(M0930-01-03) Overcoming Direct Compression Issues in Omeprazole Formulations Using Co-Processed Excipient vs. Wet Granulation

Purpose: The use of co-processed excipients is on the rise. This innovative approach effectively addresses direct compression (DC) challenges like flowability, compressibility, disintegration, and lubrication requirements. Newly launched “all-in-one” co-processed excipient Kollitab™ DC 87L contains filler, binder, disintegrant and lubricant for a blend with good flowability, compressibility, and lubrication effect. In present study, instant release mini tablets containing omeprazole were manufactured by DC method by employing an algorithm based virtual tool and the “all-in-one” excipient and compared against the pellet formulation manufactured by wet granulation followed by extrusion and spherization process.

Methods: The particle size distribution (PSD), flow, compressibility and compactibility profile of micronized omeprazole and all-in-one excipient were characterized. An online free Virtual Pharma Assistant tool (ZoomLab^TM) was used to predict the performance of the omeprazole and the co-processed blend at various drug loadings using single component data, applying proprietary mixing rules. Based on the tool prediction, a simple DC method was selected at 13.3% drug loading. Briefly, micronized omeprazole and co-processed excipient were passed through 30 mesh screen and blended in a V blender. The blend was compressed into 2.0 mm diameter mini-tablets with Piccola Tablet Press with 5 mm fill cam. Alternatively, omeprazole pellets were prepared by wet granulation. Briefly, micronized omeprazole (13.3%), microcrystalline cellulose special (15, 30 and 45%), Hydroxypropyl Methylcellulose (hypromellose 2910-5) (5%), and mannitol (q.s. 100) were mixed for 10 min and granulated by adding water (28%; 120 g/mL) in 1L bowl of mixer Key G-5 Granulator operating at 100-200 rpm of impeller speed and chopper off mode for 10 min. The wet granules were extruded (1.0 mm screen) and sermonized (2.0 mm cross-hatched friction plate) by operating at 800 RPM sermonize speed for 3 min/80-100 g load. The wet pellets were dried in a the fluid bed dryer using an inlet temperature of 60 ºC for 30-50 min (endpoint target value LOD≤ 1.0% on uncrushed pellets) and pellets passing through 12 mesh and retained on 20 mess were considered as acceptable (for 300 g batch, the yield of the final pellets were: 50%, ~ 80, and 85 % for the composition containing 15% MCC, 30% MCC and 45% MCC, respectively)

Results: The micronized form of omeprazole exhibited small yet wide particle size distribution and extremely poor flow properties, as indicated by the Carr’s Index, Hausner Ratio, and a high angle of repose. In contrast, the active pharmaceutical ingredient (API) alone tablet demonstrated greater than 5 value for overall compressibility and compactability when compressed at 100, 150, and 250 Mpa (Zoomlab^TM score were 7.1 and 5.2 out of 10, respectively), suggesting favorable compactability and compressibility properties of API alone (Figure 1 gray colored graph). As a result, pharmaceutical companies often employed omeprazole pellet strategies by focusing on improving the API particle size and flow properties via wet granulation. For this study, pellet core components (MCC, HPMC, Mannitol) were selected based on package insert of omeprazole capsule, delayed release^[1]). Various drug-to-MCC ratios (1:2, 1:1, and 2:3) were chosen to achieve an instant release profile while maintaining constant amounts of the HPMC and Mannitol. However, the dissolution profile of the omeprazole pellets exhibited a sustained release pattern, failing to achieve the desired instant release, i.e., complete dissolution within 2 hours at a pH of 6.8 (Figure 2). Hence, this strategy required further optimization. Alternatively, preparation of omeprazole mini-tablets using an "all-in-one" excipient was explored. This method was simplified by the use of a virtual pharma assistant tool. Based on recommendation from the virtual tool, a proposed value >5 for overall processability of the pure API and “all-in-one” co-processed blend up to 13.33% drug loading and a direct compression as a manufacturing route was suggested. Subsequently, the mini-tablets were formulated through a single mixing step followed by compression at a low pressure (5-6 kN) to achieve >1.5 kP tablet hardness. The resulting yield of the product exceeded 98.9%, a marked improvement compared to the pellet method mentioned earlier (45% to 85%). Additionally, no extra lubrication was required for the formulation of these mini-tablets. The omeprazole minitablets formulated with the co-processed excipients showed the desired instant release profile i.e. complete dissolution >90% drug release within 15 min.

Conclusion: The currently marketed composition of the core omeprazole pellet necessitates optimization of ingredient ratios and intricate manufacturing steps, including wet granulation, extrusion, spherization, and drying, to achieve an instant release profile for the drug-loaded pellet. For poorly flowable APIs such as omeprazole, the "all-in-one" co-processed excipient presents an ideal solution to enhance blend flowability, compressibility, and tabletability and provides simplified formulation process and reduce manufacturing complexity, which eliminates costly and labor-inducive wet or dry granulation process. Moreover, omeprazole mini-tablets exhibited an instant release profile. The benefits of “all-in-one” co-processed excipient can lead to a simplified drug development process, reduced manufacturing costs, and accelerated time-to-market for omeprazole and other drugs with similar characteristics.

References: 1. Sandoz Inc. (2022). OMEPRAZOLE- omeprazole capsule, delayed release. NDC:0781-2790


Figure 1: ZoomlabTM based risk analysis and a selection of proposed manufacturing routes for omeprazole and its co-processed excipient blend at 13% drug loading. Particle size is described by D10, D50, and D90, while physical characteristics are indicated by DSP (distribution span), DBU (bulk density), DTA (tap density), CAR (Carl index), HAR (Hausner ratio), AOR (angle of repose), CPR (compressibility), CMP (compactability), and TST 100, TST 150, and TST 250 (tensile strength of the tablet at 100, 150, and 250 MPa compression pressure, respectively).


Figure 2: Dissolution of omeprazole minitablet and pellets (various ratio of drug to MCC) at 13% drug loading in the dosage form