Evaluation of Novel Co-Processed Excipients for Direct Compression Using the Sediment Delivery Model (SeDeM) Expert System

Abstract

Background/Objectives: The development of multifaceted excipients is a requirement of the pharmaceutical industry. This study aimed to develop a granular co-processed excipient for tablets and to evaluate it using the SeDeM expert system.

Methods: Four granule formulations were developed via the powder layering technique, varying binder concentrations (15% and 20%) and filler types (microcrystalline cellulose and lactose), using sugar as the core. The granules obtained were evaluated utilising the SeDeM expert system. The unloaded granules were compressed to yield uncoated compacted granules, which were verified for dimensional parameters, mechanical properties, and disintegration ability.

Results: Varying binder concentrations (15% and 20%) together with differences in filler/disintegrant composition were associated with changes in particle-size distribution. During the SeDeM evaluation, E3 formulation exhibited good results in terms of parameter index (PI = 0.83), parameter profile index (PPI = 7.64), and Good Compressibility Index (GCI = 7.28). The recorded disintegration times were below 15 min for all compacted granules and complied with the Ph. Eur. 12 requirements for uncoated tablets.

Conclusions: For granule development, variations in formulation composition, including binder concentration, were associated with differences in particle size and lubricity. The SeDeM expert system can be used in the preformulation studies to characterize powders or granule formulations from which uncoated tablets can be obtained, but there are several pharmacotechnical properties not included in the list of parameters that need to be analysed to comply with the industrial requirements.

Introduction

Single-component excipients do not always provide the necessary compressibility and tablettability to enable the formulation or manufacture of uncoated tablets [1]. Pharmaceutical excipients are pharmacologically inert substances used during manufacturing to protect, support, or enhance stability and bioavailability, and to aid in product identification [1].

As regulatory requirements for the purity, safety, and standardization of excipients have become stricter, the International Pharmaceutical Excipients Council (IPEC) has emerged, which defines a co-processed excipient as a combination of two or more excipients intended to physically modify their properties in a way that cannot be achieved by simple physical mixing and without significant chemical modification [1]. The growing need for efficient direct-compression formulations has increased interest in multifunctional co-processed excipients. By combining the advantages of different materials in a single system, these excipients can improve flowability, compressibility, and overall tablet-manufacturing performance [1,2].

In all cases, the resulting excipients are characterized in terms of quality. One of the tools that can be used in this case scenario to evaluate the granular excipients is the Sediment Delivery Model (SeDeM) expert system, a methodology applied in drug preformulation and formulation studies, especially in the case of solid dosage forms (uncoated tablets made through direct compression) [2,3]. Besides this particular use, this mathematical tool can be used to compare different excipients from the same category (different superdisintegrants, different functional excipients, different fillers) or with the same chemical formula (different types of lactose or microcrystalline cellulose) or to characterize the same excipient from different batches [4].

The main use of this expert system is to develop uncoated tablets by characterising active ingredients and excipients. This system provides information on the physical profile of the active pharmaceutical ingredient (API) and excipients. The SeDeM expert system highlights the advantages and disadvantages of APIs and excipients, indicating whether direct compression is appropriate. This system can be used as a screening tool in order to design the formulation in the final product [5,6,7].

Through the SeDeM system, 12 parameters are evaluated, each of which is included in five distinct incidence factors:

• Dimension (Bulk density (Da) and tapped density (Dt),
• Compressibility (porosity—Ie, Carr index—CI, Cohesion index—Icd),
• Flowability (Hausner ratio—HR, Angle of repose—α, Flowability—t″),
• Lubrication/stability (loss on drying—%HR, hygroscopicity—%H),
• Dosage/lubrication (particles < 160 µm—%Pf, Homogeneity index—Iθ) [2,4,6,8,9].

The main aim of this expert system, as stated above, is to improve time management and the properties of compacted granules (better mechanical properties). Firstly, the active ingredient is characterized using the SeDeM expert system, followed by screening the excipients (usually fillers or co-processed excipients), for which the most important factor of incidence is compressibility, as expected, since the compacted granules are developed through direct compression.

Khan has used this SeDeM expert system to evaluate the granules. As expected, differences occur for the following parameters (Pf and Iθ), for which sieves with a higher mesh size are required [9].

Until now, this expert system and other SeDeM-derived tools have been used primarily to characterise powders or powder mixtures of excipients already marketed by various pharmaceutical companies. Several active ingredients have shown compressibility issues, including ibuprofen, memantine, and cannabidiol [8,10,11].

As a result, this study focuses on developing a granular functional excipient.

