(T1330-09-57) Efficient Manufacturing of Omeprazole Modified-Release Pellets Using Talc-Free Aqueous Coating System

Purpose: The study was focused on developing efficient manufacturing processes of delayed-release omeprazole pellets. The drug loaded pellets were prepared by the extrusion and spheronization method. Due to the interaction between omeprazole and the enteric coating polymer, chemical stability of the final formulation was ensured by first applying a sub-coating of instant release (IR) polyethylene glycol-polyvinyl alcohol graft copolymer (KIR; Kollicoat^® IR), followed by an enteric coating using a methacrylic acid-ethyl acrylate copolymer (1:1) dispersion (KMAE; Kollicoat^® MAE 30 DP). A talc-free enteric coating composition was evaluated to enable a fast and efficient coating process.

Methods: The particle size distribution of omeprazole was first characterized by Malvern Mastersizer. A free, online algorithm-based tool (ZoomLab^®) was used to choose the seal coating and enteric coating composition based on quality target product profile. Based on the tool prediction, a recommended composition was selected for seal and enteric coating. Micronized omeprazole (USP; Teva API, USA) (13.3%), hypromellose 2910-5 (5%), microcrystalline cellulose (MCC) (0–45% w/w), mannitol (q.s. to 100%), and crospovidone (5% in the optimized batch) were dry mixed for 15 minutes in a 3 L mixer (Key G-5, Arrow Mixing Products). Granulation was performed by adding water (13% w/w at 80 g/min) at 75 rpm with the chopper off for 5 minutes, followed by wet mixing for 1 minute at 200 rpm with the chopper at 1000 rpm. The wet granules were then extruded through 1.0 mm screen and spheronized using 2.0 mm cross-hatched friction plate, operated at 1600 RPM spherization speed for 1 min/5g load. The pellets were seal coated at 10% weight gain with coating suspension of KIR without plasticizer at 20% solid level in Freund Vector Fluidized Bed Dryer (VFC; Freund Corp). Seal coated pellets were then enteric coated in VFC fluidized bed dryer at various coating levels (15%, 25% and 30% w/w coating gains) with coating suspension containing 1) 17.5% solid with dispersion of KMAE polymer and triethyl citrate and 2) 20% solid with dispersion of KMAE polymer, triethyl citrate and talc. In vitro dissolution studies of the pellets were performed using USP type II apparatus, 750 ml of 0.1 M HCl for the first 2 h followed by 1000 mL phosphate buffer pH 6.8 for 4 h maintained at 37 ± 0.5°C with a paddle speed of 100 rpm.

Results: A range of core pellet formulations containing varying ratios of MCC and mannitol were tested, with HPMC as binder and crospovidone as disintegrant [1]. Pellets with a high MCC content (15–45%), exhibited sustained drug release and failed to achieve complete dissolution within 2 h at pH 6.8. In contrast, pellets optimized with 76% mannitol (no MCC), 5% HPMC and 5% crospovidone delivered immediate drug release (Figure 1). These results suggested that higher levels of water-insoluble matrix (MCC) result in denser pellets and slower dissolution of drug, while replacing the MCC by water-soluble (mannitol) and adding crospovidone created a rapidly dissolving matrix that enhances drug release. The particle size distribution of the manufactured pellets was analyzed using CAMSIZER XT through Dynamic Image Analysis. Results showed that manufactured core pellets and enteric coated pellets (both with and without talc) exhibited uniform particle size distribution. Enteric coating with and without talc, increased particle size and improved the particle size distribution (Table 1). The seal coating KIR solution exhibited low viscosity ( < 100 mPa-s) and enabled faster processing for a weight gain of 14-15% w/w. Comparison of the dissolution profiles of enteric-coated pellets with 30% weight gain (with talc) and 25% weight gain (no talc) for the enteric coating, showed that both exhibited no drug release at gastric pH ( < 1.2) in 2 h, and achieved complete drug release ( >85%) at pH 6.8 within 30 min (Figure 2, after 2h). These findings suggest that the talc-free coating can offer similar performance to that of talc containing coatings of omeprazole pellets, enabling simpler formulation and efficient coating solution.

Conclusion: The core pellet containing omeprazole (DSC Class II b) necessitates optimization of water-soluble and water-insoluble ingredient ratios and intricate manufacturing steps, including wet granulation, extrusion, spheronization, and drying, to achieve an instant release profile for the drug-loaded pellet. KIR was used as a seal coating polymer to avoid drug incompatibility with acidic enteric polymer during the enteric coating process. Enteric-coated omeprazole pellets exhibited the desired enteric performance in both talc and talc-free coating compositions. The enteric coating level for desired performance in the talc-free compositions was at 25% (100 min running time) which was lower than talc containing compositions (30%) (85 min running time) (15 % increase in processing time). This research presents the benefits of 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

Acknowledgements: No public funds supported this work. The authors have no conflicts of interest to disclose.

Table 1: D10, D50, D90, particle size distribution and bulk density of core and enteric pellets.
*SPAN3 is a measurement of the width of the particle size distribution (PSD). Smaller span value signifies a narrower and more uniform PSD

Figure 1. Dissolution of omeprazole pellets (core) containing water soluble and water insoluble diluent (Mannitol and various ratio of drug to MCC)

Figure 2: Comparison of in vitro dissolution data (gastric fluid, first 2 h; Intestinal fluid, after 2 h) of enterically coated omeprazole pellets coated with or without talc, n = 3