Application of Lactose Co-Processed Excipients as an Alternative for Bridging Pharmaceutical Unit Operations: Manufacturing an Omeprazole Tablet Prototype via Direct Compression
Abstract
Improving the manufacturability of drug formulations via direct compression has been of great interest for the pharmaceutical industry. Selecting excipients plays a vital role in obtaining a high-quality product without the wet granulation processing step. In particular, for diluents which are usually present in a larger amount in a formulation, choosing the correct one is of utmost importance in the production of tablets via any method. In this work, we assessed the possibility of manufacturing a small-molecule drug product, omeprazole, which has been historically manufactured via a multi-step processes such as wet granulation and multiple-unit pellet system (MUPS). For this purpose, four prototypes were developed using several diluents: a co-processed excipient (Microcelac®), two granulated forms of alpha-lactose monohydrate (Tablettose® 70 and Tabletose® 100), and a preparation of microcrystalline cellulose (Avicel® PH102) and lactose (DuraLac® H), both of which are common excipients without any enhancement. The tablets were produced using a single punch tablet press and thoroughly characterized physically and chemically in order to assess their functionality and adherence to drug product specifications. The direct compression process was used for the manufacturing of all proposed formulations, and the prototype formulated using Microcelac® showed the best results and performance during the compression process. In addition, it remained stable over twelve months under 25 °C/60% RH conditions.
Introduction
In pharmaceutical manufacturing, specifically in tablet production, various processes routes can be applied, e.g., direct compression, wet granulation, and dry granulation. Direct compression involves the mixing and processing of a tablet’s formulation ingredients, followed by compression to directly produce tablets from powdered excipients and active pharmaceutical ingredients (APIs) [1]. This tablet manufacturing method has several benefits: it is cost-effective since it requires fewer unit operations than wet granulation or any other multistep manufacturing approach. It is more suitable for moisture- and heat-sensitive APIs, and it yields better stability [2]. Additionally, changes in the drug dissolution profile during storage are uncommon [3,4]. Direct compression tablets disintegrate into API particles instead of granules; this accelerates the dissolution process and facilitates absorption for tablets containing APIs with low solubility [1,5,6]. Lastly, the use of solvents and the need for drying energy of wet granules is eliminated, making it a greener and more sustainable route of production.
However, direct compression has some drawbacks. One key limitation is that it requires careful evaluation of the drug’s physical properties, such as flowability and compressibility, as well as those of the excipients used in the formulation. These are critical factors that require precise control [4,5]. In direct compression, characteristics of the drug substance, such as the particle size, flowability, and compressibility, play a crucial role in the final product’s quality and performance. Any variations or inconsistencies in these properties can significantly impact the tablet’s assay, integrity, dissolution, and overall effectiveness. Similarly, the physical properties of excipients used in direct compression, such as their particle size, compressibility, and lubrication capacity, must be carefully evaluated. The choice and quality of excipients can influence the flowability of the powder blend and the tablet’s hardness, disintegration, and content uniformity. Therefore, to ensure the success of direct compression, manufacturers must meticulously assess and control the physical characteristics of both the drug substance and the excipients. This involves rigorous testing, monitoring, and adjustment of the formulation and process parameters to achieve the desired tablet quality, stability, and performance [2].
Selecting a suitable filler–binder component is of utmost importance when formulating directly compressed tablets. This excipient plays a pivotal role in determining the success or failure of the formulation. It is essential for the diluent to have both compressibility and flowability, which often makes it a specialized ingredient provided by a limited number of suppliers. In addition, the diluent’s required physicochemical properties cannot be provided by only one excipient and it often necessary to use a combination of materials [2]. This underscores the significance of carefully considering the filler–binder for ensuring optimal performance and quality in direct-compression tablet formulations. In this context, the use and evaluation of co-processed excipients have been on the rise recently. Co-processed excipients are solid particulate mixtures of organic or inorganic substances, i.e., a combination of compounds, produced via specialized manufacturing methods, which have improved physicochemical properties compared to simple physical mixtures of components [7,8,9]. Some of their advantages include a uniform particle size and shape distribution, an increased density, a higher sphericity and a greater porosity, resulting in improved flow and compression properties [4]. Moreover, any danger of segregation is eliminated.
