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In this work, we compared two methods (incipient wetness and melting) for the encapsulation of ibuprofen in the pores of Mobil Crystalline Material 41 (MCM-41) through NMR (nuclear magnetic resonance) spectroscopy. (1)H NMR spectra were recorded under very fast MAS (sample spinning 60 kHz) conditions in both 1D and 2D mode (NOESY sequence). We also performed (13)C cross-polarization magic angle spinning (CP/MAS) experiments, (13)C single pulse experiments (SPE), and (1)H-(13)C HSQC HR/MAS (heteronuclear single quantum coherence high resolution) HR/MAS correlations. Evaluation of the encapsulation methods included an analysis of the filling factor of the drug into the pores. The stability of Ibu/MCM in an environment of ethanol or water vapor was tested. Our study showed that melting a mixture of Ibu and MCM is a much more efficient method of confining the drug in the pores compared to incipient wetness. The optimal experiments for the former method achieved a filling factor of approximately 60%. We concluded that the major limitation to the applicability of the incipient wetness method (filling factor ca. 20%) is the high affinity of solvent (typically ethanol) for MCM-41. We found that even ethanol vapor can remove Ibu from the pores. When a sample of Ibu/MCM was stored for a few hours in a closed vessel with ethanol vapor, Ibu was transported from the pores to the outer walls of MCM. We observed a similar phenomenon with water vapor, although this process is slower compared to the analogous procedure using ethanol. Our study clearly demonstrates that existing methods used to encapsulate drugs in mesoporous silica nanoparticles (MSNs) require reevaluation.

Grinding and melting methods were employed for synthesis of pharmaceutical cocrystals formed by racemic (R/S) and entiomeric (S) ibuprofen (IBU) and nicotinamide (NA) as coformer. Obtained (R/S)-IBU:NA and (S)-IBU:NA cocrystals were fully characterized by means of advanced one- and two-dimensional solid state nuclear magnetic resonance (SS NMR) techniques with very fast magic angle spinning (MAS) at 60 kHz. The distinction in molecular packing and specific hydrogen bonding pattern was clearly recognized by analysis of H,C, and N spectra. It is concluded from these studies that both methods (grinding and melting) provide exactly the same, specific forms of cocrystals. Thermal solvent-free (TSF) approach was used for loading of (R/S)-IBU:NA and (S)-IBU:NA into the pores of MCM-41 mesoporous silica particle (MSP). The progress and efficiency of this process was analyzed by NMR spectroscopy. It has been confirmed that TSF method is an effective and safe technique of filling the MSP pores with active pharmaceutical ingredients (APIs). By analyzing the NMR results, it has been further proved that excess of IBU and NA components, which are not embedded into the pores during melting and cooling, crystallize on the MCM-41 walls preserving very specific arrangement, characteristic for crystalline samples. By investigating kinetic of release for (R/S)-IBU/MCM-41, (S)-IBU:NA/MCM-41, and (R/S)-IBU:NA/MCM-41 samples containing active components exclusively inside of the pores, it was revealed that release of IBU is much faster for the first of the samples compared to those containing IBU and NA inside the pores. The hypothesis that the rate of release of API can be controlled by specific composition of cocrystal embedded into the MSP pore was further supported by study of (R/S)-IBU:BA/MCM-41 sample with benzoic acid (BA) as coformer.

In this paper we report the influence of stereochemistry on self-organization in the solid state of cyclic dipeptides (CDP) employing two diastereomeric samples cyclo­(l-Tyr-l-Ala), cYA 1, and cyclo­(l-Tyr-d-Ala), cY­(D)­A 2, as models. Both compounds were investigated by means of differential scanning calorimetry (DSC), solid state NMR (SS NMR) spectroscopy, scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), electronic circular dichroism (ECD) spectroscopy, and attenuated total reflectance Fourier transform infrared spectroscopy (ATR–FTIR). It has been found that distinction in chirality of alanine residue causes a significant difference in self-assembling and formation of higher order structures. Sample 1 forms peptide nanotubes (PNT) and nanowires (PNW), while for sample 2 only formation of peptide microtubes (PMT) was observed. Crystal and molecular structures for 1 and 2 were refined using PXRD due to failure in attempts to grow crystals with quality suitable for single crystal studies. Both compounds crystallize in the P21 space group and monoclinic system. The size of the unit cell is highly similar; however small differences in alignment of water molecules in the hydrophilic channels and geometry of diketopiperazine rings were observed. Each technique confirmed high thermal stability of PNT, PNW, and PMT under investigation. The water molecules can be thermally removed from the lattice without destroying the subtle crystal structures of nano- and microdevices. This reversible process observed for sample 2 is a unique feature, rarely occurring for the linear dipeptide devices.

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.

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.

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