Crystal Engineering in Continuous Plug-Flow Crystallizers

Abstract

Size, shape, and polymorphic form are the critical attributes of crystalline particles and represent the major focus of today's crystallization process design. This work demonstrates how crystal properties can be tuned efficiently in solution via a tubular crystallizer that facilitates rapid temperature cycling. Controlled crystal growth, dissolution, and secondary nucleation allow a precise control of the crystal size and shape distribution, as well as polymorphic composition. Tubular crystallizers utilizing segmented flow such as the one presented in our work can provide plug flow characteristics, fast heating and cooling, allowing for rapid changes of the supersaturation. This makes them superior for crystal engineering over common crystallizers. Characterization of particle transport, however, revealed that careful selection of process parameters, such as tubing diameter, flow rates, solvents, etc., is crucial to achieve the full benefits of such reactors.

Figure 1

Gas liquid flow pattern in small channels. More details of the hydrodynamics can be found in the literature for slug flow^, and for annular flow.

Figure 2

Particle dispersion in a gas (air) liquid (40% water, 60% ethanol) segmented flow. Direction of flow is from left to right. In each subimage air bubbles can be recognized entering from the left (dark black). For all flow rates (slow, moderate and fast), top row: large particles (150–180 μm), middle row: medium particles (90–150 μm), bottom row: small particles (50–80 μm); V̇_Susp/V̇_Air = 1.6.

Figure 3

Changes in the number of particles (top) and PSD during temperature cycling determined via a population balance model assuming size-independent (middle) and size-dependent dissolution rates (bottom). The tube length (0.875 m in the heating and cooling bath) did not allow equilibration (S = 1) after every heating and cooling step. The related supersaturation profile is shown in bottom of Figure S7.

Figure 4

Schematic draft of setup used for fine removal (A), crystal shape (B), and polymorphism (C) studies. All three process start at the top left of the figure. A crystalline suspension is cycled through water baths via a peristaltic pump alternately passing two temperature-controlled water baths. Compartmentalization is achieved by introducing air bubbles via a syringe pump (2 × 100 mL syringes) keeping the pressure almost constant for ≫30 min. After passing the high-speed camera (monitoring crystals before and after temperature cycling simultaneously), the slurry was A: separated from the gas phase and pumped through the laser diffractometer before filtration; B: filtered; C: filtered while rinsing with Acetone.

Figure 5

Measured crystal size distributions of the d-mannitol suspension cycled (top) multiple times via the tubular crystallizer and (bottom) once in batch.

Figure 6

Microscope pictures of product crystals after passing through the tubular crystallizer for different temperature gradients. (a) ΔT = 0 °C (constant temperature in both baths, i.e., 22 °C). (b) ΔT = 2 °C. (c) ΔT = 4 °C. (d) ΔT = 6 °C.

Figure 7

(a) High-speed camera image of a crystal entering the reactor (upper half, movement from left to right) and another crystal after shape tuning (lower half, movement from right to left. Microscope pictures of (b) feed and (c) product crystals after 5, 10, and 15 cycles, compared to a feed sample and a noncycled sample. Length specifications correspond to the tube length distributions per loop over the two water baths.).

Figure 8

(a) Microscope picture of spray-dried α-d-mannitol as received. (b) β-d-mannitol (Pearlitol 160C, Roquette, as received). Product crystals after temperature cycling (starting suspension: 80% α-form, 20% β-form) (c) ΔT = 20 °C, (d) ΔT = 30 °C.

Figure 9

(a) Raman microscope studies on a single particle (initially mostly α form) after temperature cycling at ΔT = 30°C. The white circles on the microscope image show where Raman spectra were recorded. The relative heights of the peaks assigned to the α (1355 cm^–1) and β (1233 cm^–1) form are superimposed. (b) Raman spectra recorded at the periphery and at the center of the product particle compared to spectra of the seeded α and β form. (c–e) SEM images of (c) seeded particles, (d) cycled at ΔT = 20 °C, and (e) ΔT = 30 °C. Details on the experimental procedure are provided in the Supporting Information, section S2.6.