(W1230-07-44) Process Optimization for Benzoic Acid Spherical Agglomeration: Bridging Liquid Solubility and Supersaturation of Primary Crystallization

Purpose: Spherical agglomeration (SA) is a key particle engineering technique aimed at improving the micrometric and mechanical properties of active pharmaceutical ingredients (API) to enhance their processability and performance in downstream manufacturing. A SA process typically involves the use of a good solvent, a poor solvent, and a bridging liquid.¹ The choice of an appropriate bridging liquid is critical, as it must preferentially wet the crystals, promoting coalescence and consolidation of fine crystals into spherical agglomerates, while remaining immiscible with the continuous solution phase so that crystals can be collected by interfacial tension.² During SA process development, it has been routinely assumed that API is insoluble in the bridging liquid. Although considerable attention has been given to aforementioned criteria, the solubility of the API in the bridging liquid is a significant yet underexplored factor that influences the efficiency and outcome of the SA process. Moreover, while many studies have focused on external process parameters, including the type and amount of bridging liquid, residence time, agitation rate, API solute concentration, and solute feeding rate,^3–10 the influence of the primary crystal's intrinsic properties has received limited attention.¹¹ Given that the internal structure and characteristics of API crystals play a crucial role in determining their performance¹², a deeper understanding of the structure–property relationship in SA is essential for better process design. Therefore, this study investigates the effects of API solubility in the bridging liquid and primary crystal size, controlled with crystallization supersaturation levels, on agglomeration behavior and the resulting physico-mechanical properties of the agglomerates.

Methods: Benzoic acid (BA) was chosen as the model compound. A ternary solvent system consisting of ethanol (good solvent), water (bad solvent), and chloroform (bridging liquid) was used. The solubility of BA was measured in pure water, ethanol, chloroform, and ethanol/water co-solvent mixtures. Spherical agglomeration of BA was performed using an anti-solvent crystallization with a post-bridging method, where a BA ethanol solution was first added to the water to induce precipitation of BA crystals, followed by the addition of chloroform to form spherical agglomerates. Various parameters, including process temperature, BA concentration in ethanol, the volume ratio of ethanol to water, and the pumping rate of ethanol solution, were adjusted to achieve different supersaturation levels during primary crystallization. The internal structure, particle size, morphology, and mechanical strength of the resulting spherical agglomerates obtained under different process conditions were characterized.

Results: The SA process was conducted at two temperatures: 5°C (278.15 K) and 20°C (293.15 K). At 5°C, flocs formed after introducing the bridging liquid into the system, as precipitated crystals coalesced. These flocs were further consolidated into spherical agglomerates during agitation, remaining intact for up to one hour. In contrast, at 20°C, the agglomerates began to visibly disintegrate into smaller fragments at 30 min, eventually reverting to free-flowing loose flocs (Figure 1). This is mainly due to the collapse of agglomerates structure because of the dissolution of BA crystals into the bridging liquid. This phenomenon is critical in SA but is often overlooked, despite its potential impact on agglomerate integrity, process efficiency, and overall product yield. The morphology and size of primary crystals are influenced by the level of supersaturation. In general, a higher supersaturation level, which may be achieved through increased BA concentration, a lower ethanol-to-water volume ratio, or a faster addition rate of BA solution to water, tends to produce smaller and more irregular crystals. These primary crystals, in turn, impact the micrometric and mechanical properties of the resulting agglomerates prepared at 5 ^oC. Agglomerates formed from smaller crystals exhibit acceptable and comparable sizes, whereas those formed from larger crystals tend to be excessively large and mechanically weaker. Besides, agglomerates produced from smaller crystals (under higher degree of supersaturation conditions) demonstrate higher fracture stress (Figure 2), corresponding to their denser internal structure (Figure 3).

Conclusion: This study reveals the effects of 1) solubility of API in bridging liquid on agglomerate structural integrity during the SA process, and 2) supersaturation level on micrometrics and mechanical properties of agglomerates. High solubility of API in bridging liquid induces the disintegration of formed agglomerates into loose flocs, due to the dissolution of crystal into the bridging liquid which causes the collapse of the capillary bridge. This critical observation directly affects both the yield and the quality of the agglomerates. The properties of primary crystals are directly affected by the crystallization supersaturation level, which in turn affect the properties of agglomeration formed. Smaller and irregular primary crystals, produced from higher supersaturation levels, are preferred for making agglomerates with higher packing density and mechanical strength.

References: 1. Kawashima, Y., Okumura, M. & Takenaka, H. Spherical crystallization: Direct spherical agglomeration of salicylic acid crystals during crystallization. Science 216, 1127–1128 (1982).
2. Chen, M. et al. Strategy of selecting solvent systems for spherical agglomeration by the Lifshitz-van der Waals acid-base approach. Chem. Eng. Sci. 220, 115613 (2020).
3. Kawashima, Y. et al. Improved flowability and compactibility of spherically agglomerated crystals of ascorbic acid for direct tableting designed by spherical crystallization process. Powder Technol. 130, 283–289 (2003).
4. Thati, J. & Rasmuson, Å. C. Particle engineering of benzoic acid by spherical agglomeration. Eur. J. Pharm. Sci. 45, 657–667 (2012).
5. Amaro-González, D. & Biscans, B. Spherical agglomeration during crystallization of an active pharmaceutical ingredient. Powder Technol. 128, 188–194 (2002).
6. Morishima, K. et al. Micromeritic Characteristics and Agglomeration Mechanisms Spherical Crystallization of Bucillamine by the Spherical Agglomeration and the Emulsion Solvent Diffusion Methods 57 in The. Powder Technology vol. 76 57–64 (1993).
7. Subero-Couroyer, C., Mangin, D., Rivoire, A., Blandin, A. F. & Klein, J. P. Agglomeration in suspension of salicylic acid fine particles: Analysis of the wetting period and effect of the binder injection mode on the final agglomerate size. Powder Technol. 161, 98–109 (2006).
8. Zhang, H., Chen, Y., Wang, J. & Gong, J. Investigation on the spherical crystallization process of cefotaxime sodium. Ind. Eng. Chem. Res. 49, 1402–1411 (2010).
9. Katta, J. & Rasmuson, A. Spherical crystallization of benzoic acid. Int. J. Pharm. 348, 61–69 (2008).
10. Thati, J. & Rasmuson, Å. C. On the mechanisms of formation of spherical agglomerates. Eur. J. Pharm. Sci. 42, 365–379 (2011).
11. Peña, R., Jarmer, D. J., Burcham, C. L. & Nagy, Z. K. Further Understanding of Agglomeration Mechanisms in Spherical Crystallization Systems: Benzoic Acid Case Study. Cryst. Growth Des. 19, 1668–1679 (2019).
12. Sun, C. C. Materials science tetrahedron - A useful tool for pharmaceutical research and development. J. Pharm. Sci. 98, 1671–1687 (2009).


Collapse of spherical agglomerates at 20 ℃ (a) starting to at 30 min, (b) 40 min and (c) 50 min. (The agitation was temporarily stopped for better visualization)


Primary crystal size and fracture stress of corresponding agglomerates produced from different crystallization processes. a) BSR=0.89, b) BSR=0.74. (Factor 1: BA concentration, Factor 2: ethanol-to-water volume ratio).


SEM images of internal structure of agglomerates with different fracture stresses: a) 0.27 MPa, b) 0.32 MPa, c) 0.39 MPa, d) 0.85 MPa, e) 1.17MPa, f) 1.33 MPa