4D study of liquid binder penetration dynamics in pharmaceutical powders using synchrotron X-ray micro computed tomography.

The properties of pharmaceutical powders, and the liquid binder, directly influence the penetration behavior in the wet granulation process of the pharmaceutical industry. Conventional methods encounter challenges in understanding this fast process. In this work, an emerging synchrotron-based X-ray imaging technique (having fast imaging capability) was employed to investigate the internal process from 2D and 3D to real-time (in-situ with ms time intervals) 3D (also considered 4D) perspectives. Two commonly used excipients (lactose monohydrate (LMH) and microcrystalline cellulose (MCC)) were used to make binary mixtures with acetaminophen (APAP) as the active pharmaceutical ingredient (API). Isopropanol and water were employed as liquid binders in the single droplet impact method. Results showed that for most of the mixtures, the porosity increased at higher fractions of APAP. MCC mixtures experienced less agglomeration and more uniform pore distribution than LMH ones, resulting in a faster droplet penetration with isopropanol. Moreover, the imbibition-spreading studies showed that isopropanol penetration in MCC powders followed more unidirectional vertical movement than horizontal spreading. Our results also demonstrated that simultaneous granulation of LMH with water resulted in much slower penetration. This study revealed that synchrotron X-ray imaging can investigate 3D internal pore structures and how they affect the quantitively real-time internal penetration dynamics.

Synchrotron-based X-ray in-situ imaging techniques for advancing the understanding of pharmaceutical granulation.

Wet granulation of powders is a key unit operation in the pharmaceutical industry. Due to the complexity of the granulation process taking place in a short time, observing and measuring the granulation process is challenging with conventional experimental methods. In this study, synchrotron-based X-ray imaging techniques were, for the first time, employed to capture the dynamic granulation process with a single drop impacting method in pharmaceutical powder beds. Five common pharmaceutical excipients, two active pharmaceutical ingredients (APIs) and their mixtures were used as the powder beds. The dynamic interaction between the liquid binder and solid powders were observed from high resolution X-ray images captured. Results show that pharmaceutical powder properties, including particle size, hydrophilicity, and morphology, have significant influence on the dynamic granulation process and the final granular product.

Granule formation and structure from single drop impact on heterogeneous powder beds.

Single drop impact of liquid on a static powder bed was studied to investigate the granule formation mechanism, droplet penetration time, as well as the characterization of granules (morphology, surface structure and internal structure). Water was used as the liquid and two pharmaceutical powders, microcrystalline cellulose (MCC) and acetaminophen (APAP), were mixed to make heterogeneous powder beds. The complete drop impact and penetration was recorded by a high speed camera. Two granule formation mechanisms that have been identified previously occurred: Spreading and Tunneling. Spreading occurred for mixtures with an APAP amount of less than 20%, while Tunneling started to occur when the APAP amount increased above 20%. With an increase of APAP concentration, the mean particle size decreased, drop penetration time increased, and the granules formed became smaller in size, which was in good agreement with previous literature. The granule morphology, surface structure, and internal structure were characterized by a prism method with image analysis, scanning electron microscopy (SEM), and X-ray microtomography, respectively. The Spreading mechanism produced flat disks with a porous internal structure, while the Tunneling mechanism produced round granules with a dense internal structure. There is a clear trend of decreasing porosity and increasing roundness of granules made from heterogeneous mixtures within the transition from Spreading to Tunneling. It is believed that the mean particle size of the powder bed and the powder-liquid contact angle are the predominant factors in influencing the formation mechanism, drop penetration time, and granule properties.

Modeling the granule formation mechanism from single drop impact on a powder bed.

Granule formation from drop impact on a powder bed can occur by either Tunneling or Spreading/Crater Formation. The governing regime can be specified by the experimentally determined modified Bond number (Bo(g)*), which is a ratio of the capillary force to the gravitational force acting on a particle. It was hypothesized that Tunneling would occur when the capillary and surface tension forces exceeded the weight of a powder aggregate in contact with the drop. To confirm this hypothesis, force balances were derived for a drop in contact with a single particle and separately for a drop in contact with an aggregate to predict when a particle or aggregate will be sucked into the drop. The force ratios derived for each case were compared to the Bo(g)* force ratio used in a previously published regime map that separates Tunneling from Spreading/Crater Formation. The force balance model correctly predicts the trends of the impact of powder and liquid properties on the governing regime. However, the single particle model does not quantitatively predict the critical Bond number for regime change in Tunneling. The aggregate model gave a better prediction of the Tunneling boundary than the single particle model, but it still under predicts the experimentally determined Tunneling criterion given by the Bond number. Potential reasons for this discrepancy are discussed.