(568a) Cephalexin and Amoxicillin Crystal Shape Modification By Manipulating the Supersaturation and Wet Milling

Cephalexin and amoxicillin belong to the family of beta-lactam antibiotics and are among the most widely used small-molecule drugs. Both compounds are sparingly soluble in water, the solvent in their enzymatic synthesis process, and form hydrated crystals under typical synthesis conditions [1]. Unfortunately, both cephalexin and amoxicillin crystallization processes are reported to produce needle-like crystals with high aspect ratios, which can lead to significant agglomeration, long filtration times, and poor downstream processability [2]. There have been several efforts to address the above issue and to modify the crystal habit and shape in these systems. For example, it has been suggested that seeding and controlling the supersaturation generation through controlling either the cooling rate [3], synthesis reaction rate [4], or feeding rate [5] can be used to improve the shape of cephalexin monohydrate crystals.

In the present work, we examine the impact of wet milling on the crystal shape, aspect ratio, and size distribution in cephalexin and amoxicillin crystallization processes. Wet milling is commonly used to reduce the crystal size in different processes and to tighten the size distribution. Our results suggest that wet milling not only reduces the mean size of cephalexin monohydrate crystals, but it also leads to further improvements in crystal aspect ratio during the enzymatic synthesis and crystallization process. Based on a systematic study of different milling parameters, we will discuss the impact of milling on crystals of both cephalexin and amoxicillin. Furthermore, we investigate potential improvements in the aspect ratio of the final crystals by combining the milling with a series of pH manipulation steps where small, needle-like crystals are dissolved by periodically increasing the system pH (leading to higher solubility), giving a way to produce larger crystals with improved aspect ratios (Figs. 1A and 1B). The impact of the improved aspect ratio on the filtration rate of both crystals will also be discussed (Fig. 1C).

Fig. 1. Example of improvement in the aspect ratio of cephalexin monohydrate crystals by applying a series of pH swings (A), or periodic milling (B). Both cases lead to the formation of more platelike crystals compared to initially needle-like crystals. Example of the impact of aspect ratio (or size) on filtration rate (C).

Cited literature

[1] McDonald, Matthew A., Grant D. Marshall, Andreas S. Bommarius, Martha A. Grover, and Ronald W. Rousseau. "Crystallization kinetics of cephalexin monohydrate in the presence of cephalexin precursors." Crystal Growth & Design 19, no. 9 (2019): 5065-5074.

[2] Perini, Giulio, Carlos Avendaño, William Hicks, Anna R. Parsons, and Thomas Vetter. "Predicting filtration of needle-like crystals: A Monte Carlo simulation study of polydisperse packings of spherocylinders." Chemical Engineering Science 230 (2021): 116151.

[3] Ostergaard, Iben, Heidi Lopez de Diego, and Haiyan Qu. "Crystallization of cephradine polymorphs and hydrates from mixed solvents of methanol and water." Chemical Engineering & Technology 42, no. 7 (2019): 1512-1518.

[4] McDonald, Matthew A., Grant D. Marshall, Salami, Hossein, Andreas S. Bommarius, Martha A. Grover, and Ronald W. Rousseau. "Crystallization Optimization By Enzymatic Control of a Reactive Crystallization". AIChE annual meeting, San Francisco (2020)

[5] Li, Mingchen, Zeren Shang, and Baohong Hou. "Optimizing the Aspect Ratio of Cephalexin in Reactive Crystallization by Controlling Supersaturation and Seeding Policy." Transactions of Tianjin University 25, no. 4 (2019): 348-356.