The Synthesis And Quality Investigation Of Iloperidone

Psychosis is a group of mental illnesses. The person suffering from psychosis loses touch with reality and his thought process, feelings, emotions and perceptions are altered. Schizophrenia is one of the most severe forms. Medicines are the major part of the treatment for psychosis. The typical antipsychotics, represented by chlorpromazine, usually develop sorts of side effects, such as extrapyramidal symptoms (EPS); Otherwise, the atypical antipsychotics medications such as Clozapine introduced in1970s, have found their effectiveness in treatment of resistant schizophrenia, and have less extrapyramidal symptoms and prolactin levels. Iloperidone is one of the atypical antipsychotics.The synthetic route for the preparation of iloperidone started from isonipecotic acid. After the N-formylation with formic acid and acetic anhydride, the Friedel-Crafts acylation was proceeded to give a ketone, which was converted into the oxime with hydroxylamine hydrochloride, then the oxime intermediate was reacted with1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone and potassium carbonate to give corresponding N-alkylation product. And an intramolecular cyclization was followed to give the iloperidone in the presence of potassium hydroxide. The operation is easy, and all the starting materials and reagents are commercially available. Furthermore, the by-products are avoided and the HPLC purity of the product is over98%.In this paper, the quality of iloperidone has been investigated based on the synthetic process, and the analytical methods for the materials and intermediates have also been developed. In the investigation, the purity and physical properties of iloperidone were tested, and the impurities including the materials, intermediates, by-products produced in the procedures were also detected, meanwhile, the degradation products were investigated when iloperidone was subjected to heat, light, and chemical stress. Based on those testing data, the drug substance is chemically stable except in the oxidation condition. The validated analytical procedures can be used to analyze the impurities and the purity of the product effectively.