Atomic-Level Drug Substance and Polymer Interaction in Posaconazole Amorphous Solid Dispersion from Solid-State NMR

Abstract

Despite the wide utilization of amorphous solid dispersions (ASDs) for formulating poorly water-soluble drugs, fundamental understanding of the structural basis behind their stability and dissolution behavior is limited. This is largely due to the lack of high-resolution structural tools for investigating multicomponent and amorphous systems in the solid state. In this study, we present what is likely the first publication quantifying the molecular interaction between the drug and polymer in ASDs at an angstrom level by utilizing 19F magic angle spinning (MAS) nuclear magnetic resonance (NMR) techniques. A variant of the 19F–13C rotational-echo and double-resonance (REDOR) technique was developed to quantify interatomic distances by implementing a supercycled symmetry-based recoupling schedule and synchronized simultaneous detection. We successfully deployed the technique to identify “head-to-head” and “head-to-tail” packing of crystalline posaconazole (POSA). To probe molecular interactions between POSA and hypromellose acetate succinate (HPMCAS) in the dispersion, as a major goal of this study, two-dimensional (2D) 1H–19F correlation experiments were performed. The approach facilitated observation of intermolecular hydrogen-to-fluorine contacts between the hydroxyl group of the polymer and the difluorophenyl group of the drug substance. Atomic distance measurement, utilizing the developed 19F–13C REDOR technique, revealed the close proximity of 13COH–19F at 4.3 Å. Numerical modeling analysis suggested a possible hydrogen bonding interaction between the polymer O–H group as an acceptor and POSA fluorine (O–H···F) or difluorophenyl ring (O–H···Ph) as a donor. These 19F MAS NMR techniques, including 2D 19F–1H heteronuclear correlation and 19F–13C atomic distance measurement, may shed light on the nature (i.e., type and strength) of drug–polymer interactions in ASDs and offer a new high-resolution analytical protocol for probing the microstructure of amorphous pharmaceutical materials.

Recent Advances in the Application of Characterization Techniques for Studying Physical Stability of Amorphous Pharmaceutical Solids

“…A detailed 13 C SS-NMR deconvolution study showed that binary KET and poly (acrylic acid) (PAA) system exhibits higher prevalence of ionic and hydrogen bonds in comparison with its ternary system containing hydroxypropyl methyl cellulose (HPMC) [60]. In recent studies, two-dimensional (2D) ss-NMR was also developed to identify the type and strength of various drug-polymer interactions in ASDs with enhanced sensitivity and resolution [61,62]. Lu et al used 2D 1 H- 19 F ss-NMR to investigate the molecular interaction between the difluorophenyl group of posaconazole and the hydroxyl group of hydroxypropyl methylcellulose acetate succinate (HPMCAS) in the ASD.…”

“…Lu et al used 2D 1 H- 19 F ss-NMR to investigate the molecular interaction between the difluorophenyl group of posaconazole and the hydroxyl group of hydroxypropyl methylcellulose acetate succinate (HPMCAS) in the ASD. For hydrogen bond patterns, they proposed that the hydroxyl groups of HPMCAS act as acceptors while the fluorine or difluorophenyl rings of posaconazole act as donors [62]. Moreover, a 19 F- 13 C rotational echo and double resonance technique was used to measure the atomic dis- In recent studies, two-dimensional (2D) ss-NMR was also developed to identify the type and strength of various drug-polymer interactions in ASDs with enhanced sensitivity and resolution [61,62].…”

The Role of Hydrogen Bonding in Paracetamol–Solvent and Paracetamol–Hydrogel Matrix Interactions

“…The values of m 1 determined separately for aprotic (1)(2)(3)(4)(5)(6)(7)(8)(9) and protic (10-14) solvents, correlation coefficients and difference in the ground and excited state dipole moment (∆µ) obtained on the basis of McRae (MR), Bakhshiev (B), and Lippert and Mataga (LM) models are also summarized in Table 2.…”

“…To overcome these limitations, polymeric drug carriers are used in which the poorly soluble active substance is dispersed [4][5][6][7]. As was shown, the polymer can decrease the drug crystallization ability due to polymer-drug interactions (such as hydrogen bonding) by reducing drug mobility and limiting drug-drug molecular interactions [8][9][10]. Thus, intermolecular interactions between the drug and the polymer can improve the drug stability, and consequently its bioavailability.…”

High Sensitivity Detection of a Solubility Limiting Surface Transformation of Drug Particles by DNP SENS

“…It is a powerful structural probe, and has had many successes in solving chemical structures of active pharmaceutical ingredients (APIs), their polymorphic forms, [2][3][4][5][6][7][8][9] or of amorphous solid dispersions. 10,11 However, sometimes the active ingredient is present in low concentration (<mmol), and the inherently low sensitivity of SSNMR (due to the small difference in nuclear spin populations at ambient temperatures), prevents the acquisition of experiments in a timely manner.…”