Preparation of co-processed excipients with low content of hygroscopic material

Abstract

Co-processed excipients (CPEs) are widely used in direct compression formulations to improve powder flowability and the tensile strength of tablets. Besides compaction performance, moisture behaviour is also an important consideration in excipients design, particularly for formulations intended for moisture-sensitive active pharmaceutical ingredients (APIs) and processes involving energy-intensive drying operations. This study investigated the feasibility of producing a low-MCC lactose-based formulation containing 5% microcrystalline cellulose (MCC) and 95% lactose to reduce moisture retention while maintaining adequate tablet tensile strength.

The Co-processed excipients were prepared by spray drying and crystallization, while physical mixtures prepared by wet granulation and dry mixing were served as comparison purposes. Particle size distribution, flowability, moisture content, and tablet tensile strength were evaluated for each formulation.

The results showed that processing methods significantly influenced powder properties and tablet performance. Spray dry M/L 5/95 powders exhibited improved flowability compared with the Dry mixing M/L 5/95 due to reduced fines content, while maintaining tablet tensile strength within the commonly accepted pharmaceutical range. The Crystallization M/L 5/95 exhibited lower moisture uptake but also lower tablet tensile strength. Granulated formulations showed excellent flowability because of increased particle size.

Overall, the spray-dried low-MCC formulation provided the best balance between flowability, tensile strength, and low moisture uptake. These findings highlight the potential of low-MCC lactose-based formulations as Co-processed excipient systems for direct compression applications requiring improved drying efficiency and reduced hygroscopicity.

Introduction

Tablets are the most widely used oral dosage form because of their convenience, stability, and cost-effectiveness. The performance of tablets depends largely on the excipients employed, particularly in direct compression processes, where excipients functionality governs both powder flowability and compressibility. Lactose and MCC are widely used excipients used in the pharmaceutical industry [1]. MCC is a partially crystalline and highly compressible material capable of producing strong tablets. Although insoluble in water, it is hygroscopic due to the presence of disordered regions within its structure that can absorb moisture [2]. This hygroscopicity, while contributing to its excellent binding capacity, presents challenges during drying operations, as the absorbed water increases energy requirements and prolongs processing times [3].

The stability of moisture-sensitive active pharmaceutical ingredients (APIs) such as Aspirin [4], theophylline [5] in solid dosage forms is a key determinant of product quality and shelf life. Excipients selection is critical for minimizing moisture-induced degradation and preserving formulation stability. Moisture has been identified as a primary cause of degradation in nearly 50% of all medicinal products [6], frequently promoting impurity formation in solid dosage forms, particularly those containing moisture-sensitive APIs. The use of highly hygroscopic excipients may compromise chemical stability, storage characteristics, and processability. In addition, elevated moisture uptake increases the drying burden associated with manufacturing operations such as spray drying and wet granulation, resulting in greater energy consumption and prolonged processing times. Accordingly, the development of Co-processed excipient systems that exhibit low hygroscopicity while retaining adequate direct-compression functionality has become an important focus in pharmaceutical formulation research. The MCC proportions used by Akin-Ajani et al. [7] were 75%, 50% and 25%, indicating that the Co-processed excipients exhibited better properties than the physical mixtures under the same formulation conditions. Furthermore, increasing the MCC proportion was found to enhance the functional properties of the mixtures. Nevertheless, higher MCC contents may increase powder hygroscopicity, leading to greater moisture absorption. Hou et al. [8] and Bungău and Salman [9] used 24% MCC in their experiments. Gohel et al. [10] prepared and evaluated Co-processed diluents containing MCC and lactose. The mass ratios of MCC to lactose were 25:75 and 20:70, and the formulations showed improved direct compression performance compared with physical mixtures. However, other substances, such as native corn starch as binders have been introduced during the experiment.

