A Novel Lactose/MCC/L-HPC Triple-Based Co-Processed Excipients with Improved Tableting Performance Designed for Metoclopramide Orally Disintegrating Tablets

Orally disintegrating tablets (ODTs) are designed to dissolve in the mouth within a few seconds upon contact with saliva, eliminating the need for water [1]. Features like quick dispersion, rapid onset of action, ease of swallowing, and the ability to be taken without water make ODTs ideal drug delivery systems for patients with special needs [2]. These tablets are especially beneficial for elderly patients affected by dysphagia or paralysis, as well as infants and young children, due to their high patient compliance [3].

Currently available ODTs are typically produced through methods such as molding, mass extrusion, freeze-drying, spray-drying, and direct compression [1]. Due to its ease of large-scale production, simplified and low-cost process, and the absence of requirement for specialized equipment, direct compression becomes a preferred method for ODTs production in pharmaceutical industries [4]. However, the direct compression method necessitates excipients exhibiting good flowability and compressibility, which can be challenging for most currently available excipients [5]. Single-component excipients in particular often fail to meet the necessary requirements for direct compression of ODTs. Therefore, multifunctional co-processed excipients with enhanced properties are essential to enable feasible direct compression and improve the overall performance and characteristics of ODTs [6].

Co-processed excipients have emerged as a promising method for enhancing the properties of excipients used in direct compression. This method is more time- and cost-efficient than developing excipients with entirely new chemical structures. Unlike a simple mixture of several excipients [7], co-processed excipients are meticulously designed and produced through a series of physical co-processing steps [8]. Consequently, the most significant advantage of co-processed excipients is their superior compressibility and flowability compared to simple physical mixtures, thanks to the controlled and optimal particle size and distribution [9]. This leads to consistent tablet weight and uniformity. Additionally, co-processing of excipients improves the disintegration time and dissolution rate of ODTs due to the increase of porosity, ensuring the tablets quickly break down in the mouth without the need of water [10]. Moreover, tablets made with co-processed excipients generally exhibit higher mechanical strength, reducing friability and enhancing durability of the tablets during handling and transportation [11]. Co-processed excipients have also been reported to decrease grittiness while improving the palatability and mouthfeel of ODTs for children and the elderly [5,12]. Overall, co-processed excipients are designed to tackle multiple formulation and manufacturing challenges associated with ODTs, thereby enhancing their performance and patient acceptability [13].

Proper selection of suitable excipients based on their required functions and material properties is crucial in the formulation process. Once the appropriate excipients are chosen, determining the correct proportion of each component is essential to achieve the desired characteristics. Additionally, an effective manufacturing process for co-processed excipients is vital for optimizing co-processing. Currently, common co-processing methods include co-transformation, co-milling, co-precipitation, and co-crystallization [14,15]. These operations enable excipient particles to interact at the sub-particle level [16], providing an effective tool for developing excipients with enhanced functions. The commonly co-processed excipients used in ODTs typically consist of two or three components, including disintegrant, filler, binder, and lubricant [17]. Besides these, co-processing generally involves one plastic excipient and one brittle excipient. Maarschalk reports on co-processing that uses a large amount of brittle material and a small amount of plastic material, such as in cellactose, which consists of 75% lactose (brittle) and 25% cellulose (plastic) [18]. This specific combination prevents excessive elastic energy from being stored during compression, resulting in minimal stress relaxation and a reduced tendency for capping and laminating [19]. However, other extreme combinations exist, such as silicified microcrystalline cellulose (SMCC), which contains a large amount of microcrystalline cellulose (MCC, plastic) and a small amount of silica (brittle) [20]. These examples demonstrate that co-processing typically involves materials with both plastic deformation and brittle fracture characteristics, which are essential for optimal tableting performance.

