Solid state nuclear magnetic resonance studies of hydroxypropylmethylcellulose acetyl succinate polymer, a useful carrier in pharmaceutical solid dispersions

Abstract

Hydroxypropylmethylcellulose (HPMC) acetyl succinate (HPMC-AS) is a key polymer used for the enablement of amorphous solid dispersions (ASDs) in oral solid dosage forms. Choice of the appropriate grade within the material is often made empirically by the manufacturer of small-scale formulations, followed by extensive real time stability. A key factor in understanding and predicting the performance of an ASD is related to the presence of hydrogen (or other) bonds between the polymer and active pharmaceutical ingredient (API), which will increase stability over the parameters captured by miscibility and predicted by the Gordon-Taylor equation. Solid state nuclear magnetic resonance (NMR) is particularly well equipped to probe spatial proximities, for example, between polymer and API; however, in the case of HPMC-AS, these interactions have been sometimes difficult to identity as the carbon-13 NMR spectra assignment is yet to be firmly established. Using feedstock, selectively substituted HPMC polymers, and NMR editing experiments, we propose here a comprehensive understanding of the chemical structure of HPMC-AS and a definitive spectral assignment of the 13 C NMR spectra of this polymer. The NMR data also capture the molar ratios of the acetate and succinate moieties present in HPMC-AS of various grades without the need for post treatment required by chromatography methods commonly use in pharmacopoeia. This knowledge will allow the prediction and measurement of interactions between polymers and APIs and therefore a rational choice of polymer grade to enhance the solid state stability of ASDs.

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

“…Deconvolution in the carbonyl region of the HPMC-AS polymer reveals two signals assigned to C 15,18 (most shifted peak, S substituent the C Os) and C 13 (A’s C O). 69 The knowledge of the 13 C assignment of both the drug and HPMC-AS polymer plays an important role in the identification of drug–polymer interactions in ASDs as this is largely based on the change in chemical shifts. 4 , 43 The 13 C assignments for the 13 C CP MAS NMR spectra of all ASDs, recorded at less than 1 day at RT/ambient RH, are based on the known spectra of HPMC-AS 69 and acetaminophen form I and II 68 ( Table SI-2 ).…”

“…The four peaks in the region 105–60 ppm in the spectrum of the HPMC-AS polymer (Figure b) can be attributed to the anomeric C 1 , C 4 , C 2,3 , and C 5,10 carbons, while the shoulders at around 70 and 58 ppm correspond to C 6,9 (CH 2 s) and C 8 (methoxy group), and the three peaks in the aliphatic region to C 16,17 ( C H 2 of the S group), C 14 ( C H 3 of the A group), and C 11 (methyl group of the P moiety). Deconvolution in the carbonyl region of the HPMC-AS polymer reveals two signals assigned to C 15,18 (most shifted peak, S substituent the C Os) and C 13 (A’s C O) . The knowledge of the 13 C assignment of both the drug and HPMC-AS polymer plays an important role in the identification of drug–polymer interactions in ASDs as this is largely based on the change in chemical shifts. , The 13 C assignments for the 13 C CP MAS NMR spectra of all ASDs, recorded at less than 1 day at RT/ambient RH, are based on the known spectra of HPMC-AS and acetaminophen form I and II (Table SI-2).…”

“…Deconvolution in the carbonyl region of the HPMC-AS polymer reveals two signals assigned to C 15,18 (most shifted peak, S substituent the C Os) and C 13 (A’s C O) . The knowledge of the 13 C assignment of both the drug and HPMC-AS polymer plays an important role in the identification of drug–polymer interactions in ASDs as this is largely based on the change in chemical shifts. , The 13 C assignments for the 13 C CP MAS NMR spectra of all ASDs, recorded at less than 1 day at RT/ambient RH, are based on the known spectra of HPMC-AS and acetaminophen form I and II (Table SI-2). In the spectra of the ASDs, signals assignable to the amorphous acetaminophen generally appear broader than in the crystalline form as expected from amorphization as the loss of crystallinity brings of a range of chemical environments present that are randomly distributed in the sample resulting in severe inhomogeneous line broadening .…”

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

“…Signal assignment of the 1 H and 13 C resonances of HPC in the liquid and solid state were obtained from previous works. [ 15,16 ] The assignment of the solid 13 C and 1 H resonances of HPC is provided in Figure S4.…”

“…Indeed, the establishment of favorable HPC‐drug interactions has been proposed as a basis to rationalize the miscibility and stability of these formulations in the solid state. [ 15 ] Recently, we reported that HPC solubilizing activity in aqueous solutions might be caused by the favorable interplay between HPC chain length and hydration. [ 16 ]…”