To overcome the limitations of using individual excipients, Co-processed excipients (CPEs) have emerged as an efficient strategy to enhance excipients functionality in direct compression formulations. This approach is both time and cost effective. Unlike simple direct compression [11], CPEs are engineered through controlled physical Co-processing techniques such as spray drying and crystallization [12], [13]. Co-processing combines a plastically deforming material, such as MCC, with a brittle one, such as lactose, to achieve a desirable balance between deformation and fragmentation during compaction. Examples of commercially available CPEs include Cellactose® 80 (cellulose: lactose, 25:75), MicroceLac® 100 (MCC: lactose, 25:75). These CPEs exhibit better flowability and compressibility compared with simple powder mixtures [14], [15], owing to optimized particle morphology and size distribution, which enhance tablet uniformity and weight consistency [16]. Importantly, Co-processing does not alter the chemical nature of the excipients; rather, it modifies their physical attributes—such as surface area, bulk density, and moisture content—to improve processability and mechanical performance [17]. MCC serves as a key binder in many Co-processed systems due to its plastic deformation behaviour and strong binding properties. When combined with lactose, MCC fills interparticle voids and enhances interparticle bonding, yielding tablets with greater tensile strength than those composed of lactose alone [18]. For instance, Cellactose® 80 (Meggle), which contains approximately 25% MCC and 75% lactose monohydrate, combines the plasticity of MCC with the brittle fracture characteristics of lactose to improve direct compression performance. Nevertheless, high MCC content can introduce several challenges during the production of powders and tablets. The hydroxyl groups of MCC can form hydrogen bonds with water, giving it hydrophilic properties and causing it to swell when it comes into contact with water, therefore, MCC promotes water absorption and retention [19], [20], resulting in longer drying times and increased energy consumption during Co-processing steps such as spray drying or wet granulation.

Given these limitations, optimizing the MCC content in Co-processed formulations is important not only for improving mechanical properties but also for enhancing process efficiency and manufacturing sustainability. The present study compares four preparation approaches for lactose–MCC formulations dry mixing and granulation were included as physical- mixture references, while spray drying and crystallization were used to produce Co-processed excipients. Their impact on powder characteristics and tablet performance was evaluated, while granules produced by wet granulation were used for comparison purposes. MCC has a high water-holding capacity because of its large surface area and internal porosity [19]. MCC:lactose mass ratio of 5:95 was selected in the present study based on processing considerations and previous findings from continuous pharmaceutical manufacturing. Hou et al. [8] investigated formulations containing 6% MCC in a ConsiGma-25 continuous tablet manufacturing line incorporating twin-screw wet granulation, fluidized-bed drying and tableting. The 6% MCC formulation was successfully processed under the operating conditions investigated, demonstrating the practical feasibility of using relatively low MCC content in a continuous manufacturing process. Furthermore, the study showed that MCC concentration influenced powder caking during wet granulation, residual moisture after drying, and tablet compression behaviour and mechanical properties. Based on these processing considerations, MCC:lactose mass ratio of 5:95 was selected as a low-MCC formulation to investigate whether relatively low MCC content could provide adequate functionality while potentially reducing moisture retention. 5% MCC was treated as an exploratory formulation rather than an optimized composition. The effects of the different processing approaches on particle size, flowability, moisture behaviour, and tablet tensile strength were subsequently evaluated.

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Materials

Two materials were used in this study, Fig. 1 shows SEM images of two materials, which were collected using a scanning electron microscopy (Zeiss, Germany). 450 M lactose, an α- lactose monohydrate (Pharmatose® 450 M, DFE Pharma, Germany) is shown in Fig. 1 (a). The particles exhibited an irregular morphology, with a typical tomahawk shape and a slightly rough but dense surface, and finer lactose particles were observed adhering to the surface.

MCC (Avicel PH 102, FMC Biopolymer, Cork, Ireland).

Daiyao Wu, Shijie Liu, Riyadh B. Al-Asady, Agba D. Salman, Preparation of co-processed excipients with low content of hygroscopic material, Powder Technology, 2026, 123281, ISSN 0032-5910, https://doi.org/10.1016/j.powtec.2026.123281.

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