Crystal Shape Modification via Cycles of Growth and Dissolution in a Tubular Crystallizer

Abstract

Besides size and polymorphic form, crystal shape takes a central role in engineering advanced solid materials for the pharmaceutical and chemical industries. This work demonstrates how multiple cycles of growth and dissolution can manipulate the habit of an acetylsalicylic acid crystal population. Considerable changes of the crystal habit could be achieved within minutes due to rapid cycling, i.e., up to 25 cycles within <10 min. The required fast heating and cooling rates were facilitated using a tubular reactor design allowing for superior temperature control. The face-specific interactions between solvent and the crystals' surface result in face-specific growth and dissolution rates and hence alterations of the final shape of the crystals in solution. Accurate quantification of the crystal shapes was essential for this work, but is everything except simple. A commercial size and shape analyzer had to be adapted to achieve the required accuracy. Online size, and most important shape, analysis was achieved using an automated microscope equipped with a flow-through cell, in combination with a dedicated image analysis routine for particle tracking and shape analysis. Due to the implementation of this analyzer, capable of obtaining statistics on the crystals' shape while still in solution (no sampling and manipulation required), the dynamic behavior of the size shape distribution could be studied. This enabled a detailed analysis of the solvent's effect on the change in crystal habit.

Figure 1

Growth morphology of acetylsalicylic acid (Adapted from ref (23). Copyright 2018, Elsevier).

Figure 2

Setup of the tubular crystallizer.

Figure 3

Details of single nonconsecutive frames captured by QICPIC, showing (a) the seed crystals, (b) product in hexanol, (c) product in isopropanol, and (d) product in ethanol.

Figure 4

Modeled temperature (top) and supersaturation (bottom) profile of ASA using isopropanol as solvent during the first six temperature cycles.

Figure 5

(a) Illustration of multiple projections of the same particle depending on the orientation with respect to the plane of inspection of the camera, which is fixed at the top. One of the faces of the cuboid is shaded for easier visualization of the particle’s rotation. Using particle tracking, a single set of size characteristics is taken from all the projections observed. (b) Scheme of the particle sizing algorithm utilizing length and width (right) instead of f_min and f_max (left) to measure the aspect ratio. The thickness is defined as the smallest width among all the projections of every individual particle.

Figure 6

Influence of the implementation of particle tracking and solidity filter on the number-based cumulative distribution of (a) length, (b) width, and (c) aspect ratio in shape tuning experiments of ASA in isopropanol after 25 cycles.

Figure 7

Influence of the minimum number of views of each individual particle on the number-based cumulative distribution (including the solidity filter) of (a) length, (b) width, and (c) aspect ratio in shape tuning experiments of ASA in isopropanol after 25 cycles.

Figure 8

Scatter plot of solidity vs length for product ASA crystals after 25 cycles in isopropanol. The black dashed line corresponds to the solidity threshold applied in our analysis for the rejection of agglomerates and overlaps.

Figure 9

Influence of the number of cycles of growth and dissolution on the number-based cumulative distribution of (a) length, (b) width, (c) thickness, (d) aspect ratio, and (e) T/W ratio of ASA crystals suspended in ethanol.

Figure 10

SEM images of (a) seed and (b) product crystal (after 25 cycles in ethanol). SEM: Zeiss Ultra 55, Zeiss, Oberkochen, Germany operated at 5 kV. Sputtering of particles with gold-palladium prior to analysis.

Figure 11

Influence of solvent-influenced shape tuning on the number-based cumulative distributions of (a) length, (b) width, (c) thickness, (d) aspect ratio, and (e) T/W ratio of ASA in different solvents.

Figure 12

Horizontally taken microscope images of a single product crystal (length = 975 μm, width = 415 μm, and thickness = 240 μm) temperature cycled in ethanol. The crystal is photographed with its principal axes of inertia parallel to the line of inspection, showing (a) its (100) face, (b) its (110) faces, and (c) its (001) face. Neighboring faces are indicated in black font. The faces could be assigned to their respective indices according to the relative position of the sloped (110) face.

Figure 13

Number-based cumulative distribution of crystal volume V calculated via V = length × width × thickness for seed crystals and for product crystals after temperature cycling in different solvents.