Preparo e caracterização de coamorfos de olmesartan medoxomila para a produção de formulações farmacêuticas anti-hipertensivas

Abstract

Olmesartan medoxomil (OLM) is an antihypertensive drug classified as a Class II compound in the Biopharmaceutics Classification System (BCS), due to its low aqueous solubility and high membrane permeability. Cytosine (CYT) is a nitrogenous base present in DNA and RNA, and it is classified as a BCS Class I compound, exhibiting high aqueous solubility and high membrane permeability. The development of coamorphous drug systems, a subtype of solid dispersion (SD), has been beneficial for improving physicochemical properties such as aqueous solubility. This study aimed to obtain novel coamorphous systems through the interaction between OLM and CYT. Initially, molecular modeling was conducted using Density Functional Theory (DFT), employing the ωB97X-D functional and the 6 311++G(d,p) basis set. The Polarizable Continuum Model with the Integral Equations Formalism variant (IEFPCM), using methanol as solvent, was applied to obtain the energies of frontier molecular orbitals, which enabled the calculation of the main chemical reactivity indices of the compounds. Samples (binary OLM–CYT mixtures in molar ratios of 2.00:1.00; 1.75:1.00; 1.50:1.00; 1.25:1.00; 1.00:1.00 and 1.00:1.50) were prepared using the slow solvent evaporation (SSE) technique. Subsequently, the samples were characterized by powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FT-IR), thermogravimetry, derivative thermogravimetry, and simultaneous differential thermal analysis (TG/DTG-DTA), and differential scanning calorimetry (DSC). Aqueous solubility assays and in vitro dissolution were also performed. The DFT study indicated the predominant sites involved in the most intense intermolecular interactions between OLM and CYT. The electrophilic regions of OLM were mainly associated with hydrogen (H) atoms from the biphenyl group (C6H4-C6H4), propyl group (-CH2CH2CH3), hydroxyalkyl group (-CH2OH), tetrazolyl group (-CHN4), and ester group (C(=O)-O), which may interact with the nucleophilic regions of CYT located at the nitrogen (N) atoms of the primary (NH2), secondary (NH), and tertiary amine groups, and the oxygen (O) atom of the ketone carbonyl (C=O) group. PXRD results demonstrated the formation of amorphous materials at molar ratios of 1.75:1.00, 1.50:1.00, and 1.25:1.00, indicating the occurrence of intermolecular interactions between the starting compounds and the generation of coamorphous solid dispersions. FT-IR spectra of these coamorphous systems confirmed the presence of these interactions involving the ester C=O, the C-N bond of the tetrazolyl group, the aromatic C=C and C-H groups of the biphenyl structure in OLM, and the primary and secondary amine groups in CYT, as suggested by the DFT findings. These materials remained structurally stable for at least 200 days. TG/DTG curves of the coamorphous samples indicated good thermal stability up to 150.0 °C (Tonset). DTA and DSC thermograms showed no melting events, confirming the amorphous nature of these systems. Aqueous solubility assays demonstrated enhanced solubility of OLM in the OLM–CYT coamorphous systems at ratios of 1.75:1.00, 1.50:1.00, and 1.25:1.00, with increases of 33.4, 31.9, and 30.9 fold, respectively. In vitro dissolution studies showed that OLM dissolution efficiency in the coamorphous systems was 4.6-fold (DE30) and 2.8-fold (DE60) higher compared to the crystalline OLM raw material. Therefore, the coamorphous systems obtained in this study significantly contributed to the enhancement of OLM bioavailability and its therapeutic effectiveness in the pharmacological treatment of arterial hypertension.