Hierarchical Mass Transfer Analysis of Drug Particle Dissolution, Highlighting the Hydrodynamics, pH, Particle Size, and Buffer Effects for the Dissolution of Ionizable and Nonionizable Drugs in a Compendial Dissolution Vessel

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Abstract
Dissolution is a crucial process for the oral delivery of drug products. Before being absorbed through epithelial cell membranes to reach systemic circulation, drugs must first dissolve in the human gastrointestinal (GI) tract. In vivo and in vitro dissolution is complex due to its dependency upon drug physicochemical, drug product, and GI physiological properties. However, an understanding of this process is critical for the development of robust drug products. To enhance our understanding of in vivo and in vitro dissolution, a hierarchical mass transfer (HMT) model was developed that considers drug properties, GI fluid properties, and fluid hydrodynamics. Key drug properties include intrinsic solubility, acid/base character, pKa, particle size, and particle polydispersity. GI fluid properties include bulk pH, buffer species concentration, fluid shear rate, and fluid convection. To corroborate the model in vitro dissolution experiments were conducted in the United States Pharmacopeia (USP) 2 dissolution apparatus. A weakly acidic (ibuprofen), a weakly basic (haloperidol), and a non-ionizable (felodipine) drug were used to study the effects of acid/base character, pKa and intrinsic solubility on dissolution. 900 ml of 5 mM bicarbonate and phosphate buffers at pH 6.5 and 37 0C were used to study the impact of buffer species on drug dissolution. To investigate the impacts of fluid shear rate and convection, the apparatus was operated at different impeller rotational speeds. Moreover, pre-sieved ibuprofen particles with different average diameters were used to investigate the effect of particle size on drug dissolution. In vitro experiments demonstrate that dissolution rates of both ionizable compounds used in this study were slower in bicarbonate buffer than in a phosphate buffer with the same buffer concentration due to lower interfacial buffer capacity, a unique behavior of bicarbonate buffer. Therefore, using surrogates (i.e., 50 mM phosphate) for bicarbonate buffer for biorelevant in in vitro dissolution testing may overestimate in vivo dissolution rate for ionizable drugs. Model simulations demonstrated that assuming a monodisperse particle size when modeling, dissolution may overestimate the dissolution rate for polydisperse particle size distributions. The hydrodynamic parameters (maximum shear rate and fluid velocity) under in vitro conditions in USP 2 apparatus under different rotational speeds are orders of magnitude higher compared to the in vivo situation. The inconsistencies between the in vivo and in vitro drug dissolution hydrodynamic conditions may cause an overestimation of the dissolution rate under in vitro conditions. The in vitro dissolution data supported the accuracy of the HMT for drug dissolution. This is the first drug dissolution model that incorporates the effect of the bulk pH and buffer concentration on the interfacial drug particle solubility of ionizable compounds combined with the medium hydrodynamics effect (diffusion, convection, shear, and confinement components), and drug particle-size distribution.
Funding Information
  • Horace H. Rackham School of Graduate Studies, University of Michigan
  • U.S. Food and Drug Administration (HHSF223201310144C, HHSF223201510157C)

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