Establishment of a Continuous Sonocrystallization Process for Lactose in an Oscillatory Baffled Crystallizer

Abstract

Crystallization at production scale (>10 kg) is typically a poorly understood unit operation with limited application of first-principles understanding of crystallization to routine design, optimization, and control. In this study, a systematic approach has been established to transfer an existing batch process enabling the implementation of a continuous process in an oscillatory baffled crystallizer (OBC) using ultrasound. Process analytical technology (PAT) was used to understand and monitor the process. Kinetic and thermodynamic parameters have been investigated for lactose sonocrystallization using focused beam reflectance measurement (FBRM) (Mettler Toledo) and mid-infrared spectroscopy (mid-IR) (ABB) in a multiorifice batch oscillatory baffled crystallizer (Batch-OBC). This platform provides an ideal mimic of the mixing, hydrodynamics and operating conditions of the continuous oscillatory flow crystallizer (COBC) while requiring only limited material. Full characterization of the hydrodynamics of the COBC was carried out to identify conditions that deliver plugflow behavior with residence times of 1−5 h. The results show that continuous crystallization offers significant advantages in terms of process outcomes and operability, including particle size distribution (mean particle size <1500 μm) of alpha lactose monohydrate (LMH), as well as reduced cycle time (4 h compared to the 13−20 h in a batch process). Continuous sonocrystallization was performed for the first time at a throughput of 356 g•h −1 for 12−16 h. During the run at near plug flow, with supersaturation and controlled nucleation using sonication, no issues with fouling or agglomeration were observed. This approach has demonstrated the capability to provide close control of particle attributes at an industrially relevant scale. 50 principle of OBC has been described elsewhere. 4,5 The basic 51 design comprises a tubular network containing periodically 52 spaced orifice baffles superimposed with oscillatory motion of a 53 fluid. Oscillatory flow mixing has been developed and 54 investigated as a process intensification technology to achieve 55 efficient and controlled mixing in tubular crystallizers. Unlike 56 conventional tubular crystallizers in which the mixing is caused 57 by the turbulent net flow, the mixing achieved in an OBC is 58 mainly obtained by fluid oscillations and thereby the residence 59 time distribution within the device can be adjusted by the 60 oscillatory conditions and net flow rate allowing longer 61 residence times in short reactors and hence is more suitable 62 for slower processes like crystallization. 7−12 Previous studies 63 have shown that processing in an OBC resulted a greater 64 regularity of crystal shape with fewer defects and better control 65 over the crystallization process. A recent review provides a 66 detailed description of OBCs for crystallization as well as 67 summarizing the relevant literature. 63 These are attributed to 68 the uniform mixing when compared to a batch stirred tank 69 system. 3 Batch to ...

The Effect of Ultrasound on the Crystallisation of Paracetamol in the Presence of Structurally Similar Impurities

“…These effects of ultrasound on crystallisation have been demonstrated on pharmaceuticals and commodity chemicals including; lactose [35,39,42,55], alpha-dextrose monohydrate [20], glycine [48], p-aminobenzoic acid [47], adipic acid [28], benzoic acid [31], acetylsalicylic acid [27], protein [19] various food products [30,56,57] and in the crystallisation of inorganic materials such as potassium sulphate [26], potassium dihydrogen phosphate [32] and calcite [34]. Ultrasound has also been utilized in continuous crystallisation [28,[58][59][60]. While some authors mention that ultrasound can improve crystal purity [54]; there is very limited data on the effect of ultrasound on the purity of the final crystalline product.…”

Design of a Continuous Tubular Cooling Crystallizer for Process Development on Lab‐Scale

“…In this macro-structured tubular device, particle fluidization and a narrow RTD are achieved by a pulsed flow through baffles in the pipe, whereas the pulsation is achieved by a piston movement [23][24][25]. Seeded and unseeded operations [23] of various crystallizing systems were reported.…”

“…However, seeding enabled a more robust operation without encrustation of the walls [26]. Ultrasound was successfully applied in a COBC setup to induce primary nucleation [25]. A flexible adjustment of the axial temperature profiles, e.g., a linear profile, can be achieved by a sophisticated control system [27] or multiple thermostats, e.g., 13 heating/cooling thermostats [26].…”

“…However, scale-down to smaller dimensions for process development has not been reported, yet. Batch oscillatory baffled crystallizers are used to decrease material consumption during process development [23,25,26].…”

Separation Units and Equipment for Lab-Scale Process Development

“…Commercially available equipment ranges from V = 1.25 to 3.50 L internal volume for the DN15 device [44], and a DN25 device with V = 12 L was reported [47]. Before conducting continuous processes, initial process development is often carried out in batch oscillatory baffled devices to lower the material consumption [47,50].…”