Spherulitic Growth Strategy for Agitation-Induced Formation of Spherical Amoxicillin Sodium Products

Abstract

In industrial crystallization, spherical crystals have gained increasing interest due to their excellent physicochemical properties, such as high bulk density, flowability, stability, etc. However, their formation mechanism is still not well understood and is often oversimplified. In this work, spherical amoxicillin sodium crystals were obtained via a spherulitic growth strategy. It was found that agitation immediately after the addition of crystal seeds was critical for inducing radial noncrystallographic branching and spherulite formation of amoxicillin sodium. Without agitation during the aging period after seed addition, only discrete rodshaped crystals were obtained. The formation mechanism of amoxicillin sodium spherulites was studied using process analytical technology (PAT) tools, including focused beam reflectance measurement (FBRM) and particle video microscope (PVM). The result was indicative of a three-step morphological evolution process: formation of polycrystalline agglomerates, noncrystallographic branching, and spherulite growth. During this process, agitation immediately after seed addition could help to solute diffusion and induce the agglomeration of small crystals that result from secondary nucleation. The polycrystalline agglomerates serve as the cores for further noncrystallographic branching and growth. On this basis, a new spherulitic growth strategy was proposed by the large addition of crystal seeds as the growth substrates of new branching and spherulite growth. High agitation rates during the aging period can increase the mass ratio of spherulites, and high initial supersaturation can promote branching. Compared with the discrete rod-shaped crystals, spherulites self-regulate the final size greatly up to three times and have a higher bulk density as well as much lower hygroscopicity.

Particle Design of Drugs via Spherical Crystallization: A Review from Fundamental Aspects to Technology Development

“…It is well-known that high supersaturation is favorable to polycrystalline growth, and hence leads to the formation of spherulites. ,,, This can be attributed to dynamic heterogeneities: short induction period and high level of supersaturation lead to quick nucleation and growth rates faster than mixing. Furthermore, denser spherulites are more probable to form under higher supersaturation, as evidenced by the studies in the literature. ,, While Cui et al indicated that high supersaturation level may not be necessary for spherulitic growth. Crystallization substrates with enough defects and dislocations, such as crystal seeds with rough surfaces, could also induce non-crystallographic branching and spherulitic growth through the static heterogeneity mechanism, which aligns with the sentiment expressed in the literature …”

“…(e) The substrate-assisted SG mechanism. Reproduced from ref . Copyright 2022 American Chemical Society.…”

“…Furthermore, denser spherulites are more probable to form under higher supersaturation, as evidenced by the studies in the literature. 63,67,107 While Cui et al 67 indicated that high supersaturation level may not be necessary for spherulitic growth. Crystallization substrates with enough defects and dislocations, such as crystal seeds with rough surfaces, could also induce non-crystallographic branching and spherulitic growth through the static heterogeneity mechanism, which aligns with the sentiment expressed in the literature.…”

“…66 In the work of Xiao et al, 65 they proposed a three-step mechanism of the spherulitic crystallization of propylthiouracil−kaempferol cocrystal (Figure 7d), including the single crystal growth, radial growth via non-crystallographic branching, and filling the gaps of subunits which is similar to the SG process of nitrendipine. 62 In the SG process of amoxicillin sodium, Cui et al 67 found that substrates, such as seeds, with sufficient defects and dislocations are capable of accelerating noncrystallographic branching and, hence, resulting in spherulitic growth (Figure 7e). It can be seen that there is no unified mechanism for spherulitic growth, whereas polycrystalline growth is an essential prerequisite for the formation of spherulites.…”

Improved Spherical Particle Preparation of Ceftriaxone Sodium via Membrane-Assisted Spherical Crystallization

“…Spherical crystallization is an efficient technology that couples the crystallization and granulation processes, which is widely used in the pharmaceutical industry. − The application of the spherical crystallization technique allows the elimination of the downstream particle property via improving the tabletability and enhancing unit operations such as milling, grinding, prilling, and so forth. − Spherical or sphere-like drug particles prepared via the spherical crystallization technique can be directly used for tablet compression with improved flow properties, mechanical properties, drug solubility and bioavailability,etc. − …”