Title: Long-acting injectable antipsychotics: Contemporary formulations andsynthesis methods

Abstract

In the current treatment of the psychotic disorders, the prevention of the relapse observed inthe patients is a critical issue, which significantly improves the quality of life. Non-compliance to the oral medication or the lack of insight result in the increasedhospitalization rates. At this point, the long-acting injectable (LAI) antipsychotic drugs possess a therapeutic potential to obtain significantly fewer hospitalization rates and relapses (p<0.5). The monthly injectables of the second-generation antipsychotics have indicated an improved efficacy together with the ability of slow release in the human body. The long-acting injectables of the second generation antipsychotics such as olanzapine, paliperidone and risperidonediffer much in their formulations in comparison to the conventional ones. LAI dosage form of olanzapine is the olanzapine pamoate preparation (Zyprexa Relprevv) is in theaqueoussolution; salt of olanzapineandpamoicacid is suspended in themicro-crystalline form. To produce the injectable formulation, the solvent extraction evaporation route is used followed by filtration. After injecting the solution of the drug and polymer into the aqueous phase, the microspheres are obtained through the stirring and filtrating. In order to apply the freeze drying, it is required to be suspended in a vehicle. The paliperidonepalmitate preparation (marketed as InvegaSustenna) contains nanocrystal molecules in an aqueous suspension. From the synthesis aspect, the particle size of the nanocrystals determines the saturation solubility, based on the larger surface area. Due to the poor solubility, in preparing the formulation, the parenteral solution is obtained using the fatty acid ester of the drug. LAI dosage form of risperidone (Risperdal Consta) is infact, the encapsulation of risperidone into biodegradable polymeric microspheres. A biocompatible polymer is used for preparing the formulation, which has been approved to be used for the human due to its low toxicity. The most common dosage forms of LAI require several techniques for the preparation of their formulations. In the present review, we will present an overview of the different synthesis methods used in these contemporary formulations and the major focus will be on the biodegradable polymeric microparticles, freeze/spray drying and the nanocrystal molecules related to the synthesis of LAI dosage forms of olanzapine, paliperidone and risperidone.