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Compatibility studies with pharmaceutical excipients for aripiprazole–heptakis (2,6-di-O-methyl)-β-cyclodextrin supramolecular adduct

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Abstract

Aripiprazole (ARP) is one of the newest antipsychotic drugs, exhibiting very low aqueous solubility and high lipophilicity. Considering the necessity of improvement of ARP physicochemical properties and its biopharmaceutical profile, cyclodextrin complexation of the drug substance was performed. As selected cyclodextrin, a functionalized β-cyclodextrin was used, namely heptakis(2,6-di-O-methyl)-β-cyclodextrin (DIMEB), and the supramolecular adduct ARP/DIMEB was prepared by kneading technique and characterized using thermoanalytical tools (TG—thermogravimetry/DTG—derivative thermogravimetry/HF—heat flow), powder X-ray diffractometry patterns (PXRD), universal-attenuated total reflectance Fourier transform infrared (UATR-FTIR) and UV (ultraviolet) spectroscopy and, as well, saturation solubility studies. Job’s method was used for the stoichiometry of APR/DIMEB inclusion complex determination, which was found to be 1:2. Molecular modeling studies were complementary realized as to get a view over the way that ARP is hosted inside the cyclodextrin. The compatibility between the inclusion complex and some common pharmaceutical excipients, namely starch, magnesium stearate, lactose monohydrate, microcrystalline cellulose and methylcellulose, has been evaluated by means of thermal methods of analysis (TG/DTG/HF), UATR-FTIR spectroscopy and PXRD pattern. The preformulation data regarding the compatibility of ARP/DIMEB complex with selected excipients suggested that under ambient conditions, chemical interactions are observed solely between ARP/DIMEB inclusion complex and magnesium stearate, as indicated by the UATR-FTIR spectroscopy. The incompatibility in the system ARP/DIMEB + MgS is also confirmed by the PXRD study, this second investigational technique revealing also the advanced amorphization of components during mixing of complex with starch, microcrystalline cellulose and methylcellulose, but without indicating interactions. Later on, under thermal stress, thermally induced interactions occur between the components in the systems containing magnesium stearate and methylcellulose, while starch, microcrystalline cellulose and lactose can be safely used as excipients in developing solid formulations containing ARP/DIMEB inclusion complex as active pharmaceutical ingredient.

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Authors and Affiliations

  1. Faculty of Industrial Chemistry and Environmental Engineering, Politehnica University of Timișoara, Vasile Parvan Street 6, 300223, Timisoara, Romania

    Ionuț-Mihai Tănase & Ionuţ Ledeţi

  2. Department of Drug Analysis, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041, Timisoara, Romania

    Laura Sbârcea

  3. Department of Analytical Chemistry, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041, Timisoara, Romania

    Adriana Ledeţi & Denisa Cîrcioban

  4. Faculty of Physics, West University of Timişoara, 4 Vasile Pârvan Blvd, 300223, Timisoara, Romania

    Paul Barvinschi

  5. Research Center for Thermal Analysis in Environmental Problems, Faculty of Chemistry-Biology-Geography, West University of Timisoara, 16 Pestalozzi Street, Timisoara, Romania

    Gabriela Vlase

  6. Department of Physical Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy Craiova, 2-4 Petru Rares Str, 200349, Craiova, Romania

    Renata-Maria Văruţ

  7. Department of Physical Chemistry, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041, Timisoara, Romania

    Ionuţ Ledeţi

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  1. Ionuț-Mihai Tănase
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Tănase, IM., Sbârcea, L., Ledeţi, A. et al. Compatibility studies with pharmaceutical excipients for aripiprazole–heptakis (2,6-di-O-methyl)-β-cyclodextrin supramolecular adduct. J Therm Anal Calorim 142, 1963–1976 (2020). https://doi.org/10.1007/s10973-020-09901-7

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