Studying the dissolution of immediate release film coating using terahertz pulsed imaging.

Coated tablets introduce complexity to the dissolution process, even with readily soluble immediate release coating layers. Therefore, a more detailed understanding of the physical steps involved in the dissolution process can improve the efficiency of formulation and process design. The current study uses terahertz pulsed imaging to visualise the hydration process of microcrystalline cellulose (MCC) tablet cores that were film coated with an immediate release coating formulation upon exposure to the dissolution medium. Film coated tablets that were prepared from three levels of core porosity (10%, 20% and 30%) and with coating thickness in the range of 30µm to 250µm were investigated. It was possible to resolve and quantify the distinct stages of wetting of the coating layer, swelling of the MCC particles at the core surface, and dissolution of the coating layer followed by the ingress of dissolution media into the tablet core. The liquid transport process through the coating layer was highly consistent and scalable. The penetration rate through the coating layer and the tablet core both strongly depended on coating thickness and core porosity.

Visualising liquid transport through coated pharmaceutical tablets using Terahertz pulsed imaging.

Dissolution of pharmaceutical tablets is a complex process, especially for coated tablets where layered structures form an additional barrier for liquid transport into the porous tablet matrix. A better understanding of the role of the coating structure in the mass transport processes that govern drug release, starting with the wetting of the coating layer by the dissolution medium, can benefit the formulation design and optimisation of the production. For this study, terahertz pulsed imaging was used to investigate how dissolution medium can penetrate coated tablets. In order to focus on the fundamental process, the model system for this proof-of-principle study consisted of tablet cores made from pure microcrystalline cellulose compacted to a defined porosity coated with Opadry II, a PVA-based immediate release coating blend. The coating was applied to a single side of flat-faced tablets using vacuum compression moulding. It was possible to resolve the hydration of the coating layer and the subsequent liquid ingress into the dry tablet core. The analysis revealed a discontinuity in density at the interface between coating and core, where coating polymer could enter the pore space at the immediate surface of the tablet cores during the coating process. This structure affected the liquid transport of the dissolution medium into the core. We found evidence for the formation of a gel layer upon hydration of the coating polymer. The porosity of the tablet core impacted the quality of coating and thus affected its dissolution performance (r =  0.6932 for the effective liquid penetration rate RPeff and the core porosity). This study established a methodology and can facilitate a more in-depth understanding of the role of coating on tablet dissolution.

Insights into the Control of Drug Release from Complex Immediate Release Formulations.

The kinetics of water transport into tablets, and how it can be controlled by the formulation as well as the tablet microstructure, are of central importance in order to design and control the dissolution and drug release process, especially for immediate release tablets. This research employed terahertz pulsed imaging to measure the process of water penetrating through tablets using a flow cell. Tablets were prepared over a range of porosity between 10% to 20%. The formulations consist of two drugs (MK-8408: ruzasvir as a spray dried intermediate, and MK-3682: uprifosbuvir as a crystalline drug substance) and NaCl (0% to 20%) at varying levels of concentrations as well as other excipients. A power-law model is found to fit the liquid penetration exceptionally well (average R2>0.995). For each formulation, the rate of water penetration, extent of swelling and the USP dissolution rate were compared. A factorial analysis then revealed that the tablet porosity was the dominating factor for both liquid penetration and dissolution. NaCl more significantly influenced liquid penetration due to osmotic driving force as well as gelling suppression, but there appears to be little difference when NaCl loading in the formulation increases from 5% to 10%. The level of spray dried intermediate was observed to further limit the release of API in dissolution.

Predicting capsule fill weight from in-situ powder density measurements using terahertz reflection technology.

The manufacturing of the majority of solid oral dosage forms is based on the densification of powder. A good understanding of the powder behavior is therefore essential to assure high quality drug products. This is particularly relevant for the capsule filling process, where the powder bulk density plays an important role in controlling the fill weight and weight variability of the final product. In this study we present a novel approach to quantitatively measure bulk density variations in a rotating container by means of terahertz reflection technology. The terahertz reflection probe was used to measure the powder density using an experimental setup that mimics a lab-scale capsule filling machine including a static sampling tool. Three different grades of α-lactose monohydrate excipients specially designed for inhalation application were systematically investigated at five compression stages. Relative densities predicted from terahertz reflection measurements were correlated to off-line weight measurements of the collected filled capsules. The predictions and the measured weights of the powder in the capsules were in excellent agreement, where the relative density measurements of Lactohale 200 showed the strongest correlation with the respective fill weight ( R 2 = 0.995 ). We also studied how the density uniformity of the powder bed was impacted by the dosing process and the subsequent filling of the holes (with excipient powder), which were introduced in the powder bed after the dosing step. Even though the holes seemed to be filled with new powder (by visual inspection), the relative density in these specific segments were found to clearly differ from the undisturbed powder bed state prior to dosing. The results demonstrate that it is feasible to analyze powder density variations in a rotating container by means of terahertz reflection measurements and to predict the fill weight of collected capsules.