Effects of Roller Compaction on Dissolution of Granules and Tablets Captured in the Development of Two Real Pharmaceutical Formulations

Abstract

Roller compaction is often utilized as the first step to improve flow properties and homogeneity of pharmaceutical mixtures. Since the dry granulation process is less complicated than its counterparts in the industry, it is possible to perform screening experiments readily to investigate granulate quality for further operations. In this study, the aim of the investigation focused on the effect of roller compaction on the dissolution of granules and tablets of two pharmaceutical formulations that contain APIs of different biopharmaceutical classification. This study underscores the benefits of granule dissolution testing as a crucial early-stage technique for optimizing granulate quality and facilitating progression through formulation manufacturing operations. For active pharmaceutical ingredients characterized by poor dissolution properties, this approach provides valuable insights during the initial development phases. By integrating granule dissolution testing into the development process, product manufacturability can be enhanced and optimal product performance can be ensured.

Introduction

Pharmaceutical formulation development relies heavily on granulation techniques to enhance the physicochemical properties of raw materials, aiding their processing and performance in final dosage forms. Among these, roller compaction (RC), a dry granulation method, maintains significant importance for processing heat- and moisture-sensitive active pharmaceutical ingredients (APIs) by preserving their stability. RC involves densifying powders into ribbons under high pressure, followed by milling these ribbons into granules. The operation of dry granulation also leverages scalability, cost and time efficiency, and aligns well with the continuous manufacturing paradigm. Despite its advantages, RC presents challenges, including granule hardening and porosity reduction, which may compromise the final product quality [1,2,3,4,5,6,7,8,9].

The relationship between granule properties and tablet performance has been extensively explored, with a clear understanding that attributes such as granule porosity, size, and hardness play critical roles in determining the mechanical strength and dissolution performance of the final dosage form. The process parameters of RC induce these structural and mechanical granule characteristics [2, 6, 10,11,12]. High compaction pressures often yield dense and poorly disintegrating granules with reduced porosity, impeding water penetration and API release during dissolution. This phenomenon is further exacerbated by granule hardening, a factor that limits the fragmentation mechanism during tableting, which compromises tablet tensile strength. Additionally, the occurrence of large granule sizes, often a byproduct of high roller speeds or excessive compaction force, further restricts dissolution due to a reduction in the surface area available for drug release [1, 5, 13,14,15,16,17,18].

When this occurs in the granules, it often requires redesigning the parameters of the process or additional modifications to achieve the desired dissolution profile, such as fines recycling or post-compaction treatments, adding complexity to the manufacturing process [2, 19,20,21,22]. Therefore, the dissolution behaviour of granules is affected by mechanical factors, mainly compaction pressure, but also by formulation composition, granule morphology and fines content. These factors necessitate a more detailed investigation into how studying intermediate granules can serve as an early indicator of formulation success. Matji et al. (2019) demonstrated that increased compaction pressure during tableting of RC granules significantly delayed disintegration and reduced the quantity of early drug release (5 min) in high-drug-load ibuprofen tablets. These effects were directly linked to reductions in granule and tablet porosity, as quantified by mercury intrusion porosimetry [23]. The impact of excipient selection is equally evident; Chang et al. (2008) observed that lactose-based RC granules formed hydrophobic pellicles under accelerated stability testing, impeding dissolution, whereas mannitol-based counterparts preserved rapid-release characteristics, underscoring the importance of matrix hydration and solid-state stability in dissolution performance [24]. Inghelbrecht and Remon (1998) investigated dry granulation of microcrystalline cellulose and ibuprofen blends, showing that while high ibuprofen levels improved tablet mechanical strength through fragmentation, they also impaired granule quality.

The study highlighted that the interaction between deformable and fragmenting excipients introduces complex behaviour in RC, with MCC influencing dissolution more than particle size [25]. While Dular Vovko et al. (2022) conducted a comprehensive multivariate analysis of 25 carvedilol matrix tablet batches prepared via roller compaction, revealing that granule-level particle size distribution (d50 and d90) and roll speed exerted a stronger impact on drug release than hypromellose content or tablet hardness. Unexpectedly, higher d90 values increased release, while higher d50 values decreased it, reflecting complex densification-fragmentation interactions during compression. Granules with smaller d90 (fewer large particles) allowed tighter packing and reduced porosity, thus slowing release, while granules with high d50 were softer and fragmented easily, also resulting in lower porosity and slower release. These effects were confirmed through friability analysis, compactibility testing, and compressibility plots, highlighting that tablet porosity—not just matrix composition—drives early release behaviour in hypromellose-based systems [26].

