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.

It is well known that reduced gastric acidity, for example with concomitant administration of acid reducing agents, can result in variable pharmacokinetics and decreased absorption of weakly basic drugs. It is important to identify the risk of reduced and variable absorption early in development, so that product design options to address the risk can be considered. This article describes the utilization of in vitro and in silico tools to predict the effect of gastric pH, as well as the impact of adding pH modifiers, in mitigating the effect of acid reducing agents on weak base drugs' dissolution and absorption. Palbociclib, a weakly basic drug, was evaluated in low and high gastric pH conditions in a multicompartmental dissolution apparatus referred to as a gastrointestinal simulator (GIS). The GIS permits the testing of pharmaceutical products in a way that better assesses dissolution under physiologically relevant conditions of pH, buffer concentration, formulation additives, and physiological variations including GI pH, buffer concentrations, secretions, stomach emptying rate, residence time in the GI, and aqueous luminal volume. To predict drug dissolution in the GIS, a hierarchical mass transport model was used and validated using in vitro experimental data. Dissolution results were then compared to observed human clinical plasma data with and without proton pump inhibitors using a GastroPlus absorption model to predict palbociclib plasma profiles and pharmacokinetic parameters. The results showed that the in silico model successfully predicted palbociclib dissolution in the GIS under low and high gastric pH conditions with and without pH modifiers. Furthermore, the GIS data coupled with the in silico tools anticipated (1) the reduced palbociclib exposure due to proton pump inhibitor coadministration and (2) the mitigating effect of a pH-modifying agent. This study provides tools to help in the development of orally administered formulations to overcome the effect of elevated gastric pH, especially when formulating with pH modifiers.

A Mechanistic Study of Drug Mass Transport from Supersaturated Solutions Across PAMPA Membranes.

There is an increasing shift from dissolution testing to dissolution-permeation testing of formulations during formulation development and this has led increasing application of permeability measurements using parallel artificial membrane permeability assay (PAMPA) membranes. However, there is a lack of thorough analysis of the impact of variabilities in the PAMPA setup on the mass flow rate outcomes, particularly for complex solubility-enabling formulations. In this study, we investigated the impact of amorphous drug-rich nanodroplets, formed in supersaturated solutions by liquid-liquid phase separation, on membrane transport by measuring mass flow rate across PAMPA membranes. In addition, we explored the impact of PAMPA variants such as lipid composition, hydrophobicity and pore size of the filter support, as well as receiver sink properties on membrane mass flow rates of solutions containing amorphous nanodroplets. Filter properties and lipid composition did not show a notable influence on the mass flow rates for lipophilic molecules, while a marked impact was observed for hydrophilic molecules. High sink conditions in the receiver compartment, arising from addition of micellar surfactant, altered the membrane integrity for lipid-impregnated hydrophilic membranes. In contrast, no such effect was observed for a hydrophobic filter support. Membrane integrity tests also suggested that monitoring water transport may be an improved approach over using Lucifer yellow. Furthermore, high sink conditions in the receiver compartment resulted in an increase in the overall mass flow rate. This was due to the effect of asymmetric conditions, generated across the membrane, on mass transport kinetics. Linearity between mass flow rate and donor concentration was observed until the donor concentration reached the amorphous solubility. Above the amorphous solubility, a gradual increase in mass flow rate was observed i.e., with an increasing number of nanodroplets in the solution. This was attributed to decrease in the permeability barrier across unstirred water layer due to reduction of the concentration gradient as nanodroplets dissolved to replenish absorbed drug. Observations made in this study provide insights into the mechanisms associated with mass transport of supersaturated solutions across PAMPA membranes, which are critical for improved evaluation of enabling formulations.

Interplay of Adsorption, Supersaturation and the Presence of an Absorptive Sink on Drug Release from Mesoporous Silica-Based Formulations.

