Particle Size Distribution and yield control in continuous Plug Flow Crystallizers with recycle

Abstract

ABSTRACT:Crystallization of Active Pharmaceutical Ingredients (APIs) has traditionally been carried out using the batch or semi-batch manufacturing processes, techniques which remain prevalent to this day. Continuous processing affords significant production advantages including enhanced reproducibility of results, optimal control of process conditions, shorter downtime and the elimination of scale-up problems.The Plug Flow Crystallizer (PFC) is one of the most widely employed forms of continuous crystallizer. PFCs are usually selected for processes with fast kinetics and short residence times. One key limitation of PFCs, which has partially constrained their adoption in industry, is that normally they do not allow for equilibrium conditions to be achieved; this is in effect a consequence of the short residence times. Thus, the resultant yield from PFCs is generally less than that of the equivalent batch process. 2Recycling the mother liquor back through the PFC is one approach which can potentially be used in order to mitigate against this drawback, allowing for an amelioration in the continuous process yield.In the present work, the effects of introducing a recycle stream and adjusting critical recycling parameters, namely recycling ratio and axial extraction position, on an idealized PFC are examined. Particular attention is focused on the resultant volume average size of particles d 4,3 , and the process yield η. The influence of residence time on the maximum and minimum yield and size of crystals achievable is investigated. In addition, the effect of recycle parameters on the Particle Size Distribution (PSD) is ascertained, at specified values of yield.The proposed continuous PFC, as conceptualized and modelled with recycle, facilitates practical application in an industrial setting, allowing for augmented continuous process yields, whilst furthermore facilitating PSD control.

The coupling of in-flow reaction with continuous flow seedless tubular crystallization

“…Crystallisation determines chemical purity and physical properties: particle habit and size, crystal structure and degree of crystal imperfection 11 . For this reason, continuous and semi-continuous crystallisation routines have been developed, intending to have a better control over these characteristics [12][13][14][15][16] . Almost all methods based on tubular flow crystallisers mention the use of crystal seeds in order to retain a small particle distribution [15][16][17][18][19][20][21][22] .…”

A Novel Shadowgraphic Inline Measurement Technique for Image-Based Crystal Size Distribution Analysis

“…FBRM is the state of the art technique in crystallization, because it is commercially available and easy to use [4]. A probe that is inserted in the apparatus and measures the chord lengths of the crystals from backscattered light originating from a fast-rotating laser beam [7,[16][17][18][19][20][21][22][23][24], yielding a one-dimensional chord length distribution (CLD) instead of a real crystal PSD. The conversion of a CLD to a PSD is based on models and assumptions, but is lacking for complex and elongated particle shapes [25][26][27][28].…”

On the effect of flow restrictions on the nucleation behavior of molecules in tubular flow Nucleators

“…[1,6] Some of the approaches to reach a continuous crystallization process like Mixed Suspension Mixed Product Removal (MSMPR), Oscillatory Baffled Crystallizers (OBC), tubular reactors and others are well documented; typically these methods focus on crystal growth and use crystal seeds as starting material inside a slightly supersaturated solvent. [7][8][9][10][11][12][13][14][15][16][17][18] As an exception, tubular reactors can be applied to generate nuclei in flow conditions. After the exit of the growing nuclei out of the reactor further crystal growth is reported to be conducted in storage vessels, tubing, or directly casted on filters, both for direct nucleation in one single solvent or by addition of antisolvent.…”

“…After the exit of the growing nuclei out of the reactor further crystal growth is reported to be conducted in storage vessels, tubing, or directly casted on filters, both for direct nucleation in one single solvent or by addition of antisolvent. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25].…”