From this, we draw the argument that intermediate dissolution performance is dictated not only by excipient ratios, but also by microstructural properties modulated by RC settings, and underscores the need for PSD monitoring. Moreover, Anuschek et al. (2023) used terahertz time-domain spectroscopy (THz-TDS) as a process analytical tool to non-destructively measure granule internal structure. Their findings confirmed that granule densification signatures obtained via THz-TDS could be used to predict disintegration performance in real-time monitoring of compaction effects across granulation platforms [27]. In parallel, Matji et al. (2019) showed that manipulating the fines content in RC ibuprofen formulations had a dual impact: while some fines improved compactibility and mechanical strength, excess fines (> 20%) reduced flowability and disrupted dissolution, indicating the need for tightly controlled fines levels during post-compaction sieving [23]. While in erlotinib formulations, Hwang et al. (2019) showed that fines recycling during RC improved flow and maintained tensile strength, yet excessive compaction reduced early dissolution, underlining the balance between densification and performance [28]. Several modeling studies and alternative granulation routes also support the relevance of intermediate granule-level evaluation.

Comparative studies focused on the process parameters and the intermediate granules. Matsunami et al. (2023) developed surrogate models to forecast dissolution behaviour from granule-level input parameters such as bulk density, porosity, and water uptake, revealing that dry-granulated formulations, particularly those of BCS Class II drugs, exhibited slower and more variable dissolution compared to their wet-granulated analogs. These differences were attributed to more extensive granule densification and poorer wetting properties in RC systems [29]. Kim et al. (2022) used a QbD framework to map how roller force and screen size propagated through the process chain to affect dissolution variability, validating Monte Carlo-based risk modeling for roller compaction [30]. Mitchell et al. (2003) explored dry granulation using polymeric carriers like HPMC and found that matrix hydration and swelling kinetics could override densification effects and enhance dissolution of poorly soluble APIs [31]. These studies converge in realizing that granule-level structural and compositional properties shaped by RC parameters and formulation design govern disintegration and dissolution outcomes. Despite extensive research into granule attributes and their impact on tablet performance, the role of intermediate granule dissolution remains underutilized. These insights support the inclusion of granule-level dissolution testing for anticipating formulation behaviour prior to tableting. Current methodologies primarily assess tablet disintegration or dissolution rates, overlooking the diagnostic potential of granule dissolution profiles [32].

Quality by Design (QbD) underscores the significance of process understanding and CQA monitoring, with increasing interest in its application for formulation development. This framework naturally extends to encompass granule attributes and, by extension, granule dissolution analysis, though this is not always the case. As critical intermediates in these pharmaceutical production processes, granules offer an opportunity to screen formulations early in the development cycle. Establishing correlations between granule dissolution behaviour and final product performance could streamline formulation development, reduce experiment-intensive tablet testing, and provide earlier insights into formulation suitability [3, 33,34,35,36,37,38,39]. The USP4 flow-through cell method adequately provides a dynamic and reproducible platform for studying dissolution behaviour, particularly beneficial for poorly soluble compounds. It simulates physiological conditions with controlled fluid flow, offering distinct advantages over traditional methods like the USP2 paddle method by producing more detailed data and better replicating in vivo conditions. This method has shown promise in predicting the dissolution behaviour of final dosage forms based on their precursors, saving time and reducing experimental effort during formulation development. By allowing early-stage evaluation of formulations, USP4 helps optimize processing parameters and excipient combinations while ensuring reliable performance in the final dosage form [7, 33, 40,41,42,43,44].

With this in mind, the aim is to highlight the utility of the USP4 flow-through cell method for evaluating the dissolution behaviour of roller-compacted granules from two real pharmaceutical formulations during development. This approach will be assessed against conventional USP2 paddle dissolution testing of tablets prepared from the same granules. Using USP4 to study granule dissolution specifically addresses the industry’s demand for early-stage testing aligned with the expanding QbD principles. The ability to evaluate process variables early enables the identification of potential formulation issues, optimizing workflows and supporting more informed decision-making in formulation development.

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Table 1: Dapagliflozin Formulation Components (D-mixture)

Marinko, N., Medrano, S.M., Krpelan, T. et al. Effects of Roller Compaction on Dissolution of Granules and Tablets Captured in the Development of Two Real Pharmaceutical Formulations. AAPS PharmSciTech 26, 225 (2025). https://doi.org/10.1208/s12249-025-03217-1

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