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 co...

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Bibliographic Details
Published in:Pharmaceutics 2022-05, Vol.14 (5), p.1099
Main Authors: Yeh, Kuan-Lin, Lee, Hung-Lin, Lee, Tu
Format: Article
Language:English
Subjects:
Acids
Additives
Analgesics
Cooling
COVID-19
Crystallization
Drug dosages
fumaric acid
Manufacturing
oxalic acid
Pharmaceutical industry
Phase transitions
Polymorphism
purification
Reproducibility
seeding
solution complex
Ultrasonic imaging
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Summary: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.
ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics14051099