PURPOSE: Mesoporous silica-based formulations of poorly soluble drugs may exhibit incomplete drug release due to drug remaining adsorbed on the silica surface. The goal of this study was (1) to evaluate the adsorption tendency of atazanavir from aqueous solution onto mesoporous silica (SBA-15) and (2) to determine if the drug release from mesoporous silica formulations was promoted by the presence of an absorptive compartment during dissolution testing. METHODS: Atazanavir (ATZ) formulations with different drug loadings were prepared by incipient impregnation. The solid-state properties of the formulations were analyzed by X-ray diffraction (XRD), differential scanning calorimetry (DSC), infrared spectroscopy and thermogravimetric analysis. Drug release was compared for closed compartment versus absorptive dissolution testing at gastric and intestinal pH. RESULTS: XRD and DSC showed that all formulations were amorphous. Infrared spectra indicated intermolecular interactions between silanol groups in SBA-15 and carbonyl groups in atazanavir. Nanoconfinement of drug in silica mesopores was suggested by thermal analysis. Closed compartment dissolution testing showed incomplete drug release, largely due to the adsorption tendency of ATZ. However, coupled dissolution-absorption studies showed complete release over a 240 min time period. This suggested that the depletion of drug in the dissolution medium due to drug diffusion across the membrane promotes drug release. Drug release was further improved when the formulation was first added to fasted state gastric pH conditions followed by pH-shift to intestinal conditions, which was attributed to the higher solubility of atazanavir at low pH. However, ATZ mesoporous silica formulations showed a poorer overall absorption behavior relative to a polymer-based amorphous solid dispersion formulation. CONCLUSION: This study highlights that absorptive dissolution conditions promote drug desorption from the silica surface and hence, enhance drug release. Further, the influence of solution pH on drug release underscores the need to consider how variations in physiological conditions may impact the performance of mesoporous silica-based formulations. Graphical Abstract Drug release and adsorption tendency in the absence and presence of an absorptive sink during dissolution testing.

Influence of Drug-Silica Electrostatic Interactions on Drug Release from Mesoporous Silica-Based Oral Delivery Systems.

Mesoporous silica particles are attractive carriers for poorly soluble drugs whereby confinement of drugs in the mesopores leads to amorphization, which makes them potential carriers for enhanced oral delivery. However, interactions between the drug molecules and the silica surface can lead to incomplete drug release. The strength of the interaction depends on the silica surface chemistry, which varies as a function of pH, as well as on drug chemistry and ionization states. Herein, the adsorption and dissolution behavior of weakly basic drugs were evaluated as a function of pH to understand the impact of electrostatic interactions on the performance of mesoporous silica-based formulations. A higher adsorption was noted when the drug interacted with the silica surface via electrostatic interactions compared to hydrogen bonding. Higher adsorption, in turn, led to a lower extent of drug release. In two-stage release studies of drugs with pKa values close to the intestinal pH, a shift from low to higher pH solutions resulted in a decrease in the solution concentration. Further investigations demonstrated that this was due to readsorption of the drug, initially released in the acidic medium when the pH was increased. Two-stage release studies were also coupled with mass transport measurements. Only a slight improvement in drug release due to simultaneous absorption across a membrane was observed, suggesting strong drug adsorption to the silica surface arising from favorable electrostatic interactions, which diminishes the effect of sink conditions provided by the absorptive environment. This study highlights that physiological parameters, such as solution pH, are important considerations when designing mesoporous silica-based formulations for poorly soluble drugs. It also underscores the importance of incorporating in vivo-relevant conditions in in vitro testing to better evaluate these complex formulations due to the notable effect of dissolution media on the release behavior.

Impact of Hypromellose Acetate Succinate Grade on Drug Amorphous Solubility and In Vitro Membrane Transport.

The goal of this study was to evaluate the effect of polymer substituent type on drug amorphous solubility as well as drug membrane transport rate. Two grades of hypromellose acetate succinate (HPMC-AS), AS-LF and AS-HF, were studied with 4 model drugs. Experimental techniques used to evaluate the drug-polymer systems included solution 1H nuclear magnetic resonance spectroscopy (NMR) and absorptive dissolution testing. AS-HF substantially reduced the drug amorphous solubility, while AS-LF had only a minor impact. By NMR spectroscopy, AS-HF was found to distribute extensively into the drug-rich phase formed via liquid-liquid phase separation. Polymer distribution into the drug-rich phase accounts for the reduction in the drug amorphous solubility. Absorptive dissolution testing showed that drug mass transport was lower in the presence of AS-HF compared to AS-LF for drug concentrations above the amorphous solubility. Thus, the decrease in drug amorphous solubility by AS-HF reduced drug transport. This study highlights the need to consider the polymer impact on drug amorphous solubility and subsequent drug transport, when optimizing amorphous solid dispersion formulations, with the goal of maximizing drug absorption.

