Improving Dissolution Behavior and Oral Absorption of Drugs with pH-Dependent Solubility Using pH Modifiers: A Physiologically Realistic Mass Transport Analysis

Abstract

Orally dosed drugs must dissolve in the gastrointestinal (GI) tract before being absorbed through the epithelial cell membrane. In vivo drug dissolution depends on the GI tract’s physiological conditions such as pH, residence time, luminal buffers, intestinal motility, and transit and drug properties under fed and fasting conditions (Paixão, P. et al. Mol. Pharm. 2018 and Bermejo, et al. M. Mol. Pharm. 2018). The dissolution of an ionizable drug may benefit from manipulating in vivo variables such as the environmental pH using pH-modifying agents incorporated into the dosage form. A successful example is the use of such agents for dissolution enhancement of BCS class IIb (high-permeability, low-solubility, and weak base) drugs under high gastric pH due to the disease conditions or by co-administration of acid-reducing agents (i.e., proton pump inhibitors, H2-antagonists, and antacids). This study provides a rational approach for selecting pH modifiers to improve monobasic and dibasic drug compounds’ dissolution rate and extent under high-gastric pH dissolution conditions, since the oral absorption of BCS class II drugs can be limited by either the solubility or the dissolution rate depending on the initial dose number. Betaine chloride, fumaric acid, and tartaric acid are examples of promising pH modifiers that can be included in oral dosage forms to enhance the rate and extent of monobasic and dibasic drug formulations. However, selection of a suitable pH modifier is dependent on the drug properties (e.g., solubility and pK a) and its interplay with the pH modifier pK a or pK as. As an example of this complex interaction, for basic drugs with high pK a and intrinsic solubility values and large doses, a polyprotic pH modifier can be expected to outperform a monoacid pH modifier. We have developed a hierarchical mass transport model to predict drug dissolution of formulations under varying pH conditions including high gastric pH. This model considers the effect of physical and chemical properties of the drug and pH modifiers such as pK a, solubility, and particle size distribution. This model also considers the impact of physiological conditions such as stomach emptying rate, stomach acid and buffer secretion, residence time in the GI tract, and aqueous luminal volume on drug dissolution. The predictions from this model are directly applicable to in vitro multi-compartment dissolution vessels and are validated by in vitro experiments in the gastrointestinal simulator. This model’s predictions can serve as a potential data source to predict plasma concentrations for formulations containing pH modifiers administered under the high-gastric pH conditions. This analysis provides an improved formulation design procedure using pH modifiers by minimizing the experimental iterations under both in vitro and in vivo conditions.

Use of Gastrointestinal Simulator, Mass Transport Analysis, and Absorption Simulation to Investigate the Impact of pH Modifiers in Mitigating Weakly Basic Drugs’ Performance Issues Related to Gastric pH: Palbociclib Case Study

“…The model assumes rapid equilibrium reactions between all reactive species in the drug boundary layer and predicts the interfacial pH and solubility as a function of the bulk pH, buffer and pH modifier concentration, and pH modifier and buffer p K a , as well as drug p K a and intrinsic solubility. The details of these equations are provided in the Supporting Information document and equations for drugs and pH modifiers of different ionization properties can be found in a recent publication of our research group . The model assumes that dissolution of the pH modifier is not rate-limiting, and the pH modifier species are dissolved in the bulk solution from the beginning of the dissolution process.…”

“…Furthermore, the work provided a framework for the selection of the optimal pH-modifying agent for a given weakly basic drug. 7 In the current study, we aimed to develop an in vivo predictive dissolution method to assess the influence of high gastric pH and the effect of pH modifiers on the dissolution of weakly basic drugs under physiologically realistic conditions of pH and buffer capacity. As a case example, the impact of high gastric pH on the dissolution and pharmacokinetic parameters of palbociclib was simulated to compare with in vitro and reported in vivo data for two commercially available formulations of palbociclib administered alone or coadministered with PPIs.…”

“…Palbociclib is an inhibitor of cyclin-dependent kinases 4 and 6 used in combination with letrozole for the treatment of postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. , Palbociclib is a BCS class II weakly dibasic drug (p K a’s of 3.7 and 7.1 at 37 °C), thus exhibiting pH-dependent solubility and susceptibility to reduced absorption under elevated gastric pH conditions. In fact, DDI studies conducted under fasted conditions using capsules of palbociclib free base (125 mg) showed reduced mean C max and AUC by 80 and 62%, respectively, when it was administered with PPI rabeprazole at steady state .…”

Antiallergic Treatment of Bariatric Patients: Potentially Hampered Solubility/Dissolution and Bioavailability of Loratadine, but Not Desloratadine, Post-Bariatric Surgery

“…In addition, the contractile force of the stomach is severely limited. , Under these conditions, disintegration of the drug product and dissolution of the drug dose, the two necessary steps toward drug absorption, may be hampered. , The third affected physiologically relevant parameter, the gastric pH, is dramatically increased immediately after the bariatric procedure, with higher pH after OAGB than after sleeve gastrectomy (SG) (Figure ). This may be critical when the drug in question contains acidic and/or basic functional groups . Indeed, some oral drugs may be more prone to dissolution problems after bariatric surgery than others, based on certain physicochemical properties; these include marginally soluble and weakly basic (alkaline) agents. , …”

“…32 This may be critical when the drug in question contains acidic and/or basic functional groups. 33 Indeed, some oral drugs may be more prone to dissolution problems after bariatric surgery than others, based on certain physicochemical properties; these include marginally soluble and weakly basic (alkaline) agents. 34,35 The aim of this work was to study whether loratadine/ desloratadine antiallergic treatment of a bariatric patient is at risk of being ineffective due to insufficient solubility/ dissolution.…”