Understanding Molecular Interactions in Rafoxanide–Povidone Amorphous Solid Dispersions from Ultrafast Magic Angle Spinning NMR

Abstract

In solid dosage formulations, probing intermolecular interactions between active pharmaceutical ingredients (APIs) and polymeric excipients, which have a mechanistic impact on physical stability as well as bioavailability, remains a challenge. In recent years, solid-state NMR spectroscopy has been demonstrated to be a powerful tool to provide structural details with an atomic resolution of therapeutic organic compounds and formulation products. However, conventional 13 C-detected techniques often suffer from poor resolution and low sensitivity due to the disordered structure of certain materials such as amorphous pharmaceuticals and 13 C natural abundance, hindering in-depth investigations. In this study, we utilize the magic angle spinning (MAS) technique with ultrafast speeds (UF-MAS: ν R = 60 and 110 kHz) and demonstrate the enabled methods with 1 H detection to study the amorphous molecular complex of rafoxanide and povidone in the solid state. The downfield shift of the RAF amide proton, resolved under UF-MAS, and its correlations with aliphatic protons of PVP, serve as strong evidence of the existence of intermolecular hydrogen bonding. Two-dimensional (2D) 1 H-detected 1 H{ 13 C} and 1 H− 1 H correlation experiments, interestingly, exhibit distinct API−polymer interactions in the spray-dried amorphous solid dispersions (ASDs), utilizing aqueous and organic cosolvents and organic solvents mixtures. The rich intermolecular interactions in the aqueously prepared ASDs presumably contribute to the physical stability, and the interactions are retained in the solution state to maintain supersaturation for an enhanced dissolution profile. This study presents the first application of UF-MAS NMR characterization of therapeutic solid dosages at a spinning frequency of 110 kHz and uncovers the molecular mechanisms of solvent-mediated pharmaceutical dispersions.

Drug–Polymer Interactions in Acetaminophen/Hydroxypropylmethylcellulose Acetyl Succinate Amorphous Solid Dispersions Revealed by Multidimensional Multinuclear Solid-State NMR Spectroscopy

“…The change in the 15 N chemical shift and broadening of the 15 N spectra observed between crystalline and amorphous species suggests a different hydrogen-bonding network and intramolecular interactions ( Table 2 ). 42 , 45 , 74 The 15 N CP spectrum of the 40 wt % ASD shows a single resonance at −243 ppm (FWHM of 24 Hz) at the same chemical shift for crystalline form I and likely arises from acetaminophen that underwent recrystallization during data acquisition. Although acetaminophen forms I and II in the 40 wt % ASD have been observed in both PXRD and 13 C NMR data, the two expected 15 N signals are not resolved at 9.4 T, likely due to their very similar chemical shift values only separated by 0.4 ppm.…”

“…It has been demonstrated that the deprotonation effect, promoted by the solvent during the spray dry process, might impact API–polymer interactions. 45 It is well known that evaluation of the length scale of spin diffusion allows the degree of mixture miscibility to be determined by recording the 1 H relaxation times of all components. 75 − 78 1 H T 1 and T 1ρ values have therefore been measured for the API and polymer in the ASD ( Tables SI-4 and SI-6 ) and revealed that, for the 20 wt % formulation, they are similar (e.g., 1 H T 1 values for H d a and H 1 are 1.7 ± 0.2 and 1.9 ± 0.3 s, respectively, and 1 H T 1ρ (H d a ) = 3.8 ± 1.1 ms ≈ 1 H T 1ρ (H 1 ) = 4.4 ± 0.3 ms at a spin-lock frequency of 40 kHz), indicating that in the 2–5 nm length scale, 79 there is miscibility in the acetaminophen–HPMC-AS ASD.…”

“…In particular, in the field of pharmaceutical sciences, , NMR allows the determination of the structure of drugs and polymers . Recently, NMR has emerged as a robust approach in (pharmaceutical) amorphous dispersions to identity site-specific API–polymer intermolecular interactions from changes in chemical shift values. − For example, using one-dimensional (1D) and two-dimensional (2D) NMR experiments, electrostatic interactions and H-bonding were identified in amorphous posaconazole (POSA) dispersion in HPMC-AS and involved the POSA’s triazole and difluorophenyl ring moieties with some of the HPMC-AS’s substituent groups . The presence of π–π aromatic packing interaction between POSA and HPMC-phthalate (HPMC-P) amorphous dispersion has also been highlighted .…”

Structure determination of an amorphous drug through large-scale NMR predictions

“…Solid-state NMR is among the most popular methods to study the structure of amorphous materials. While two-dimensional correlation experiments are able to identify intermolecular contacts between atom pairs 15 – 17 , obtaining complete atomic-level structures is a challenge due to the disordered molecular environments present in amorphous solids.…”

New insights into the use of hydroxypropyl cellulose for drug solubility enhancement: An analytical study of sub‐molecular interactions with fenofibrate in solid state and aqueous solutions

“…Hence, the study of these excipients is valuable in terms of product quality control and evaluation of long‐term stability. Furthermore, the precise method of their preparation serves to modulate specific aspects at the molecular level, including the miscibility of the components, [ 1 ] and the strength of interactions between components, either in the solid [ 2 ] or aqueous [ 3 ] states, thereby enhancing various properties, such as drug solubility in water, which can impact the performance of the drug formulation.…”