RESUMEN
Considering the health relevance of Chagas' disease, recent research efforts have focused on developing more efficient drug delivery systems containing nifurtimox (NFX). This paper comprehensively investigates NFX through conformational analysis and spectroscopic characterization. Using a conformer-rotamer ensemble sampling tool (CREST-xtb), five distinct conformers of NFX were sampled within a 3.0 kcal mol-1 relative energy window. Subsequently, such structures were used as inputs for geometry optimization by density functional theory (DFT) at B3LYP-def2-TZVP level of theory. Notably, harmonic vibrational frequencies were calculated to establish an in-depth comparison with experimental results and existing literature for the NFX or similar molecules and functional groups, thereby achieving a widely reasoned assignment of the mid-infrared band absorptions for the first time. Moreover, UV-VIS spectra of NFX were obtained in several solvents, enabling the determination of the molar absorptivity coefficient for the two electronic transitions observed for NFX. Among the aprotic solvents, a bathochromic effect was observed in the function of the dielectric constants. Furthermore, a hypochromic effect was observed when the drug was dissolved in protic solvents. These findings offer crucial support for new drug delivery systems containing NFX while demonstrating the potential of spectrophotometric studies in establishing quality control assays for NFX drug products.
Asunto(s)
Enfermedad de Chagas , Conformación Molecular , Nifurtimox , Enfermedad de Chagas/tratamiento farmacológico , Nifurtimox/química , Espectrofotometría Ultravioleta , Tripanocidas/química , Modelos Moleculares , Teoría Funcional de la Densidad , Trypanosoma cruzi/efectos de los fármacos , Solventes/químicaRESUMEN
Despite nifurtimox (NFX) being a traditional drug for treating Chagas disease, some of its physicochemical properties are still unknown, especially its thermal behavior, which brings important outcomes regarding stability and compatibility. In this work, a comprehensive study of NFX's thermal properties was conducted to assist incremental innovations that can improve the efficacy of this drug in novel pharmaceutical products. For this purpose, thermal analyses associated with spectroscopy and spectrometry techniques were used. DSC analyses revealed that the melt crystallization of the NFX led to its amorphous form with the possible formation of a minor fraction of a different crystalline phase. Coats-Redfern method using TGA results indicated the activation energy of NFX non-isothermal degradation as 348.8 ± 8.2 kJ mol-1, which coincides with the C-NO2 bond dissociation energy of the 2-nitrofuran. Investigation of the isothermal degradation kinetics using FTIR 2D COS showed the possible detachment of radical NO2 and ethylene from the NFX structure, which could affect its mechanism of action. A preliminary mechanism for the thermal degradation of this drug was also proposed. The results enhanced the understanding of NFX's thermal properties, providing valuable insights, especially for developing NFX-based pharmaceutical products that involve thermal processing.
Asunto(s)
Nifurtimox , Nitrofuranos , Nifurtimox/metabolismo , Nifurtimox/uso terapéutico , Cristalización , Dióxido de Nitrógeno , Preparaciones FarmacéuticasRESUMEN
INTRODUCTION: Although the administration of drugs on the skin is a safe and noninvasive therapeutic alternative, producing formulations capable of disrupting the cutaneous barriers is still a challenge. In this scenario, extrusion-based techniques have emerged as disruptive technologies to ensure unique drug-excipient interactions that facilitate drug skin diffusion for systemic or local effect and even mean the key to obtain viable industrial products. AREAS COVERED: This article presents a comprehensive overview of extrusion-based techniques in developing pharmaceutical dosage forms for topical or transdermal drug delivery. First, the theoretical basis of how extrusion-based techniques can optimize the permeation of drugs through the skin is examined. Then, the current state-of-the-art of drug products developed by extrusion-based techniques, specifically by hot-melt extrusion (HME) and fused deposition modeling (FDM) 3D printing, are discussed and contrasted with the current pharmaceutical processes. EXPERT OPINION: A wide variety of pharmaceutical products can be obtained using HME and FDM 3D printing, including new dosage forms designed for a perfect anatomical fit. Despite the limitations of pharmaceutical products produced with HME and FDM 3D printing regarding thermal stability and available excipients, the advantages in industrial adaptability and improved bioavailability allied with patient-match devices certainly deserve full attention and investment.
Asunto(s)
Tecnología de Extrusión de Fusión en Caliente , Tecnología Farmacéutica , Humanos , Tecnología Farmacéutica/métodos , Preparaciones Farmacéuticas , Composición de Medicamentos/métodos , Administración Cutánea , Excipientes , Liberación de Fármacos , Sistemas de Liberación de Medicamentos/métodos , ComprimidosRESUMEN
The in-situ formation of nanoparticles from polymer-based solid medicines, although previously described, has been overlooked despite its potential to interfere with oral drug bioavailability. Such polymeric pharmaceuticals are becoming increasingly common on the market and can become even more popular due to the dizzying advance of 3D printing medicines. Hence, this work aimed to study this phenomenon during the dissolution of 3D printed tablets produced with three different polymers, hydroxypropylmethylcellulose acetate succinate (HPMCAS), polyvinyl alcohol (PVA), and Eudragit RL PO® (EUD RL) combined with plasticizers and the model drug naringenin (NAR). The components' interaction, dissolution behavior, and characteristics of the formed particles were investigated employing thermal, spectroscopic, mechanical, and chromatographic assays. All the systems generated stable spherical-shaped particles throughout 24 h, encapsulating over 25% of NAR. Results suggest encapsulation efficiencies variations may depend on interactions between polymer-drug, drug-plasticizer, and polymer-plasticizer, which formed stable nanoparticles even in the drug absence, as observed with the HPMCAS and EUD RL formulations. Additionally, components solubility in the medium and previous formulation treatments are also a decisive factor for nanoparticle formation. In particular, the treatment provided by hot-melt extrusion and FDM 3D printing affected the dissolution efficiency enhancing the interaction between the components, reverberating on particle size and particle formation kinetics mainly for HPMCAS and EUD RL. In conclusion, the 3D printing process influences the in-situ formation of nanoparticles, which can directly affect oral drug bioavailability and needs to be monitored.