A Refined Thin-Film Model for Drug Dissolution Considering Radial Diffusion - Simulating Powder Dissolution.

PURPOSE: We aim to present a refined thin-film model describing the drug particle dissolution considering radial diffusion in spherical boundary layer, and to demonstrate the ability of the model to describe the dissolution behavior of bulk drug powders. METHODS: The dissolution model introduced in this study was refined from a radial diffusion-based model previously published by our laboratory (So et al. in Pharm Res. 39:907-17, 2022). The refined model was created to simulate the dissolution of bulk powders, and to account for the evolution of particle size and diffusion layer thickness during dissolution. In vitro dissolution testing, using fractionated hydrochlorothiazide powders, was employed to assess the performance of the model. RESULTS: Overall, there was a good agreement between the experimental dissolution data and the predicted dissolution profiles using the proposed model across all size fractions of hydrochlorothiazide. The model over-predicted the dissolution rate when the particles became smaller. Notably, the classic Nernst-Brunner formalism led to an under-estimation of the dissolution rate. Additionally, calculation based on the equivalent particle size derived from the specific surface area substantially over-predicted the dissolution rate. CONCLUSION: The study demonstrated the potential of the radial diffusion-based model to describe dissolution of drug powders. In contrast, the classic Nernst-Brunner equation could under-estimate drug dissolution rate, largely due to the underlying assumption of translational diffusion. Moreover, the study indicated that not all surfaces on a drug particle contribute to dissolution. Therefore, relying on the experimentally-determined specific surface area for predicting drug dissolution is not advisable.

Risks of Powder Flow Obstruction in Hopper and Bin Discharge in Solid Dosage Form Manufacture should be Predicted Under The Active Stress State.

Discharge of powder from a hopper or bin is a common operation in solid dosage form manufacture. Powder flow obstruction during hopper/bin discharge, such as arching or ratholing, remains an outstanding risk and cannot be reliably diagnosed using the existing flow function coefficient-based method. In this study, we showed that the major principal stress (σ1) at the bin outlet is required for an accurate prediction of powder flow obstruction risks. We noted that powder is susceptible to flow obstruction when the unconfined yield strength exceeds the stress facilitating powder failure. We presented a complete model to calculate the stress conditions and subsequently predict flow obstruction risks in hopper/bin discharge based on this criterion. The method was experimentally verified by hopper/bin discharge experiments encompassing 10 powder blends and 2 equipment systems. Importantly, we showed that the active stress state assumption should be employed for the powder flow obstruction prediction because σ1 is high and powder is more susceptible to flow obstruction. Prediction under the passive stress state can lead to significant under-estimation of flow obstruction risks. Therefore, the hopper design protocol, which assumes the passive stress state in arching prediction, should not be indiscriminately used toward pharmaceutical powder flow applications.

Finite Element Analysis of Extrinsic Parameters on the Onset of Tensile Strength in Powders.

Most food, pharmaceutical, and chemical industries rely heavily on the supply of free-flowing powders that finds their application in raw materials, additives, and manufactured products. Improper storage conditions combined with environmental factors affect the free-flowing ability of powders. An undesirable transformation of these free-flowing powders into a coherent mass that resists flow is called caking. An important metric that can be used to measure the caking propensity of a material is the tensile strength, which is essentially the resistant stress needed to separate two layers of materials using an isostatic tensile strain. Even though several models have quantified the propensity of caking, the complex nature of interactions between the powder and its micro-environment makes the prediction of caking a challenging task. In the present work, the onset of tensile strength in isomalt with changes in temperature, relative humidity, and consolidation pressures using a shear cell was modeled using a finite element approach. The study found that at a consolidation pressure of 3 kPa and relative humidity of 85±0.1%, an increase in temperature by 5˚C increased the tensile strength of isomalt by a factor of 2. On the other hand, at a constant temperature of 25˚C, an increase in relative humidity from 85±0.1% to 86±0.1% registered an increase in tensile strength by 42.7%. This study also found that an increase in consolidation pressure from 3 kPa to 6 and 9 kPa increased the tensile strength by a factor of 1.79 and 2.54, respectively. The model had good agreement with the measurements and had an overall MAPE of 12.13%. This model can be applied to study the influence of extrinsic parameters on the propensity of caking during storage of bulk solids.