Characterizing ¹³C Spectral Assignments and Substituent Distributions of Hydroxypropylmethylcellulose Acetyl Succinate Using Dynamic Nuclear Polarization Nuclear Magnetic Resonance Spectroscopy

Hydroxypropylmethylcellulose acetyl succinate (HPMC-AS) is the most widely used polymer in commercially available amorphous solid dispersions (ASDs), due to its ability to aid dissolution of poorly soluble drugs while impeding drug recrystallization. Nuclear magnetic resonance (NMR) spectroscopy is a well-suited approach to provide structural information on amorphous solids and access intermolecular interactions in multicomponent materials such as ASDs. The ¹³C spectral assignments for HPMC-AS differ in the literature, largely due to the significant structural complexity of this polymer, but are critical to identify drug-polymer interactions in ASDs containing HPMC-AS. A dynamic nuclear polarization (DNP) enhanced 2D ¹³C-¹³C refocused incredible natural abundance double quantum transfer experiment (INADEQUATE) spectrum is obtained to identify the one-bond ¹³C-¹³C connectivity in the polymer, which confirms the most recent ¹³C spectral assignments of HPMC-AS. Moreover, the spatial distribution of substituents in cellulose-based polymers is known to affect their physical properties and hence the dissolution or absorption of a formulated drug. Here, we use the definitive ¹³C spectral assignments of HPMC-AS and exploit the relayed-DNP of enhanced 1D cross-polarization (CP) spectra to determine that the HPMC-AS substituents are homogeneously distributed in three commercial grades of the polymer. Now, NMR experiments performed on ASDs containing HPMC-AS can more accurately correlate observed drug-polymer interactions to specific sites of the polymer. Therefore, a greater understanding into the mechanisms by which HPMC-AS stabilizes amorphous drugs.