Development of low dose micro-tablets by high shear wet granulation process

Area of Science:

• Pharmaceutical Technology
• Drug Delivery Systems
• Formulation Development

Background:

• Low dose micro-tablets offer enhanced dose flexibility and reduced excipient burden, especially for pediatric populations.
• Direct compression of low dose micro-tablets presents challenges in achieving acceptable content uniformity (CU).
• High shear wet granulation (HSWG) is explored as a viable alternative to improve CU in micro-tablet manufacturing.

Purpose of the Study:

• To evaluate the high shear wet granulation (HSWG) process for manufacturing low dose micro-tablets with reduced content uniformity (CU) variability.
• To investigate the impact of active pharmaceutical ingredient (API) particle size and loading on critical quality attributes of micro-tablets.
• To assess the weight variability, CU, and dissolution profiles of micro-tablets produced via HSWG.

Main Methods:

• Micro-tablets (1.2 and 1.5 mm) were manufactured using the HSWG process.
• The study evaluated various active pharmaceutical ingredient (API) particle sizes (D90: 18–180 µm) and loadings (0.67–16.67% w/w).
• Critical quality attributes including weight variability, content uniformity (CU), and dissolution were assessed.

Main Results:

• Final blends with a flow function coefficient (ffc) ≥ 5.4 or Hausner ratio (HR) ≤ 1.43 ensured robust micro-tablet compression.
• Most batches met USP <905> CU acceptance criteria for individual and composite micro-tablets, with specific exceptions noted for 1.2 mm tablets and certain 2.0 mm formulations.
• API particle size and loading significantly influenced in-vitro dissolution; smaller API particles and lower loadings resulted in faster drug release.

Conclusions:

• The HSWG process provides a framework for developing low dose micro-tablets with acceptable quality attributes, meeting stringent CU requirements.
• This granulation technique enables precise micro-dosing, offering dose titration in increments as small as 11 mcg.
• HSWG facilitates enhanced dose flexibility and reduced excipient burden, crucial for pediatric formulations and personalized medicine.