Effect of Drug–Polymer Interactions through Hypromellose Acetate Succinate Substituents on the Physical Stability on Solid Dispersions Studied by Fourier-Transform Infrared and Solid-State Nuclear Magnetic Resonance

Abstract

The present study evaluated the specific intermolecular interactions between carbamazepine (CBZ) and substituents of hypromellose acetate succinate (HPMC-AS), as well as the mechanism of inhibition of recrystallization of solid dispersions (SDs) using Fourier-transform infrared (FTIR) and solid-state nuclear magnetic resonance (NMR) spectroscopy. CBZ and HPMC derivatives, including HPMC, hypromellose acetate (HPMC-A), and hypromellose succinate (HPMC-S), were spray-dried to prepare CBZ/polymer spray-dried samples (SPDs). CBZ/HPMC SPD and CBZ/HPMC-A SPD recrystallized within 10 days at 60 °C and 0% relative humidity, whereas CBZ/HPMC-S SPD maintained its amorphous state for a longer period. FTIR and solid-state NMR measurements using 13 C cross polarization (CP), 1 H single-pulse, and 1 H− 15 N CP-based heteronuclear single quantum correlation filter experiment with very fast magic angle spinning (MAS) at 70 kHz identified molecular interactions in CBZ/polymer SPDs. Although the HPMC backbone and substituents did not interact notably with CBZ and disrupt CBZ−CBZ intermolecular interactions (formed in the amorphous CBZ), acetate and succinate substituents on HPMC-A and HPMC-S disrupted CBZ−CBZ intermolecular interactions through formation of CBZ/polymer interactions. The acetate substituent formed a hydrogen bond with the NH 2 group of CBZ, whereas the succinate substituent formed molecular interactions with both the CO and NH 2 groups of CBZ. Formation of relatively strong molecular interactions between CBZ and the succinate substituent followed by disruption of CBZ−CBZ intermolecular interactions effectively stabilized the amorphous state of CBZ in CBZ/HPMC-S SPD. The correlation between CBZ−polymer interactions and ability of polymers to effectively inhibit CBZ recrystallization is reflected in various commercial HPMC-AS. For example, HPMC-AS LF grade, containing higher amounts of the succinate group, was found to effectively inhibit the recrystallization of CBZ through strong molecular interactions as compared with the HPMC-AS HF grade. The present study demonstrated that a detailed investigation of molecular interactions between the drug and the polymer using FTIR and solid-state NMR continued...

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

“… 44 The presence of π–π aromatic packing interaction between POSA and HPMC-phthalate (HPMC-P) amorphous dispersion has also been highlighted. 44 Drug–polymer interactions in carbamazepine (CBZ) in HPMC, HPMC-A, and HPMC-S dispersions have also been established 42 and identified H-bonding between the CBZ’s −NH 2 group with the acetyl moiety in HPMC-A and between both CBZ −NH 2 ’s and carbonyl groups of the succinyl group in HPMC-S. This demonstrates the important role that both acetyl and succinyl groups of HPMC-AS could play in the formation of stable API–polymer connections.…”

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

“…[21] Due to the presence of acetyl (A) and succinoyl (S) groups, HPMC-AS allows the formation of stable ASD and inhibition of the API crystallisation by the formation of intermolecular interactions. [23,24] A and S can establish specific interactions with the drug, which could be tuned by different levels of acetyl and succinoyl substitution in the polymers. Materials with different contents of A and S are commercially available and labelled as L, M, and H grades depending on the A/S ratio according to the specifications given by different vendors.…”

“…[35] Drug-polymer interactions between polystyrene sulfonic acid and lapatinib and gefitinib have been shown via the presence of acid-base interactions using a combination of analytic techniques, including solid-state NMR, ultraviolet spectroscopy, and Fourier-transform infrared spectroscopy. [36] Recently, a study by Ishizuka et al [23] has probed intermolecular interactions between carbamazepine (CBZ) and HPMC-AS collating data obtained by studying CBZ in HPMC-A and CBZ in HPMC-S in individual solid dispersions. Without a complete assignment of the 13 C spectrum and only attributing the signal at~170 ppm to the carbonyl of the acetyl group in HPMC-AS spectrum, the authors were able to identify the presence of intermolecular bonds between the drug and HPMC-AS.…”

“…Due to the presence of acetyl (A) and succinoyl (S) groups, HPMC‐AS allows the formation of stable ASD and inhibition of the API crystallisation by the formation of intermolecular interactions . A and S can establish specific interactions with the drug, which could be tuned by different levels of acetyl and succinoyl substitution in the polymers.…”

Degrees of order: A comparison of nanocrystal and amorphous solids for poorly soluble drugs

“…In the same way, the saturation solubility of amorphous griseofulvin was improved with the addition of hydroxypropyl methylcellulose acetate succinate (HPMCAS) due to hydrogen bonding, but increase in the saturation solubility with polyvinyl pyrrolidone (PVP) was much lower (Al-Obaidi et al, 2013). The precipitation of amorphous carbamazepine has been inhibited by interactions between the acetate and succinate groups of hypromellose acetate succinate (HPMC-AS) and carbamazepine (Ishizuka et al, 2019). Acetate and succinate groups disturbed intermolecular carbamazepine interactions in amorphous carbamazepine by forming polymer carbamazepine interactions with C=O and NH 2 groups in carbamazepine.…”