(W1230-10-56) Efficient Manufacturing of Omeprazole Modified-Release Minitablets Using “All-in-One” Co-Processed Excipient and Talc-Free Aqueous Coating System

Purpose: The primary objective of this study was to develop delayed-release omeprazole minitablets using a co-processed excipient (Kollitab^TM DC 87L, BASF) with a direct compression method. To ensure the stability of omeprazole, core tablets were seal coated with polyethylene glycol-polyvinyl alcohol graft copolymer (Kollicoat^® IR) followed by the enteric coating using methacrylic acid-ethyl acrylate co-polymer (1:1) dispersion (Kollicoat^® MAE 30 DP, BASF). Additionally, a talc-free enteric coating composition was evaluated to enable fast and efficient coating process.

Methods: Omeprazole was characterized for particle size distribution, flow, and compressibility, and compactability profile. A free, online, algorithm-based tool (ZoomLab^TM) was used to predict the processability of the omeprazole and the co-processed blends at various drug loadings, and choice of seal coating and enteric coating based on quality target product profile. The tool predicted blend properties using mixing rules of single-component data (1). Based on the tool prediction, a simple direct compression method (DC) was selected at 13.3% drug loading. Tool recommended composition was selected for seal and enteric coating (2). As per predictions, the directly compressible tablet blend was prepared by screening and mixing the drug and co-processed excipient in a PK shell V blender. The blend was compressed into minitablets on Piccolo Press (RIVA S.A., Argentina) using 2.00 mm standard concave round shaped multi-tip punch at a precompression force 0.2 kN and compression force 4-6 kN. The minitablets were seal coated at 10% weight gain using 20% coating solution of Kollicoat® IR without plasticizer in in Freund Vector LDCS Coater (with 0.5 L pan). Finally, minitablets were enteric coated at various coating levels (8%, 12% 16%, and 20% w/w coating weight gains) using 20% coating dispersion of Kollicoat® MAE 30 D containing triethyl citrate, with talc and without talc compositions. In vitro dissolution studies of minitablets were performed using USP type II apparatus, 750 ml of 0.1 M HCl (2 hr.) followed by 1000 mL phosphate buffer pH 6.8 for 3h at paddle speed of 100 rpm and 37± 0.5°C.

Results: Minitablets containing only omeprazole demonstrated a score of greater than 5 (ideal 10, good 5-10 on a radial chart) for overall compressibility and compactability suggesting favorable compactability and compressibility properties. However, the micronized form of omeprazole exhibited a small yet wide particle size distribution and very poor flow properties, as indicated by the Carr’s Index, Hausner Ratio, and a high angle of repose (data are not shown). Therefore, processability with various excipients/blends was evaluated in the tool. A co-processed excipient was predicted to offer desired flow and mechanical properties at 13.33% drug load. This is a unique and all-in-one excipient consisting of lactose (filler), Kollicoat^® IR (binder), Kollidon^® CL-F (disintegrant) and sodium stearyl fumarate (lubricant) and offers good flowability, compressibility, and lubrication properties. Uncoated minitablets containing 20 mg of omeprazole (tablet weight 150 mg) exhibited adequate mechanical strength ( >1.7 mPa-s) and passed the friability test indicating their suitability for the coating process. Kollicoat IR polymer at 20% solids level was selected for seal coating given its higher elasticity without the use of plasticizer, peroxide free nature, and ability to use higher solids over conventional hydroxypropyl methyl cellulose coatings. The seal coating solution exhibited low viscosity ( < 100 mPa-s) and enabled faster processing for a weight gain of 14-15% w/w (5.8 – 6.2 mg/cm²). Further, the enteric coating properties of Kollicoat MAE 30D were investigated on seal coated minitablets. Results of the study indicated that a minimum 13.6% weight gain (no talc) and 16% weight gain (with talc) for enteric coating was required for functionality i.e., no drug release at gastric pH ( < 1.2) in 2 h (Figure 1). Interestingly, talc and talc free coated minitablets demonstrated similar dissolution performance even at higher coating level (f2= 78.75 ± 6.72, 16% weight gain with no talc, and f2 = 67.49 ± 1.80, 20% weight gain with talc, 16% weight gain, reference dissolution is the 16% weight gain enteric coating with talc), and complete drug release ( >85%) at pH of 6.8 within 90 min (Figure 2). These findings suggest talc free coating may offer similar performance to that of talc containing coatings for omeprazole minitablets, enabling simpler formulation and efficient coating solution.

Conclusion: For poorly flowable APIs such as omeprazole, the "all-in-one" co-processed excipient presents an ideal solution to enhance flow, compressibility, and tabletability, leading to simplified formulation process and reduce manufacturing complexity. The enterically coated omeprazole minitablets exhibited desired enteric performance in both talc and talc-free coating compositions. The minimum enteric coating level for desired performance in the talc free compositions was at 13.6 % which was lower than talc containing compositions (16%). This paper presents the benefits of combining use of digital tool, “all-in-one” co-processed excipient, and talc-free enteric coating processing for an efficient drug development, 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
(2) Ji et al “Formulation of Omeprazole Minitablets with Delayed Release: A Seal and Enteric Polymer Coating Approach” AAPS
PharmSci 360 Poster, 2023, M1030-03-18.

Figure 1: Comparison of in vitro dissolution data (gastric fluid) of enterically coated omeprazole minitablets coated with or without talc.

Figure 2: Comparison of in vitro dissolution data (Intestinal fluid) of enterically coated omeprazole minitablets coated with or without talc.