Solid-State Spectroscopic Investigation of Molecular Interactions between Clofazimine and Hypromellose Phthalate in Amorphous Solid Dispersions

Abstract

It has been technically challenging to specify the detailed molecular interactions and binding motif between drugs and polymeric inhibitors in the solid state. To further investigate drug-polymer interactions from a molecular perspective, a solid dispersion of clofazimine (CLF) and hypromellose phthalate (HPMCP), with reported superior amorphous drug loading capacity and physical stability, was selected as a model system. The CLF-HPMCP interactions in solid dispersions were investigated by various solid state spectroscopic methods including ultraviolet-visible (UV-vis), infrared (IR), and solid-state NMR (ssNMR) spectroscopy. Significant spectral changes suggest that protonated CLF is ionically bonded to the carboxylate from the phthalyl substituents of HPMCP. In addition, multivariate analysis of spectra was applied to optimize the concentration of polymeric inhibitor used to formulate the amorphous solid dispersions. Most interestingly, proton transfer between CLF and carboxylic acid was experimentally investigated from 2D H-H homonuclear double quantum NMR spectra by utilizing the ultrafast magic-angle spinning (MAS) technique. The molecular interaction pattern and the critical bonding structure in CLF-HPMCP dispersions were further delineated by successfully correlating ssNMR findings with quantum chemistry calculations. These high-resolution investigations provide critical structural information on active pharmaceutical ingredient-polymer interaction, which can be useful for rational selection of appropriate polymeric carriers, which are effective crystallization inhibitors for amorphous drugs.

Physico-Chemical Properties, Aerosolization and Dissolution of Co-Spray Dried Azithromycin Particles with L-Leucine for Inhalation

“…Hence, breaking such intramolecular interactions can lead to the carbonyl peaks shifting towards higher wavenumber. Interestingly, hypsochromic shifts of Peak A (from 1513 to 1526 cm −1 ) and Peak B (from 1579 to 1584 cm −1 ) in the IR spectra of the co-spray dried formulation are noted (52,60). These blue shifts indicate the new molecular interactions are formed during the process of co-spray drying azithromycin with L-leucine.…”

“…Samples were analysed at a resolution of 4 cm −1 in the range on 400–4000 cm −1 . A background scan was collected prior to collecting the sample spectra to minimize the interferences of water and CO 2 signals (52). …”

Understanding Surface and Interfacial Chemistry in Functional Nanomaterials via Solid‐State NMR

“…We use this study as a representative case of how SSNMR can be used in these polymeric drug‐delivery systems. Many related studies have been carried out, for example, Aso et al employed 19 F NMR to study the molecular mobility of flufenamic acid in PVP or HPMC . Vogt and co‐workers studied APIs (acetaminophen, diflunisal, indomethacin) dispersed in different polymeric matrices, employing 1D and 2D NMR spectroscopy combined with 1 H T 1 measurements…”

“…Many recent SSNMR techniques are still waiting to be introduced into the workflow of the pharmaceutical industry. For example, ultrafast MAS and direct detection of protons can improve the detection of the ubiquitous 1 H nucleus, and the DNP technique can offer a better assessment of low‐natural‐abundance nuclei, such as 13 C and 15 N . Quantitative analysis has also been proven feasible with SSNMR spectroscopy under specific procedures, which is of enormous value to formulations development and quality control.…”

In situ solid‐state NMR characterization of pharmaceutical materials: An example of drug‐polymer thermal mixing

“…A variety of advanced methods have been utilized to characterize ASDs, [17] including powder X-ray diffraction, [18,19] differential scanning calorimetry (DSC), [20] infrared spectroscopy, [21,22] Raman spectroscopy, [4,21,23] rheology, [9] and solid-state nuclear magnetic spectroscopy (ssNMR). [24][25][26] In particular, ssNMR is an indispensable technique to analyze the structural details of drug-polymer interactions in the ASD systems at the molecular level. Several advanced multi-nuclei and multidimensional ssNMR strategies have been developed for the comprehensive study of molecular interactions.…”