| dc.description.abstract | Polymorphism is one of the important topics in pharmaceutical industry due to its ability in modulating the physicochemical properties and extending the life cycle of a drug substance. Form II paracetamol (PCA) is a popular drug substance attracting the interest of researchers due to its improvement for compressibility of PCA. However, its low stability has made it difficult to be produced in a large scale with a good reproducibility. In the present study, multicomponent crystallization was developed to prepare the metastable Form II PCA. Form II PCA crystals could be yielded by cooling crystallization in the presence of five additives: adipic acid (ADI), fumaric acid (FUM), DL-malic acid (MLC), oxalic acid (OXA) and succinic acid (SUC). The effects of the amounts of additives, seeding, and the degree of supersaturation, S, of PCA, on the polymorphic formation of PCA were thoroughly investigated. It was found that: (1) the more additives were added, the higher probability of forming Form II PCA crystals, (2) Form II PCA crystals could be induced by seeding the PCA aqueous solution with FUM, while the other four additives had failed to do so, (3) a new solution complex of PCA-OXA, evidenced by a concave upward curve in the solubility diagram, might be responsible for the selective nucleation of Form II PCA in the PCA-OXA aqueous solution, and (4) the range of S for nucleating Form II PCA was modulated from S = 3.3 to 3.6 in the absence of additive, and extended to 1.5 to 5.7 in the presence of 50 wt% of FUM. About 1.47 g of Form II PCA crystals (i.e. yield = 73.55 %) could be obtained by cooling crystallization from 75o to 10oC with 50 wt% of FUM with a concentration of 58.82 mg/mL and a cooling rate of 1oC/min.
Multicomponent crystallization was applied in a stirred tank for batch crystallization, and in a tubular crystallizer for continuous crystallization. In the experiments of batch crystallization, Form II PCA crystals could be nucleated by cooling crystallization with the assistance of FUM, and then the Form II PCA crystals were transformed to stable Form I PCA crystals after a long time upon agitation. On the other hand, the Form II PCA crystals were isolated by continuous crystallization with a concentration of 44 mg of PCA/mL of water with 50wt% of FUM and a flow rate of 150 mL/min.
In addition, the color of PCA aqueous solution had changed to yellow upon the addition of MAL, but the yellow color was not seen for the aqueous solution of each individual component. The IR spectrum, photoluminescence spectrum, solubility diagram, and phase diagram of PCA-MAL co-crystals were established. | en_US |