Reducing the mean size of API crystals by continuous manufacturing with product classification and recycle

Griffin, Derek W.; Mellichamp, Duncan A.; Doherty, Michael F.

doi:10.1016/j.ces.2010.05.026

Cited by 49 publications

(38 citation statements)

References 42 publications

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“…7 Derivatives of these two designs have resolved some of the practical concerns related to the continuous crystallization, such as the use of: (1) a continuous oscillatory baffled crystallizer (COBC) to deal with the sedimentation of crystals at low through-flow 3 MSMPR crystallizer with a fines trap and a product classifier to achieve a high production rate and a low polydispersity of the crystals; 16 (6) similar work was also reported of using an "inverted" product classifier unit in a modified continuous MSMPR crystallizer, wherein small crystals are withdrawn as product, and larger crystals recycled to a dissolver. 17 However, one of the important issues for these two designs, in terms of the material residence time, has often been the concern for chemical engineers. For example, although a narrow residence time distribution could be achieved, a relatively long tube is necessary for slow growing crystals to achieve sufficient residence time and to reach a desired particle size for tubular crystallizers.…”

Section: Introductionmentioning

confidence: 99%

Mathematical modelling and experimental validation of a novel periodic flow crystallization using MSMPR crystallizers

Rielly

Powell

et al. 2016

AIChE Journal

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The challenges of insufficient residence time for crystal growing and transfer line blockage in conventional continuous mixed‐suspension mixed‐product removal (MSMPR) operations are still not well addressed. Periodic flow crystallization is a novel method whereby controlled periodic disruptions are applied to the inlet and outlet flows of an MSMPR crystallizer to increase its residence time. A dynamic model of residence time distribution in an MSMPR crystallizer was first developed to demonstrate the periodic flow operation. Besides, process models of periodic flow crystallizations were developed with an aim to provide a better understanding and improve the performance of the periodic flow operation, wherein the crystallization mechanisms and kinetics of the glycine‐water system were estimated from batch cooling crystallization experiments. Experiments of periodic flow crystallizations were also conducted in single‐/three‐stage MSMPR crystallizers to validate the process models and demonstrate the advantages of using periodic flow operation in MSMPR stages. © 2016 American Institute of Chemical Engineers AIChE J, 63: 1313–1327, 2017

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Section: Introductionmentioning

confidence: 99%

Mathematical modelling and experimental validation of a novel periodic flow crystallization using MSMPR crystallizers

Rielly

Powell

et al. 2016

AIChE Journal

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“…[1,9,10] and further handling of the crystals, since flowability, storage characteristics, dusting [11], segregation phenomena, compactibility and tabletability [12] are functions of the aforementioned CSSD. In the context of APIs, this has a major impact on disintegration and dissolution rates [2] and hence on the bioavailability of the compound [13,14]. Polymorphism control is another critical objective during crystallization operations [15,16].…”

Section: Introductionmentioning

confidence: 99%

Seed loading effects on the mean crystal size of acetylsalicylic acid in a continuous‐flow crystallization device

Eder

Schmitt

Grill

et al. 2011

Cryst. Res. Technol.

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This study investigates the effects of seed loading on the mean crystal size of the model substance, acetylsalicylic acid, crystallized from ethanol in a continuously seeded tubular crystallizer. A hot, highly concentrated ethanolic acetylsalicylic acid solution was mixed with an acetylsalicylic acid-ethanol seed suspension. Subsequent cooling of the slurry in the tubing promoted supersaturation and hence crystal growth. The tubular shape of the 15 m-long crystallizer with an inner diameter of 2 mm enabled narrow residence time distributions of the crystals in the pipe and excellent temperature control in the radial direction and along the tubing. Crystals entering the crystallizer had both identical growth conditions in each section and about the same time for crystal growth. Narrow crystal size distributions were achieved with decreasing differences in the volume-mean-diameter sizes of the seed and product crystals as seed loadings increased. Decreasing the seed size had a similar effect as increasing the seed loading, since in that case the same amount of seed mass resulted in more individual seed particles. Altering the arrangement of the coiled crystallizer with respect to spatial directions (horizontal, vertical) did not lead to a significantly different outcome. All experiments produced considerably larger product crystals in comparison to the seeds despite relatively short crystallization times of less than 3 min. Moreover, product mass gains of a few hundred percent at a g/min-scale were achieved. Similarities in product crystal samples taken at different times at the outlet of the crystallizer showed that steady-state conditions were rapidly reached in the continuous flow crystallization device.

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“…Population balance equations have been used to model particulate processes including crystallization, mixing, milling, granulation, drying and dissolution, all of which are of great interest in the manufacture of solid dosage forms for pharmaceutical products [66,[111][112][113][114][115] The general form of the population balance equation in 2 dimensions is given below.…”

Section: Population Balance Modelsmentioning

confidence: 99%

Modeling of Particulate Processes for the Continuous Manufacture of Solid-Based Pharmaceutical Dosage Forms

2013

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Abstract:The objective of this work is to present a review of computational tools and models for pharmaceutical processes, specifically those for the continuous manufacture of solid dosage forms. Relevant mathematical methods and simulation techniques are discussed, as is the development of process models for solids-handling unit operations. Continuous processing is of particular interest in the current study because it has the potential to improve the efficiency and robustness of pharmaceutical manufacturing processes.

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Reducing the mean size of API crystals by continuous manufacturing with product classification and recycle

Cited by 49 publications

References 42 publications

Mathematical modelling and experimental validation of a novel periodic flow crystallization using MSMPR crystallizers

Mathematical modelling and experimental validation of a novel periodic flow crystallization using MSMPR crystallizers

Seed loading effects on the mean crystal size of acetylsalicylic acid in a continuous‐flow crystallization device

Modeling of Particulate Processes for the Continuous Manufacture of Solid-Based Pharmaceutical Dosage Forms

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