Overcoming the Solubility Barrier of Ibuprofen by the Rational Process Design of a Nanocrystal Formulation

Abstract

Wet media milling, coupled with spay drying, is a commonly proposed formulation strategy for the production and solidification of nanosuspensions in order to overcome the solubility barrier of BCS Class II substances. However, the application of mechanically and thermally intensive processes is not straightforward in the cases of ductile and/or low melting point substances that may additionally be susceptible to eutectic formation. Using ibuprofen (IBU) as a model drug with non-favorable mechanical and melting properties, we attempt to rationalize nanocrystal formulation and manufacturing in an integrated approach by implementing Quality by Design (QbD) methodology, particle informatics techniques and computationally assisted process design. Wet media milling was performed in the presence of different stabilizers and co-milling agents, and the nanosuspensions were solidified by spray-drying. The effects of key process parameters (bead diameter, milling time and rotational speed) and formulation variables (stabilizer type and drug/stabilizer ratio) on the critical quality attributes (CQAs), i.e., Z-average size, polydispersity index (PDI), ζ-potential and redispersibility of spray-dried nanosuspensions were evaluated, while possible correlations between IBU free surface energy and stabilizer effectiveness were studied. The fracture mechanism and surface stabilization of IBU were investigated by computer simulation of the molecular interactions at the crystal lattice level. As a further step, process design accounting for mass-energy balances and predictive thermodynamic models were constructed to scale-up and optimize the design space. Contemplating several limitations, our multilevel approach offers insights on the mechanistic pathway applicable to the substances featuring thermosensitivity and eutectic tendency.

Analysis of the Effects of Process Parameters on Start-Up Operation in Continuous Wet Granulation

“…While this study focused on wet granulation, subsequent unit operations should be performed simultaneously. The latter could also be modeled by a systems-based approach simulating the complete process line of unit blocks [47]. Further studies are needed to analyze the propagation of the start-up in twin-screw wet granulation to the final product quality, e.g., dissolution.…”

Sildenafil 4.0—Integrated Synthetic Chemistry, Formulation and Analytical Strategies Effecting Immense Therapeutic and Societal Impact in the Fourth Industrial Era

“…A lot of research effort has been devoted on transdermal drug delivery systems for nanosized sildenafil particles [ 123 ] to improve drug solubility and bioavailability, while achieving high drug loading [ 124 ]. The nano comminution of starting material is a credible, scalable technique to increase the available contact surface and dispersion capacity of the BCS II APIs [ 125 ]. The Elnaggar group used a modified high-shear homogenization technique to fabricate sildenafil citrate-loaded nanostructured lipid carriers (NLCs) and solid lipid nanoparticles (SLNs) achieving entrapment efficiency of 96.7% and 97.5%, respectively.…”

Integrating Elastic Tensor and PC-SAFT Modeling with Systems-Based Pharma 4.0 Simulation, to Predict Process Operations and Product Specifications of Ternary Nanocrystalline Suspensions

“…Moreover, the Vickers hardness and fracture toughness were calculated according to Mazhnik et al (2019) [19] using the USPEX Hardness tool (available online at https://uspex-team.org/online_utilities/hardness3/, accessed on 9 September 2021). The Bond Work Index was calculated by the empirical Equation (1) given by the tentative method developed by Gent et al (2012) [20]:…”

“…Comminution of poorly soluble active pharmaceutical ingredients (APIs) below the 1 µm threshold by wet media milling (WMM), followed by solidification of the obtained nanosuspensions via spray drying (SD), is an industrially feasible, scalable framework for solubility/dissolution enhancement [1,2]. Shear stress applied during WMM on crystals exhibiting surface defects [3] induces crack propagation, which results in fracture-creating new surfaces, increasing the Gibbs free energy [4].…”