NMR Study of BA/FBA Cocrystal Confined Within Mesoporous Silica Nanoparticles Employing Thermal Solid Phase Transformation

Abstract

In this work, we report drug-loading procedure based on the solid state thermal transformation of a physical mixture of two ingredients: mesoporous silica nanoparticles (MSN) and an organic cocrystal. This procedure, known as the melting method, allows loading of the guest species into the host pores with high yield and an equimolar ratio of both components of the cocrystal. The study was carried out with commercial MSNs (MCM-41 and SBA-15) and a cocrystal consisting of equimolar amounts of benzoic acid (BA) and fluorinated benzoic acid (FBA). The BA/FBA sample was obtained by grinding crystalline acids. The structural constraints and molecular dynamics of BA/FBA in the crystal lattice were characterized employing 19 F magic angle spinning (MAS), 13 C MAS, 1 H very fast (VF) MAS with sample rotation at 60 kHz, 2D NMR, 19 F− 19 F BABA, and 1 H− 19 F HETCOR correlations. We conclude that the system is very rigid with short distances between intermolecular aromatic layers. In contrast, BA/FBA loaded into MCM-41 and SBA-15 is very mobile in a broad range of temperatures. The structure and molecular dynamics of the guest assembly trapped in the MSN pores was established by 1 H MAS, 19 F MAS, 1 H− 19 F HOESY MAS and 19 F T 2 ′ relaxation time measurements as well as 2 H MAS. We conclude that the filling factor for the melting method, defined as the ratio of BA/FBA to MSN (weight to weight), is much higher compared to those for commonly used wet procedures. These results show new perspectives for future applications of MSNs as carriers of pharmaceutical cocrystals.

Nanocrystallization of Rare Tolbutamide Form V in Mesoporous MCM-41 Silica

“…[18][19][20] Therefore, application of methods sensitive to the local environment of atoms (namely solid-state NMR) is of high importance for molecular-level understanding of crystallisation and phase transitions of pharmaceuticals. [21][22][23][24] Recently we have demonstrated controllable crystallisation and stabilisation of metastable indomethacine form V inside the 30 nm pores of MCF material (Mesoporous Cellular Foam). 18 Furthermore, we developed a 19 F MAS NMR protocol to probe the local environment of confined flufenamic acid in situ and showed for the first time the simultaneous presence of confined molecules as nanocrystalline, amorphous and highly mobile species adsorbed at the silica surface during confined crystallisation.…”

Encapsulation of drug into mesoporous silica by solvent evaporation: A comparative study of drug characterization in mesoporous silica with various molecular weights

“…Recently, about 90% of drug candidates, currently under development, possess low aqueous solubility and high hydrophobicity characteristics ( Dening and Taylor, 2018 ). Therefore, formulation strategies are required to enhance drug solubility and improve absorption from the gastrointestinal tract, especially in the formulation of oral administration ( Skorupska et al., 2015 ). Some of the strategies adopted to improve oral bioavailability include the use of additives such as surfactants or complexing agents, salts ( Takano et al., 2010 ), and amorphous solid dispersions ( Almeida E Sousa et al., 2016 ).…”

Structural variety of heterosynthons in linezolid cocrystals with modified thermal properties

“…MSNs may increase drug solubility and/ or change its pharmacokinetics, as well as serve as sustained release systems, decreasing the risk of side-effects caused by one-time release of a high dosage of a drug (Manzano & Vallet-Regí, 2019;Jafari et al, 2019). To load a given API into MSNs a number of methods have been introduced, including the solid-state based thermal solvent-free approach (Mellaerts et al, 2008;Limnell et al, 2011;Skorupska et al, 2015Skorupska et al, , 2016. It is based on transforming a crystal of an API into the melt phase in the presence of silica carriers, which leads to recrystallization of a drug inside the pores.…”