MCC is a rod-shaped or granular crystal produced by hydrolyzing natural fibers with strong acid under heated conditions. It features a spongy, porous structure. Under pressure, the disordered porous structure of MCC becomes linearly arranged and undergoes plastic deformation, enabling water molecules to enter the tablet, break the hydrogen bonds between microcrystals, and promote rapid disintegration [21]. The small, low-density MCC particles lead to a higher proportion in formulations for the same mass, resulting in tablets with low actual density and high porosity. This allows water to quickly enter the core and accelerate disintegration. MCC has good compressibility and is suitable for direct compression methods. However, due to its weak swelling properties, it is generally not used alone as a disintegrant but often combined with other excipients with strong swelling properties, such as low-substituted hydroxypropyl cellulose (L-HPC) [22]. L-HPC is a long fibrous powder with rough and uneven surface structures and a large specific surface area. When mixed and compressed with other excipients or drugs, it forms voids and capillaries within the tablet core. L-HPC’s high porosity accelerates water absorption, allowing the tablet to disintegrate rapidly. Additionally, the rough surface structure of L-HPC particles leads to substantial interlocking between particles during compression, enhancing the adhesion between the drug and the particles. This contributes to excellent compressibility, strong hardness, and tablets with improved gloss and appearance [23]. Consequently, L-HPC is frequently employed as a binder in solid dosage forms. Lactose is available as white to off-white crystalline granules or powder. It is tasteless with a slight sweetness. The stable crystalline forms of lactose are α-lactose monohydrate, β-anhydrous lactose, and stable α-anhydrous lactose. The sweetness of α-lactose is about 20% that of sucrose, while β-lactose is 40%. Lactose is stable, non-hygroscopic, and has good compressibility. It is compatible with most drugs, making it widely used as a filler and diluent in tablets and capsules.

Metoclopramide, classified as a BCS III drug [24], is a white crystalline powder that is odorless, bitter, and nearly insoluble in water [25]. Metoclopramide ODTs were approved by the FDA (METOZOLV^TM ODT) for short-term treatment of patients with acute and recurrent diabetic gastroparesis and symptomatic gastroesophageal reflux disease. These ODTs offer a valuable option for individuals who have difficulty swallowing tablets or capsules due to conditions such as odynophagia, nausea, vomiting, dysphagia, and heartburn, or in situations where oral administration is challenging [26]. However, the excipients used in commercial metoclopramide ODTs are not co-processed, and the preparation method is freeze-drying [27], which is complex, requires specialized equipment, and is costly. Therefore, developing new co-processed excipients that combine various properties of excipients can enhance the performance of ODTs, including flowability, disintegration time, and dissolution stability. This approach is suitable for direct compression, which could simplify the production of metoclopramide ODTs, reduce costs, and improve patient compliance.

The objective of this study was to develop a novel co-processed excipient, comprising lactose, low-substituted hydroxypropyl cellulose (L-HPC), and MCC, suitable for orally disintegrating tablets (ODTs) through an appropriate formulation process. Metoclopramide, chosen as the model drug due to its poor solubility, was incorporated into ODTs using these co-processed excipients via direct compression. Lactose was selected as a brittle excipient due to its predominant brittle deformation upon compression. However, lactose alone often lacks optimal compressibility as a filler. In contrast, MCC, characterized by its sponge-like porous structure, primarily undergoes plastic deformation after compression, providing excellent compressibility and earning the designation of a “dry adhesive” for direct compression processes [28]. L-HPC, with its high hygroscopicity and favorable swelling properties in water, contributes to the linear arrangement of MCC’s porous structure when combined and compressed. Moreover, the interaction between MCC and water facilitates rapid tablet disintegration by disrupting hydrogen bonds between crystallites within the tablet core.

In this research, single-factor and Box–Behnken experiment designs were utilized to obtain the optimal formulation of co-processed excipients. Subsequently, MCP ODTs based on this co-processed excipient technology were prepared and characterized. Furthermore, both in vitro dissolution and in vivo pharmacokinetic studies of the metoclopramide ODTs were conducted.