Abstract
Lovastatin crystals often exhibit an undesirable needle-like morphology. Several studies have shown how a needle-like morphology can be modified in antisolvent crystallisation with the use of additives, but there is much less experimental work demonstrating crystal shape modification without the use of additives. In this study, a series of unseeded continuous antisolvent crystallisation experiments were conducted with the process conditions of supersaturation, total flow rate, and ultrasound level being varied to determine their effects on crystal size and shape. This experimental work involved identifying acetone/water as the most suitable solvent/antisolvent system, assessing lovastatin nucleation behaviour by means of induction time measurements, and then designing and implementing the continuous antisolvent crystallisation experiments. It was found that in order to produce the smallest and least needle-like particles, the maximum total flow rate and supersaturation had to be combined with the application of ultrasound. These results should aid development of pharmaceutical manufacturing processes where the ability to control particle size and shape would allow for optimisation of crystal isolation and more efficient downstream processing.
Highlights
Crystallisation is an important unit operation which is widely used for particle formation, purification, and separation in the pharmaceutical industry
The solvent/antisolvent screen involved broadly classifying solvents as either soluble or insoluble based solely on literature solubility data [42,43,44]. Solvents considered in this screen were restricted to class 2 and 3 solvents from the ICH classification for residual solvents [45]
Potential solvents and antisolvents were excluded if they had extreme physical properties
Summary
Crystallisation is an important unit operation which is widely used for particle formation, purification, and separation in the pharmaceutical industry. The traditional approach in the pharmaceutical industry is to operate the antisolvent crystallisation process batch-wise in a stirred tank reactor (STR), but this presents several challenges [1]. The major challenge is that of scaling up, as it is usually very difficult to transfer from the batch antisolvent addition method used in the laboratory to the batch antisolvent addition method used in production. For this reason, there has been greater effort put into utilising continuous mixing methods in place of batch addition methods.
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