(T1330-04-20) Hydrodynamic Robustness of New Hydroxypropyl Cellulose Grade for Modified Release Matrix Systems

Purpose: Extended-release formulations may provide several benefits, including reduced dosing frequency, improved efficacy, reduced adverse effects, and improved patient compliance. Among the various types of extended-release dosage forms, the hydrophilic matrix is the most widely used platform for drug delivery. Hydroxypropyl methylcellulose (HPMC) is the most common polymer used for controlled release oral dosage forms. To overcome limitations of commercially available HPMC grades, a new high molecular weight hydroxypropyl cellulose (HPC) grade has been evaluated its hydrodynamic robustness in modified release matrix systems.

Methods: Polymer gel strength of the new high molecular weight hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) K100M were determined using a Discovery Hybrid Rheometer (DHR-3) with Peltier heating stage. Next, the effect of polymer levels in the tablet formulation on drug release were investigated using Ibuprofen and Metformin as model drugs. Table 1 lists the direct-compression tablet formulation used for each drug, with different polymer levels. For melt granulation, each drug-polymer was extruded using a Leistritz 18 mm twin-screw extruder. The extrudate of each drug was milled and blended with the other ingredients listed in Table 2. Due to the high melting point of metformin HCl and non-extrudable nature of HPMC, only one level of polymer was evaluated for the metformin tablet formulation. Tablets made by direct compression and melt granulation were characterized. Dissolution (n=3) of each formulation was conducted in 900 mL of pH 7.2 phosphate buffer 0.050M (for ibuprofen tablets) and pH 6.8 phosphate buffer 0.05M (for metformin tablets) maintained at 37°C with USP Apparatus 1 (baskets) at 100 RPM. Samples were taken at 0.25 hr intervals up to 1 hr, then at 1 hr intervals to 24 hours; quantitation was by online UV detection.

Results: Pure polymer characterization showed that the new high molecular weight hydroxypropyl cellulose (HPC) has much higher gel strength (53.3%) than hydroxypropyl methylcellulose (HPMC) K100M, indicating that the new HPC grade can maintain better hydrated tablet integrity than hydroxypropyl methylcellulose (HPMC). For Ibuprofen tablet formulations made by both direct compression and melt granulation, the tablet formulation with the new HPC grade has similar tablet strength to the formulation with HPMC. However, the tablet formulations with new HPC have slower drug release than the tablets with HPMC K100M. Due to the greater gel strength, ibuprofen tablets with 10% of new HPC grade show similar drug release profiles to the 20% HPMC formulation (Figure1). For metformin tablet formulations, direct compression formulations with both polymers also had similar tablet hardness. However, the new HPC tablets have better controlled-release profiles than the HPMC tablets. Due to non-extrudable nature and high melting point of metformin, only 20% polymer can be used for this comparison between two polymers. As a results, the melt granulation tablet formulation with 20% new HPC yielded much harder tablets and slower drug release than the formulation with HPMC.

Conclusion: Although HPMC is the most commonly used polymer for controlled release, one limitation is that HPMC is not suitable for very highly water-soluble drugs. New high molecular weight hydroxypropyl cellulose (HPC) grade has high gel strength, which can limit any burst effect for delivery of highly-soluble drugs. In addition, the new grade HPC not only can enable smaller tablet sizes by usage of lower polymer level in the formulation, but also is excellent for hot melt extrusion or continuous processing technologies.

Figure 1: Better Controlled Release of Ibuprofen by New HPC Than HPMC in 0.05M Phosphate pH 7.2 Buffer



Table 1: Direct compression tablet formulations



Table 2: Melt granulation tablet formulations