Developing Models to Improve Oral Drug Product Delivery in the Human Gastrointestinal Tract

• Main Author: Salehi, Niloufar
• Other Authors: Ziff, Robert M, Al-Gousous, Jozef, Amidon, Gordon L, Amidon, Gregory E, Larson, Ronald G, Thurber, Greg Michael
• Format: Thesis
• Language: English
• Published: 2021
• Subjects: Mass transfer analysis; oral drug delivery; dissolution; in vivo-relevant in vitro dissolution; proton pump inhibitors; pH-modifiers; USP 2 design; Pharmacy and Pharmacology; Health Sciences; Carbonic acid
• Online Access: https://hdl.handle.net/2027.42/170070; https://doi.org/10.7302/3115

Oral drug products must dissolve in the gastrointestinal (GI) tract before being absorbed and reaching the systemic circulation. The rate and extent of drug dissolution and absorption depend on the characteristics of the active ingredient, properties of the drug product, physiological parameters such as buffer species, pH, bile salts, gastric emptying rate, intestinal motility, and hydrodynamic conditions. Drug products may overcome small-molecule drug's low solubility or permeability under the standard and disease conditions of the GI tract by adding compounds called excipients to the formulations. Since the conventional compendial dissolution and absorption tests often fail to predict drug compounds' behavior in the GI tract, designing and testing the newly designed drug formulations remains a challenge for the pharmaceutical industry. Therefore, developing cost-effective, reliable bio-relevant predictive dissolution and absorption models that can improve and accelerate product development is in high demand. This work develops mathematical mass transfer models for drug dissolution in a variety of physiologically-relevant media including bicarbonate buffer, which is the main buffering system in the GI tract. Dissolution in bicarbonate buffer, which takes into account the hydration and dehydration reaction rate constants of carbon dioxide and carbonic acid, is called the reversible non-equilibrium (RNE) model. Also, a mechanistic mass transfer model for weak-base, weak-acid, and non-ionizable drug compounds dissolution is developed; this in silico model, which is called hierarchical mass transfer (HMT) successfully predicts drug dissolution under the in vitro and simulated in vivo conditions by accounting for the effect of drug properties (i.e., solubility, acid/base character, pKa, particle size), GI fluid properties (i.e., bulk pH, buffer species concentration), and fluid hydrodynamics (i.e., shear rate, convection) on drug dissolution through a mathematical transport model. Next, a mass transfer model is ...