Crystallization of Form II Paracetamol with the Assistance of Carboxylic Acids toward Batch and Continuous Processes

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.

Automated summary

Form II paracetamol, with improved compressibility, has attracted researchers' attention. This study focused on the selective polymorphic formation of paracetamol using cooling crystallization with four types of additives. The results showed that the addition of more additives increased the probability of forming Form II paracetamol. By seeding the paracetamol solution with Form II paracetamol and fumaric acid crystals, Form II paracetamol could be induced, while the other three carboxylic acids were not effective. The study also discovered a new solution complex of paracetamol-oxalic acid, responsible for the selective nucleation of Form II paracetamol in the oxalic acid solution. Additionally, the range 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 successfully produced using continuous crystallization in a fumaric acid aqueous solution.