Justification of the solvent choice for the industrial amizon substance production


  • V. A. Georgiyants
  • V. N. Kushniruk
  • N. V. Garnaya




Amizon, Synthesis, Quality Control, Solvents



In recent years, the rapid development gets implementing principles of quality management in the pharmaceutical industry. It should be noted that instead of the mechanical control of the quality associated with the chemical characteristics of pharmaceutical substances and drugs innovative ways to ensure the quality associated primarily with the understanding of the processes occurring during the manufacturing process come.

Objective: To study solvent selection for the industrial production of methiodide benzyl amide isonicotinic acid substance considering the conception “Quality by design”.


Solution of 0.1 moles of isonicotinic acid in 0.12 moles of benzylamine was heated at 160-185°C during 4-5 hours while distilling off water and excess benzylamine. The resulting melt - cooled isonicotinic acid benzylamide was dissolved in acetone and filtered. It was used in further synthesis without further purification.

0.1 moles of isonicotinic acid benzylamide was dissolved in0.6 litersof a suitable solvent and 0.12 mole of methyl iodide was added to the solution at room temperature. The mixture was heated at 40-50 ° C for 3-4 hours, the reaction mixture was cooled, filtered the product was dried.

After calculating the aim product was recrystallized from an appropriate solvent. Isonicotinic acid benzylamide iodomethylate quantitative content was determined by acid-base titration in non-aqueous medium (fixing the endpoint - potentiometrically). The impurity content benzylamide isonicotinic acid – by HPLC.


When solvent have been chosen we took into account previously developed scheme of laboratory synthesis. We guided primarily data about security and efficiency.

The least toxic solvents conventionally used in pharmaceutical production , included 2- propanol and ethanol (limit of residual amounts of these solvents, allowable HFC substances was 0.5 % and 1 %, respectively). Therefore, these solvents as the most similar in their properties and acceptable cost, we considered for possible use in industrial amizone production. In the first phase the solubility of the intermediate (Bink) and amizone in these solvents were studied. It was found that substance was very slightly soluble in cold organic solvents and was easily soluble in boiling. Water adding to these solvents in various ratios significantly improved solubility, and the best solubility, as expected, had water.

To justify the choice of solvents for the first and second stage of the synthesis and crystallization an experimental study of the efficacy of using ethanol, acetone and 2-propanol in various processes of synthesis was done. Thus the yield of final product was evaluated and the amount of associated impurities before and after crystallization was measured. It was proved that at the synthesis stage it is expedient to use 2-propanol and as crystallization solvent – ethanol.


1. Experimental studies for the justification for the choice of solvent for the industrial synthesis of isonicotinic acid benzylamide iodomethylate substance considering QbD concepts and classes of toxic solvents were done.

2. It was established that in the synthesis is optimal to use 2-propanol and for crystallization - ethanol.



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How to Cite

Georgiyants VA, Kushniruk VN, Garnaya NV. Justification of the solvent choice for the industrial amizon substance production. Zaporozhye Med J [Internet]. 2014Sep.5 [cited 2023Dec.5];(4). Available from: http://zmj.zsmu.edu.ua/article/view/27450



Problems of pharmacy