Risperidone/Randomly Methylated β-Cyclodextrin Inclusion Complex-Compatibility Study with Pharmaceutical Excipients.

Laura Sbârcea,Renata-Maria Văruţ,Marinela Miclău,Denisa Cîrcioban,Adriana Ledeți,Gabriela Vlase,Oana Suciu,Ionuț-Mihai Tănase,Ionuț Ledeți,Paul Barvinschi

doi:10.3390/molecules26061690

Abstract

Risperidone (RSP) is an atypical antipsychotic drug used in treating schizophrenia, behavioral, and psychological symptoms of dementia and irritability associated with autism. The drug substance is practically insoluble in water and exhibits high lipophilicity. It also presents incompatibilities with pharmaceutical excipients such as magnesium stearate, lactose, and cellulose microcrystalline. RSP encapsulation by randomly methylated β-cyclodextrin (RM-β-CD) was performed in order to enhance drug solubility and stability and improve its biopharmaceutical profile. The inclusion complex formation was evaluated using thermal methods, powder X-ray diffractometry (PXRD), universal-attenuated total reflectance Fourier transform infrared (UATR-FTIR), UV spectroscopy, and saturation solubility studies. The 1:1 stoichiometry ratio and the apparent stability constant of the inclusion complex were determined by means of the phase solubility method. The compatibility between the supramolecular adduct and pharmaceutical excipients starch, anhydrous lactose, magnesium stearate, and cellulose microcrystalline was studied employing thermoanalytical tools (TG-thermogravimetry/DTG-derivative thermogravimetry/HF-heat flow) and spectroscopic techniques (UATR-FTIR, PXRD). The compatibility study reveals that there are no interactions between the supramolecular adduct with starch, magnesium stearate, and cellulose microcrystalline, while incompatibility with anhydrous lactose is observed even under ambient conditions. The supramolecular adduct of RSP with RM-β-CD represents a valuable candidate for further research in developing new formulations with enhanced bioavailability and stability, and the results of this study allow a pertinent selection of three excipients that can be incorporated in solid dosage forms.

Highlights

Risperidone (RSP), 3-[2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one (Figure 1), is a benzoxazole derivative used in treating schizophrenia, behavioral, and psychological symptoms of dementia and irritability associated with autism [1,2]
The apparent stability constant (K1:1 ) of the inclusion complex calculated from the slope of the phase solubility diagram, using Equation (1) is 173.38 ± 5.54 M−1 ; this value is within the range of 100 and 5000, which is considered ideal for the formation of an inclusion complex that may improve the bioavailability profile [39,40]
This study investigates the encapsulation of antipsychotic drug RSP by randomly methylated β-cyclodextrin (RM-β-CD)

Summary

Introduction

Risperidone (RSP), 3-[2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one (Figure 1), is a benzoxazole derivative used in treating schizophrenia, behavioral, and psychological symptoms of dementia and irritability associated with autism [1,2]. This atypical antipsychotic drug blocks the serotonin-2 (5TH2) and dopamine-2 (D2) receptors in the brain. System (BCS) [1,3,4] It exhibits the tendency of forming polymorphs [1], which could present different solubility, dissolution rates, and stability, leading to variations in the biopharmaceutical profile of its drug substance [5]. Among the various approaches used to enhance the solubility of BCS II class drugs, encapsulation of the active pharmaceutical substances in cyclodextrins is a valuable strategy [5]

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