Yeh Kuan-Lin, Lee Hung-Lin, Lee Tu
Department of Chemical and Materials Engineering, National Central University, 300 Zhongda Road, Zhongli District, Taoyuan City 320317, Taiwan.
Pharmaceutics. 2022 May 20;14(5):1099. doi: 10.3390/pharmaceutics14051099.
Form II paracetamol has captured the interest of researchers due to its improved compressibility. However, its low stability has made it difficult to be produced on a large scale with good reproducibility. In the present study, the selective polymorphic formation of paracetamol was carried out by cooling crystallization with four types of additives: adipic acid, fumaric acid, oxalic acid, and succinic acid. It was found that: (1) the more additives that were added, the higher the probability of forming Form II paracetamol; (2) Form II paracetamol could be induced by seeding the paracetamol aqueous solution with Form II paracetamol and fumaric acid crystals, and not the other three carboxylic acids; (3) a new solution complex of paracetamol-oxalic acid, evidenced by the solubility diagram, was responsible for the selective nucleation of Form II paracetamol in the oxalic acid aqueous solution; and (4) the range of the degree of supersaturation for nucleating Form II paracetamol was extended with the assistance of oxalic acid or fumaric acid. In large-scale crystallization, Form II paracetamol was produced by the continuous crystallization of 44 mg of paracetamol/mL in 50 wt% of fumaric acid aqueous solution with a flow rate of 150 mL/min.
II型对乙酰氨基酚因其改善的可压缩性而引起了研究人员的兴趣。然而，其低稳定性使得难以大规模生产且具有良好的重现性。在本研究中，通过用四种添加剂（己二酸、富马酸、草酸和琥珀酸）进行冷却结晶来实现对乙酰氨基酚的选择性多晶型形成。结果发现：（1）添加的添加剂越多，形成II型对乙酰氨基酚的概率越高；（2）用II型对乙酰氨基酚和富马酸晶体而不是其他三种羧酸对乙酰氨基酚水溶液进行晶种接种，可以诱导形成II型对乙酰氨基酚；（3）由溶解度图证明的对乙酰氨基酚 - 草酸新溶液络合物，是草酸水溶液中II型对乙酰氨基酚选择性成核的原因；（4）在草酸或富马酸的辅助下，II型对乙酰氨基酚成核的过饱和度范围得以扩展。在大规模结晶中，通过在50 wt%的富马酸水溶液中以150 mL/min的流速连续结晶44 mg/mL的对乙酰氨基酚来生产II型对乙酰氨基酚。
