didibromo-3,5-dichloroacetophenone (Dibromo Impurity), that is generated in the previous step.2 The formation of the Dibromo Impurity was investigated through a series of Design of Experiments (DoE) analyses. The results from these analyses, presented within, determined the optimum bromination conditions to reduce the Dibromo Impurity. These conditions were able to reduce the Dibromo Impurity by 75%. A series of water spiking experiments with both the starting material of the amination/reduction step and the Dibromo Impurity were performed to investigate the formation of the Dihydroxy Impurity. Based on the results, a mechanism for the formation of the Dihydroxy Impurity is presented. The three-fold increase of the Dihydroxy Impurity was concluded to be due to ≥ 15% water in the amination reaction mixture reacting with the starting material. REFERENCES 1. Powner, T. H. Process Development Report: Preparation of Clenbuterol Hydrochloride USP, EP; Document No. DRCLEN Rev 0; Boehringer Ingelheim Chemicals, Inc.: Petersburg, VA, 2002; 1 – 194. 2. Brown, J. Clenbuterol Free Base C124A (Lot 1011974) Impurity; Boehringer Ingelheim Chemicals, Inc.: Petersburg, VA, 2007; 1 – 2.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

May 2014

Included in

Chemistry Commons

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