What Did the Patent for the Synthesis of Highly Purified Trazodone Bring?

Introduction

In the production of pharmaceuticals, it is always necessary to account for the fact that the final product will never be 100% pure. The aim of the conditions and course of the synthesis is to approximate this ideal state; however, medicinal substances usually contain certain amounts of impurities. These can be impurities of the starting materials, intermediates of chemical reactions, or residues of reactants entering the synthesis. Each medicinal substance has an approved limit of the content of precisely defined impurities. These may exhibit biological effects, and therefore it is necessary to identify and quantify them in the manufacturing process. It is also important to test and analyze their potential impact on the human organism.

Multimodal Trazodone and Its Production

Trazodone is classified among multimodal antidepressants with combined serotonergic activity. It is an antagonist of the serotonin receptor 5-HT_2A and a serotonin reuptake inhibitor (SARI). At low doses, it acts as a hypnosedative, while at higher doses, its antidepressant effect manifests.

Trazodone is most commonly used in the form of hydrochloride (trazodone-HCl). The synthesis of trazodone and trazodone-HCl consists of several intermediate steps – reactions in which alkylating agents with proven or suspected genotoxicity enter as reactants, the residues of which can be found in the final product. Angelini's patent filed in 2008 represents an optimization of the synthesis, achieving highly purified trazodone and trazodone hydrochloride with < 15 ppm of these genotoxic substances. Earlier registered patents described several methods of producing trazodone or trazodone-HCl, but none allowed the product to be obtained with a lower concentration of alkylating agents. The latest patent thus offers the advantage of eliminating these residues while maintaining a high yield of the synthesis.

Occurrence of Alkylating Agents in the Final Product

Alkylating agents cause changes in the structure of DNA and its expression. High exposure to these substances increases the risk of developing cancer, and therefore it is desirable to achieve as low as possible content of these substances in the final product through available technological processes.

The toxicological threshold for the ingestion of these substances is 1.5 μg per day. With an expected daily dose of 100 mg of trazodone-HCl, an acceptable amount of residual alkylating agents is < 15 ppm. However, if we consider a patient taking a maximum daily dose of 600 mg of trazodone-HCl/day, it is necessary to achieve an even lower amount of residues in the product, namely < 2.5 ppm.

Description of the Patent

The most common impurities present in the manufactured trazodone are 2,2-dichloroethylamine, 1-bromo-3-chloropropane, and N-(3-chlorophenyl)-N’-(3-chloropropyl)-piperazine. Chemists at Angelini found that adding a basic aqueous solution to a solution of trazodone in an organic solvent significantly reduces the residues of these alkylating agents in the trazodone solution. The patent thus describes and further specifies a purification process consisting of the following steps:

• Preparation of the organic phase containing trazodone in at least one organic solvent;
• Preparation of the aqueous phase containing at least one basic compound;
• Heating at a temperature of at least 40°C for at least 30 minutes;
• Separating the organic phase from the aqueous phase to obtain trazodone;
• Acidification of the obtained trazodone with hydrochloric acid to obtain trazodone hydrochloride.

High Purity of the Obtained Trazodone

The production process according to this patent allows for a clear reduction in the content of harmful alkylating agents in the final product to < 15 ppm. Adhering to technological processes can achieve purified trazodone with an alkylating agents content below 10 ppm or even below 2.5 ppm. Under ideal conditions, the process allows the reduction of genotoxic alkylating agents in the final product to < 1 ppm. In addition to significant reduction in the content of genotoxic substances, a high yield of the final product is also maintained, above 85%, ideally above 90%.

Conclusion

The production of highly purified trazodone by patent-determined methods ensures high yield with a maximum concentration of genotoxic alkylating agents < 15 ppm.

(lexi)

Source: Marchetti M., Iacoangeli T., Ciottoli G. B., Biondi G. Trazodone and trazodone hydrochloride in purified form. EP2178850B1. Aziende Chimiche Riunite Angelini Francesco, 2014.