Enabling Direct Compression of Low Dose Sustained-Release Tablets
by Integrated Particle Engineering
Wei-Jhe Sun and Changquan Calvin Sun
Pharmaceutical Materials Sciences and Engineering Laboratory, Department of
Pharmaceutics, University of Minnesota, 55455
Purpose:
A sustained-release (SR) tablet is advantageous for better clinical outcomes due to the
minimized risk of side effects and increased patient compliance. Hydroxypropyl
methylcellulose (HPMC) is often used in matrix SR tablets to control release of the drug
but it is unfit for direct compression due to its poor flowability. In addition, when the
drug dose is extremely low, the direct compression process is challenged by the
problem of poor content uniformity. The purpose of this work is to develop a platform
tablet formulation to enable the direct compression of low dose sustained-release
tablets. This is achieved through integrated particle engineering to address poor
flowability of HPMC by nanocoating and to ensure content uniformity of tablets by
loading drug in a porous carrier.
Methods:
Acetaminophen was used as a model compound. Neusilin® S1, having a high specific
surface area and high water adsorbing capacity, was chosen as a drug carrier. To load
drug into Neusilin®, a suitable amount of drug was dissolved into dimethylformamide to
prepare a solution with the desired drug concentration. The drug solution was then
added to Neusilin® powder under stirring, followed by drying in a vacuum oven to
obtain a drug-carrier composite. Nanocoated HPMC was prepared by depositing silica
nanoparticles on the HPMC particle surfaces using an under-driven Comil® with 20
comilling cycles. The drug-carrier composite, nanocoated HPMC, spray-dried lactose,
microcrystalline cellulose, and magnesium stearate were mixed using a V-shaped
laboratory blender. Tablets were compressed on a compaction simulator. Drug
content in individual tablets was determined by dissolving each tablet in water and
measuring the absorbance by a UV/Vis Spectrophotometer at a wavelength of 247 nm.
Dissolution was assessed using a USP type II dissolution apparatus.
Results:
Surface coating with colloidal silica led to free-flowing HPMC. Consequently, the
platform formulation shows excellent powder flowability as shown by the essentially
constant weight of tablets prepared on the compaction simulator operated at a high
speed. The platform formulation also exhibited good tabletability, where higher than
2 MPa tablets could be prepared. Good content uniformity (approximately 100% of
the expected potency and < 1.0% relative standard deviation (RSD)) was obtained over
the entire range of 0.01% - 1% drug loading in the tablet. This is far superior to the
physical mixtures (70% - 175% of the expected potency and 3.6% - 34.0% RSD over the
same range of drug loading). The platform tablet formulation, enabled by integrated
particle engineering, is suitable for manufacturing low dose sustained-release tablets
using the direct compression process. The sustained release behaviors of these tablets
were confirmed by dissolution data.
Conclusion:
We have developed a platform direct compression tablet formulation, through
integrated particle engineering, to enable the manufacture of low dose SR tablets with
superior content uniformity and manufacturability.
This novel platform DC
formulation is robust and has the potential to expedite the development of high quality
SR tablet products using the economical DC process.