Purpose: Direct compression (DC) formulations are greatly impacted by excipients and active pharmaceutical ingredient (API) properties. In this simple method, formulation blends compress into tablets without a pre-granulation or agglomeration process. Therefore, direct compression formulations require excipients with improved quality and consistency. API physical and mechanical properties, such as particle size and compactibility, may also significantly influence the manufacturing process and product attributes. In this study, the effect of particle size of acetaminophen (APAP), as a poorly compactible model API, on physical properties and in vitro performance of direct compression matrix tablets was evaluated. A DC grade of hydroxypropyl methylcellulose (HPMC), METHOCEL™ K100M Premium DC2 was used as release rate-controlling polymer in the study.
Methods: Three grades of acetaminophen (APAP) with a wide range of particle size, d50 27 – 360 micron were characterized and studied. Formulation blends containing each grade of APAP at 20% level, HPMC (35%), microcrystalline cellulose (22%), lactose monohydrate (22%), fumed silica and magnesium stearate (0.5% each) were prepared. Each formulation was blended in a V-blender, lubricated and evaluated for powder properties. Next, the blends were compressed into 400 mg tablets on a rotary tablet press equipped with four sets of tooling at 25 rpm press speed. Tablets were characterized for weight, dimension, crushing strength and friability. Tensile strength (TS) of tables were calculated and tablets with TS of 2 MPa were tested for dissolution using USP II apparatus and FloVitro™ technology, a patented biorelevant dissolution test.
Results: The formulation with small crystal APAP had greatest Carr’s index, 29.3. The blend with medium size crystal had lowest Carr’s index, 18.3 and the best flow. All tested tablets demonstrated low weight variation with RSD < 0.7% for the tablets with small crystal and RSD < 0.4% for the tablets with large crystal APAP, indicating satisfactory flow properties of the blends. Compaction profiles (tabletability, Figure 1), displayed no significant impact from the drug particle size studied. All three formulations demonstrated high TS and low friability. Regardless of the significant differences in APAP crystal particle size, there were no significant changes in release profile (not shown) of the tablets using USP II dissolution in DIW or 0.1N HCl. However, formulations with extreme difference in APAP particle size showed different Cmax, 11 mg/L vs 9 mg/L, respectively, when testing with FloVitro, a biorelevant dissolution testing unit (Figure 2).
Conclusion: It is demonstrated that METHOCEL™ K100M Premium DC2 HPMC may be used to develop a robust controlled release matrix formulation for acetaminophen tablets using a simple direct compression process. Acetaminophen tablets, regardless of significant difference in drug crystal particle size, demonstrated low tablet weight variation, high tensile strength and consistent extended-release performance indicating formulation robustness and excellent properties of the release rate-controlling polymer. It is also shown that an in vitro biorelevant dissolution study using FloVitro™ technology may detect the hidden impact of drug particle size on drug release, tablet performance and potentially predict in vivo impact of API particle size. While in vitro dissolution studies using USP II indicated similar dissolution performance, results of a biorelevant dissolution testing with FloVitro demonstrated higher Cmax for tablets containing smaller particle size API compared to that of tablets containing large particle size API.