Although SeDeM was initially conceived as a preformulation and material characterization instrument, numerous investigations have broadened its application towards the development and refinement of innovative co-processed excipients for direct compression. Illustrative examples include starch–microcrystalline cellulose composites (Salim et al., 2021) [2], rice starch-based multifunctional excipients (Trisopon et al., 2021) [12], and spray-dried mannitol–pregelatinized rice starch systems (Saokham et al., 2025) [13]. In all three cases, the developed excipients were powders; in the study conducted by Salim et al. [2], the co-processed excipient was developed via co-dispersion, whereas in the latter two, the excipients were prepared by spray-drying [12,13]. The co-processed excipients developed in this study were manufactured by powder layering onto starter cores, an approach that generates spherical granular excipients rather than powder-based systems.

The SeDeM Expert System constitutes a valuable preliminary formulation and screening instrument that can mitigate development duration and assist in predicting compatibility with direct compression [7,14]. Nonetheless, it should serve as a decision-support tool rather than an exclusive solution and should be complemented with experimental validation, stability assessments, and more comprehensive methodologies.

The SeDeM Expert System has notable limitations to consider when developing pharmaceutical formulations. While it effectively assesses powder properties and predicts suitability for direct compression, it primarily focuses on physical attributes such as flowability, compressibility, density, and moisture content [14,15]. It does not comprehensively evaluate critical factors such as active ingredient–excipient compatibility, chemical stability, dissolution behavior, or bioavailability. Additionally, its predictions are derived from mathematical indices, which may not fully capture the complexities of large-scale manufacturing [15]. Since the system depends heavily on the accuracy of experimental data, measurement errors can lead to inaccurate conclusions. Moreover, SeDeM was primarily designed for direct compression and may be less suitable for complex dosage forms or manufacturing processes. Therefore, it should serve as a preliminary screening and decision-support tool rather than a standalone method. Its results should be validated with compatibility studies, stability tests, dissolution testing, and pilot-scale production [2,7,15,16].

This study aims to develop a new co-processed excipient by preparing granules via the layering technique and to compare formulations developed with a modified SeDeM expert system to determine which granules are most suitable for uncoated tablet production. Until now, Khan (2019) has used this expert system to analyze granular formulations with ribavirin, modifying methods to meet formulation requirements for dosage and lubrication (homogeneity index and particles < 160 μm) [9]. In summary, while SeDeM has been widely used as a preformulation tool, its primary function has been the characterization and selection of excipients, rather than the systematic development of novel co-processed materials [3,10,17,18]. Previous investigations rarely concentrate on the optimization of excipient ratios or provide structured methodologies for property enhancement [2,12,13]. This study advances the field by applying SeDeM as a formulation-screening and decision-support tool.

Another aspect targeted in this study was to produce granules that meet flow, compressibility, particle-size, and stability requirements and function as a versatile excipient for standard-release tablets. If the granules are compacted, the resulting compacted granules must also meet criteria such as friability, mechanical strength, and disintegration. It is expected that differences in excipient type and concentration may influence granule-size distribution and consequently affect the physical attributes of the granular excipient and the resulting tablet quality.

During our research, the developed excipients were compared with other functional excipients, both granular and powder, to highlight the improvements achieved in this study. The proposed compositions exhibited improved compressibility and flow-related properties compared with several literature-reported co-processed excipients [2,12,13]. Limitations and future directions include the absence of a formal Design of Experiments (DoE) and potential multicollinearity among SeDeM indices, which future investigations should address.

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Materials

Granules were prepared by powder layering onto starter cores using AquaPolish® STA (a binder composed of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and other cellulose ethers, supplied by Biogrund GmbH, Hünstetten, Germany) at concentrations of 15% and 20%. Sugar (AGRANA Beteiligungs-AG, Vienna, Austria) was used as the core, yielding four formulations (E1–E4). The remaining excipients were sorbitol (Merck KGaA, Hesse, Germany) for its sweetening properties; sodium alginate (gifted by JRS Pharma GmbH & Co. KG, Rosenberg, Germany), which can serve as a disintegrant; sodium stearyl fumarate (Pruv® sodium stearyl fumarate—JRS Pharma GmbH & Co. KG, Rosenberg, Germany), a lubricant; microcrystalline cellulose (Alfa Aesar, Ward Hill, MA, USA); and lactose (DFE Pharma, Goch, Germany), the latter two serving as fillers. Table 2 shows the quantities and roles of the components.

Ciurba, A.; Antonoaea, P.; Rédai, E.M.; Pintea, A.; Pintea, C.; Cojocariu, A.-A.; Bîrsan, M.; Mihalcea, M.-F.; Vlad, R.-A. Evaluation of Novel Co-Processed Excipients for Direct Compression Using the Sediment Delivery Model (SeDeM) Expert System. Pharmaceuticals 2026, 19, 1481. https://doi.org/10.3390/ph19091481