(98f) Spherical Agglomeration of Paracetamol: A Mechanistic Approach

Spherical agglomeration is a size enlargement technique which offers many advantages such as ease of active pharmaceutical ingredient (API) handling and improved tabletability. Consequently, this reduces the need for further downstream processing during the manufacture of pharmaceuticals. In the spherical agglomeration process, an immiscible bridging liquid is added to agglomerate a suspension of primary particles. There are many process and formulation parameters that influence the final agglomerate properties, and the bridging liquid to solid ratio (BSR) is considered to be highly important. Although there has been a considerable amount of research regarding spherical agglomeration, there are a lack of studies that focus specifically on mechanistic understanding and the rate processes involved [1].

In this work, experiments have been designed to study the spherical agglomeration mechanism via immersion nucleation, i.e. where the bridging liquid droplets are larger than the primary particles to be agglomerated. Here, particles cover the droplets and subsequently penetrate the droplets forming agglomerate nuclei. A model system using paracetamol crystals suspended in heptane with water as the bridging liquid is used in this study.

A range of bridging liquid to solid ratios was investigated by adding the appropriate amount of bridging liquid directly to a stirred suspension of paracetamol crystals in heptane, at different solid loadings using a novel methodology. The product was characterized using image analysis (optical microscopy and digital photography). To establish the kinetics of the process, residence time studies were conducted. Samples were taken from the reactor at different time intervals and analysed. Agglomerate size and shape were determined via image analysis. Agglomerate density was measured using a combination of mass measurement and image analysis. The extent of agglomeration as a function of time was determined using a wet sieving technique. In certain experiments, the bridging liquid was dyed with acid red. This allowed visualization of the droplets, and confirmed that the spherical agglomeration process was via the immersion nucleation mechanism.

An optimum BSR range (0.7-0.8) has been identified where 100% agglomeration occurs. Here, stable, dense and highly spherical agglomerates with excellent flow properties are formed. This optimum BSR is independent of solid loading. Below the optimum BSR, a mixture of primary particles and agglomerates is produced. Above the optimum BSR, 100% agglomeration occurs, followed by formation of a paste; the timescales of which are dependent on both the BSR and the solid loading, as are the properties of the agglomerates prior to paste formation.

Changes in the extent of agglomeration and agglomerate properties (density, size) as a function of residence time also give insights into the mechanisms of spherical agglomeration via immersion nucleation. These kinetic studies will be used to validate a recently developed immersion nucleation mathematical model [2].

[1] K. Pitt et al. Powder Technol. 326 (2018) 327-343

[2] O. Arjmandi-Tash et al. Chem. Eng. Sci. X 4 (2019) 100048