Thermal Solvent-Free Method of Loading of Pharmaceutical Cocrystals into the Pores of Silica Particles: A Case of Naproxen/Picolinamide Cocrystal

Abstract

The degradation of drugs during melting was found to be one of the obstacles which restricts the application of the thermal solvent-free (TSF) method as a simple and efficient technique for loading active pharmaceutical ingredients (APIs) into the pores of mesoporous silica particles (MSPs). The naproxen (NPX) with melting point at 158 °C is an example of a drug which belongs to this group. In the current report we show that this limitation can be overcome by converting NPX into new crystallographic form by synthesis of cocrystal with significantly lower melting temperature as compared to pure compounds. In the course of the study it was found that picolinamide (PA) is an appropriate coformer which fulfills the assumed thermal requirements. NPX:PA cocrystal was obtained by grinding component forms of two polymorphs (α and β) which were fully characterized by solid-state NMR techniques, differential scanning calorimetry (DSC), and FTIR. The α polymorph of PA undergoes thermal-phase transition into form β below the melting temperature of 95 °C. Two MSPs with different size of pores, MCM-41 with 37 Å pore diameter and SBA-15 with pore diameter 100 Å, were tested as drug carriers. It has been found that during melting NPX:PA is embedded into the pores of SBA-15, while MCM-41 acts rather as a separation medium. It is concluded that effectiveness of the filling process is very likely related to complementarity between the size of the NPX:PA unit cell crystal and the dimension of MSP pores. The filling of pores was confirmed by adsorption−desorption of nitrogen measurements.

Manipulating the physical states of confined ibuprofen in SBA-15 based drug delivery systems obtained by solid-state loading: Impact of the loading degree

“…Namely, the impregnation method 27 which requires the use of toxic organic solvents for placing poorly water-soluble drugs in the liquid state and thus, is not consistent with a pharmaceutical application. On the other hand, adsorption of drug molecules into the pores after melting 23 can induce chemical degradation if the melting temperature is high 28 .…”

Enhanced Dissolution of Naproxen by Combining Cocrystallization and Eutectic Formation

“…(We note that more precise eutectic compositions could be obtained with a much lower heating rate of DSC.) Additionally, small endotherms related to the polymorphism of PA and INA are visible in the thermograms of neat PA, neat INA, and NPX/INA = 2:3 [ 28 , 29 , 30 ].…”

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.…”