Omeprazole belongs to the class of substituted benzimidazoles, which suppress gastric acid secretion by inhibiting the H+/K+-ATPase enzyme system on the secretory surface of gastric parietal cells. It acts as a proton pump inhibitor and is indicated for the treatment of acid reflux and heartburn [10]. Omeprazole is known for its sensitivity to acidic environments, moisture, heat, and certain solvents. It readily degrades in aqueous solutions at low pH, which necessitates protective formulation strategies. To ensure drug stability and targeted release, omeprazole oral dosage forms are typically enteric-coated, allowing for release in the duodenum (pH > 5) or terminal ileum (pH ~ 6.8–7.5) [10,11,12] However, many enteric coating polymers possess acidic functional groups that can interact unfavorably with omeprazole. To prevent this degradation pathway, a stabilizing sub-coating layer is often applied between the drug-containing core and the enteric coating, effectively serving as a barrier to protect the active ingredient [12].
Omeprazole as well as its stereoisomers belong to class II of the Biopharmaceutical Classification System, due to their poor solubility in water and high permeability through cell membranes [13]. Listed by the World Health Organization (WHO) as an essential medicine, since its introduction, omeprazole has been widely available on the market in the forms of tablets and other oral formulations. It is sold as a non-prescription medicine and over-the-counter medication (OTC) in some countries with different dosages of 10 mg, 20 mg, and 40 mg [14,15,16,17,18,19,20,21]. Historically, omeprazole was manufactured using a wet granulation technology, e.g., via low-shear granulation [18,21,22,23]. Currently, the dosage forms are manufactured using a multiple-unit pellet system (MUPS), in which enteric-coated pellets are either compressed into a tablet coated with an immediate-release polymer or directly filled into a hard gelatin capsule [13,17,24].
This study was based on the hypothesis that a directly compressible omeprazole tablet formulation can be developed by selecting appropriate excipients and formulation strategies that protect the drug’s stability while maintaining pharmaceutical equivalence, with the subsequent goal of streamlining the conventional manufacturing process by minimizing intermediate unit operations, thereby enhancing production efficiency, reducing processing time, and maintaining product quality and stability.
The suitability of the proposed formulation was evaluated based on the degree of compliance using the Quality Target Product Profile (QTPP) (See Supplementary Materials Table S1) of the reference-listed drug Prilosec® OTC 20 mg delayed-release tablets (AstraZeneca Pharmaceuticals LP distributed by Procter & Gamble) (Cincinnati, OH, USA). While we acknowledge that Prilosec® utilizes a multi-unit pellet system and our formulation is a single-unit tablet, the comparison remains relevant from a regulatory standpoint, as both are classified as delayed-release tablet dosage forms. Our intention is to demonstrate compliance with the desired release characteristics defined for this category.
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2.1.2. Standards, Samples, and Excipients
Omeprazole powder was procured from Shenzhen Nexconn Pharmatechs Ltd., (Shenzhen, China) (100.0%). MicroceLac® (75% alpha-lactose monohydrate and 25% microcrystalline cellulose), Tabletosse® (agglomerated lactose), and DuraLac® H (anhydrous beta-lactose and alpha-lactose) were supplied by MEGGLE GmBH & Co. (Wasserburg, Germany). EXPLOTAB®, Type A (Sodium Starch Glycolate), and PRUV® (Sodium Stearyl Fumarate) were purchased from JRS Pharma (Polanco, Spain). Avicel® PH102 (microcrystalline cellulose, MCC) was supplied by Dupont—Pharma (Wilmington, NC, USA). As a sub-coat, Opadry® II clear polyvinyl alcohol (PVA) film coating from Colorcon (Harleysville, PA, USA) was utilized, and the enteric coating was applied via the Aquarius™ Control ENA film coating system from Ashland (Wilmington, NC, USA). The commercial omeprazole 20 mg delayed-release tablets are listed as Prilosec® OTC from Procter & Gamble Distributing (Cincinnati, OH, USA).
Tableting
A high-speed rotary press simulator, model Stylcam 200R by MEDELPHARM (Beynost, France), was used for tableting small batches in order to compare the different formulations and tableting settings in a pre-test using an 8 mm concave punch provided by Adamus S.A. (Szczecin, Poland). For the selected scale-up batch, we used a rotary tablet press, model Fette 102i, by Fette Compacting GmbH (Schwarzenbek, Germany), using, in this case, eight sets of punches with the same characteristics as the one used in the Stylcam pre-test. All formulations were compressed using the same procedure. The performance during compression was a target as well: stable weight variation and stable compression force in the table press for measuring processability.
Lara Garcia, R.A.; Afonso Urich, J.A.; Afonso Urich, A.I.; Jeremic, D.; Khinast, J. Application of Lactose Co-Processed Excipients as an Alternative for Bridging Pharmaceutical Unit Operations: Manufacturing an Omeprazole Tablet Prototype via Direct Compression. Sci. Pharm. 2025, 93, 24. https://doi.org/10.3390/scipharm93020024
Read also our introduction article on DC Excipients here:
