Directly compressible hydroxypropyl methylcellulose (HPMC) to support continuous manufacturing

This work was undertaken to evaluate a novel hydroxypropyl methylcellulose excipient used in the manufacture of hydrophilic matrix tablets for oral controlled release. This material was coprocessed with a small amount of silicon dioxide to provide improvements over the standard material and was shown to have better flow, compactability and less triboelectric charging demonstrating an improved performance in a loss-in-weight feeder. As a result, this material is preferred for use in continuous manufacturing via direct compression which would be problematic for the standard grade. Finally, a methodology was developed to calibrate the material properties for a computer simulation of the loss-in-weight feeder using the discrete element method which was shown to have good correlation with the experimental results.

Download the full thesis here: Directly compressible hydroxypropyl methylcellulose (HPMC) to support continuous manufacturing

or continue reading here: Allenspach, Carl. Directly compressible hydroxypropyl methylcellulose (HPMC) to support continuous manufacturing. Retrieved from https://doi.org/doi:10.7282/t3-evex-3w38

Introduction
Hydroxypropyl methylcellulose (HPMC, hypromellose) is frequently utilized to create hydrophilic matrix tablets for modified release dosage forms. The popularity of these tablets is due to their simple formulation, good safety profile, reproducible release profiles, global acceptability, and cost effectiveness along with well understood diffusion and erosion mechanisms. Patients have benefited from having controlled release dosage forms by reducing the required dosing frequency since the drug is released over time which also improves patient compliance leading to more efficacious medicines. A clinical benefit with extended release dosage forms is the reduced peak plasma concentrations which can allow higher doses and sustained exposure while minimizing adverse safety events compared to immediate release.
HPMC has a long history of use in modified release tablets for almost 60 years with significant research occurring early on. One of the greatest challenges with HPMC when used without being granulated is the poor flow due to the long, fiber like particle morphology. The poor flow of HPMC negatively impacts charging of materials, Loss-in-Weight (LIW) feeding, blending and compression weight variability. Recent material science advances for HPMC have resulted in co-processed materials which have improved flow and compactability. These direct compression (DC) HPMC materials were designed for direct compression and are better suited for use in the LIW feeders which is required for use in continuous manufacturing.

Continuous manufacturing is seeing an increased utilization in pharmaceutical manufacturing since the first product was approved in July 2015 (Orkambi®, Vertex Pharmaceuticals, Boston, USA). There have been a significant number of journal articles, books, and draft guidance from the FDA which encouraged many pharmaceutical companies to explore continuous manufacturing approaches. Development of continuous processes is well suited to the Quality by Design (QbD) approaches already being implemented and facilitated by the advances in Process Analytical Technology (PAT) for continuous monitoring of the product. Some of the advantages of continuous manufacturing include the following: reduced manual handling of materials (leading to improved safety and reduced human error), shorter processing times, improved efficiency, smaller physical footprint, eliminated need for process scale- up, and overall improved product quality. One of the cornerstones of continuous manufacturing is the implementation of modeling approaches. Models can be used during operation to control the process, set limits on excursions, and determine if material needs to be diverted during excursions and for how long. Models can also be used during development to simulate the process providing additional knowledge into the process.
Process modeling of pharmaceutical processes via mechanistic models is advantageous as they capture the underlying physical phenomena through application of fundamental first principles of particles and surfaces such as mass, momentum and energy. They have been shown to have good predictability and are often preferred as they can provide additional scientific insight into modeled operations.

There are different approaches to modeling pharmaceutical processes including computational fluid dynamics (CFD), finite element method (FEM), discrete element method (DEM) and combinations of those being the most widely utilized. The discrete element method also referred historically as distinct element method, is not a new approach to simulate the motion and path of each particle. In fact, an early publication on a discrete numerical model for granular assemblies which introduced DEM concepts, has been referenced over 16,000 times. It describes how motion and momentum are solved for each particle three dimensionally with normal and tangential contact forces included.
While DEM models are computationally intense they can provide more process insight compared to CFD models. Utilization of DEM has become significantly more valuable in recent years as computational speed has increased and modeling approaches become optimized. Research in this area has also increased with an increase in the number of journal publications in recent years. There are also a number of books dedicated to the subject of DEM and applications. Increased computer processing power has allowed for an increased number of particles to be simulated, improved commercially available software has made it easier to model processes. Novel calibration techniques and the improved process and modeling understanding have led to more accurate results of the simulations. DEM in particular provides detailed information into granular flows allowing for increased process knowledge. Powder systems are typically represented by spherical particles to reduce the computational load and extrapolation of results to nonspherical particle systems is highly challenging. For this reason an alternative approach to spheres was required for simulating the elongated HPMC particles.

LIW feeding has the potential to directly impact the homogeneity of the powder mixture resulting in potential impact to the content uniformity of the drug in the final dosage form  and as such it is considered a critical process in continuous manufacturing. This work will look at combining the challenging particle morphology and flow properties of HPMC into the first component of a continuous manufacturing line, the LIW feeder system, utilizing a DEM approach accounting for the nonspherical morphology of HPMC. The different aspects of this work include:

1) Characterization of three different standard HPMC grades and the equivalent three
direct compression grades for particle properties including size, morphology, surface
area, many techniques to evaluate powder flow and tablet compression studies.

2) Loss-in-weight feeder studies of the same six materials and additional characterization studies including triboelectrification, powder flow in a drum, angle
of repose and bulk and tap density

3) Modeling of the LIW Feeder for HPMC

a. Creation of a DEM model material that represents the HPMC K100M DC excipient with appropriate geometrical characteristics.
b. Creation of DEM models for multiple characterization tests to facilitate calibration of the DEM material using measured data for HPMC.
c. LIW feeder DEM simulations with different particle sizes, rates and amounts of material.