Inhibitory Effect of Hydroxypropyl Methylcellulose Acetate Succinate on Drug Recrystallization from a Supersaturated Solution Assessed Using Nuclear Magnetic Resonance Measurements

• Published in: Molecular pharmaceutics 2013-10, Vol.10 (10), p.3801-3811
• Main Authors: Ueda, Keisuke, Higashi, Kenjirou, Yamamoto, Keiji, Moribe, Kunikazu
• Format: Article
• Language: English
• Subjects: Carbamazepine - chemistry; Chromatography, High Pressure Liquid; Crystallization; Magnetic Resonance Spectroscopy - methods; Methylcellulose - analogs & derivatives; Methylcellulose - chemistry; Molecular Structure; Phenytoin - chemistry
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/mp400278j

We examined the inhibitory effect of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) on drug recrystallization from a supersaturated solution using carbamazepine (CBZ) and phenytoin (PHT) as model drugs. HPMC-AS HF grade (HF) inhibited the recrystallization of CBZ more strongly than that by HPMC-AS LF grade (LF). 1D-1H NMR measurements showed that the molecular mobility of CBZ was clearly suppressed in the HF solution compared to that in the LF solution. Interaction between CBZ and HF in a supersaturated solution was directly detected using nuclear Overhauser effect spectroscopy (NOESY). The cross-peak intensity obtained using NOESY of HF protons with CBZ aromatic protons was greater than that with the amide proton, which indicated that CBZ had hydrophobic interactions with HF in a supersaturated solution. In contrast, no interaction was observed between CBZ and LF in the LF solution. Saturation transfer difference NMR measurement was used to determine the interaction sites between CBZ and HF. Strong interaction with CBZ was observed with the acetyl substituent of HPMC-AS although the interaction with the succinoyl substituent was quite small. The acetyl groups played an important role in the hydrophobic interaction between HF and CBZ. In addition, HF appeared to be more hydrophobic than LF because of the smaller ratio of the succinoyl substituent. This might be responsible for the strong hydrophobic interaction between HF and CBZ. The intermolecular interactions between CBZ and HPMC-AS shown by using NMR spectroscopy clearly explained the strength of inhibition of HPMC-AS on drug recrystallization.