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

Kuan Lin Yeh, Hung Lin Lee, Tu Lee

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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.

Original languageEnglish
Article number1099
Issue number5
StatePublished - May 2022


  • fumaric acid
  • oxalic acid
  • purification
  • seeding
  • solution complex


Dive into the research topics of 'Crystallization of Form II Paracetamol with the Assistance of Carboxylic Acids toward Batch and Continuous Processes'. Together they form a unique fingerprint.

Cite this