(M0930-02-08) Impact of Excipient Properties on Coning during Dissolution for Ibuprofen Formulations

Purpose: Coning due to accumulation of undissolved material during dissolution (Higuchi, Nishida et al. 2015) can disrupt media flow and lead to misleading drug release profiles, making dissolution testing a less reliable predictor of in vivo behavior. Despite its impact, dissolution coning remains poorly understood, with limited data on the material properties that drive this phenomenon (Arnold-Lockwood, Brady et al. 2023). This study aims to identify and characterize the physicochemical properties of drugs and excipients that predispose formulations to coning during dissolution testing. The research will potentially establish a predictive framework for scientists for optimizing formulation design and preventing coning-related variability. This work also has the potential to inform regulatory guidelines, minimizing costly reformulation efforts and enhancing the reliability of dissolution as a quality control tool.

Methods: Ibuprofen (Ibu 70, BASF, USA), a hydrophobic BCS Class II drug, was selected for this study based on preliminary screening and literature evidence (Higuchi, Nishida et al. 2015). Formulations were prepared using different excipients: Avicel PH 102 (microcrystalline cellulose, FMC Corporation, USA), Pharmatose 110M (lactose monohydrate, DFE Pharma USA), and three grades of dicalcium phosphate anhydrous, Fujicalin (Fuji chemicals), Calipharm A and Atab (Innophos Pharma), each at drug loadings of 20%, 50%, and 70%. The formulation blends were prepared using optimized blending protocol on V-blender (Blend Master, Model B) and tablets were compressed at low pressure (Carver, Inc., USA). Dissolution studies were conducted using USP Apparatus (USP II SOTAX, Switzerland) at both the compendial 50 RPM and the No Coning RPM (NC_rpm), which is defined in literature as the minimum paddle speed at which cone formation is visibly disrupted (Higuchi, Terada et al. 2015). This comparison was used to assess if cone formation was causing drug entrapment. Physicochemical characterization of formulation blends is ongoing, targeting key material attributes such as true and bulk density, particle size distribution, surface wettability, and surface adhesivity.

Results: Preliminary dissolution testing revealed distinct coning behaviors across excipients. Avicel PH 102 formed a porous cone that allowed media penetration (good cone), while DCPA-based formulations exhibited varying degrees of drug entrapment, particularly at low drug loads (fig 1). Among the DCPA grades, Calipharm A showed the most pronounced drug retention within the cone. A trend was observed where lower drug load increased the severity of coning, reinforcing the role of excipients in influencing hydrodynamics. Notably, NC_rpm values did not consistently correlate with drug entrapment; higher NC_rpm did not always indicate more severe coning (fig 2). Physicochemical analysis of blends is underway, but early observations show distinct differences in bulk properties between formulations, which may contribute to coning behavior.

Conclusion: Coning behavior in dissolution testing was found to be formulation-dependent, with excipient type and drug load significantly impacting the extent of drug entrapment. While Avicel PH 102 permitted medium access and maintained drug release, DCPA grades demonstrated varying degrees of coning, emphasizing the role of excipient properties. The observed disconnect between NC_rpm and drug release indicates that NC_rpm alone is not a sufficient marker of coning severity. Ongoing efforts to characterize critical material attributes such as density, flow, and wettability aim to deepen mechanistic understanding and enable predictive formulation strategies. These insights will support preformulation decision-making and regulatory justification for dissolution method optimization.

References: 1. Arnold-Lockwood, E., et al. (2023). "The impact of formulation on dissolution coning: Supporting development of a classification system and predictive tool." British Journal of Pharmacy 8(2): S1-S2.
2. Higuchi, M., et al. (2015). "Prediction of coning phenomena for irregular particles in paddle dissolution test." European Journal of Pharmaceutical Sciences 76: 213-216.
3. Higuchi, M., et al. (2015). "Coning phenomena under laminar flow." European Journal of Pharmaceutical Sciences 80: 53-55.


Fig 1: Release of ibuprofen from Avicel PH 102(A), DCPA grades Fujicalin (B), ATAB (C) and Calipharm A (D). The difference in release at NCrpm and 50rpm indicates the degree of drug entrapment.


Fig 2: NCrpm values evaluated experimentally through visual observation of formulations with Avicel PH102, grades of DCPA (Fujicalin, Atab and Calipharm A) at 20, 50 and 70%