Absorptive Dissolution Testing: An Improved Approach to Study the Impact of Residual Crystallinity on the Performance of Amorphous Formulations.

Amorphous solid dispersions typically improve the oral bioavailability of poorly soluble drugs. However, residual crystallinity is always a concern, in terms of potential impact on the product stability and performance. Consequently, in vitro tools that allow biorelevant assessment of residual crystallinity are of interest. The goal of the present study was to use absorptive dissolution testing to evaluate the impact of different levels of crystallinity in an amorphous formulation on membrane mass transport kinetics and supersaturation-time profiles. Partial crystallinity was induced in commercially available tacrolimus formulations by exposure to moderate temperature and high relative humidity. A hollow fiber membrane was coupled to a dissolution vessel to create an absorptive dissolution testing apparatus, and concentration-time profiles were simultaneously monitored during dissolution (donor compartment) and after absorption across the membrane (receiver compartment). The coupled dissolution-absorption measurements indicated that residual crystallinity impacted the absorption profiles in a manner that depended on the volume of fluid used for the dissolution measurement. A high percentage of residual crystallinity hampered the drug release from the formulation. Higher supersaturation in nonsink dissolution conditions improved mass transfer rates; however, the presence of seed crystals led to rapid desupersaturation. Further systematic studies to delineate the interplay between the rate of absorption and desupersaturation revealed that for a given dissolution rate, the crystallization rate would supersede the absorption rate only at high supersaturations. Thus, seeds have a lower impact on absorption when the overall supersaturation generated is lower. This study underscores the importance of considering competing physical processes when evaluating amorphous formulations. A further consideration highlighted is that different fluid volumes may impact the absorption profile for supersaturating dosage forms. Absorptive dissolution testing appears to be a potentially valuable tool to mechanistically investigate amorphous solid dispersion formulation release and phase behavior under more biorelevant conditions.

Impact of Surfactant and Surfactant-Polymer Interaction on Desupersaturation of Clotrimazole.

The impact of surfactants on supersaturation of clotrimazole solutions was systematically evaluated. Four clinically relevant surfactants, sodium dodecyl sulfate, vitamin E TPGS, Tween 80, and docusate sodium were studied. The induction time for nucleation and rate of desupersaturation were determined at a supersaturation ratio of 90% amorphous solubility. Measurement was also performed in the presence of predissolved hydroxypropyl methylcellulose acetate succinate to study the effect of surfactant-polymer interaction on desupersaturation. The 4 surfactants showed varied effects on desupersaturation. From supersaturation maintenance perspective, in the presence of hydroxypropyl methylcellulose acetate succinate, the rank order for the 4 surfactants was found to be: docusate sodium > vitamin E TPGS > sodium dodecyl sulfate > Tween 80. Given the importance of maintaining supersaturation and varied effect of surfactants on nucleation kinetics and desupersaturation rate, a careful examination of active pharmaceutical ingredient, polymer and surfactant interaction on an individual basis is recommended for selecting an appropriate surfactant for use in amorphous solid dispersion formulation.

Insight into Amorphous Solid Dispersion Performance by Coupled Dissolution and Membrane Mass Transfer Measurements.

The tendency of highly supersaturated solutions of poorly water-soluble drugs to undergo liquid-liquid phase separation (LLPS) into drug-rich and water-rich phases when the concentration exceeds the amorphous solubility, for example, during dissolution of some amorphous solid dispersions, is thought to be advantageous from a bioavailability enhancement perspective. Recently, we have developed a high surface area, flow-through absorptive dissolution testing apparatus that enables fast mass transfer providing more in vivo relevant conditions and time frames for formulation testing. Using this apparatus, the absorption behaviors of solutions with different extents of supersaturation below and above the amorphous solubility were evaluated. In addition, simultaneous dissolution-absorption testing of amorphous solid dispersions (ASDs) with varying drug loadings and polymer types was carried out to study and distinguish the absorption behavior of ASDs that do or do not undergo LLPS. When compared with closed-compartment dissolution testing, a significant influence of the absorptive compartment on the dissolution rate of ASDs, particularly at high drug loadings, was observed. The formation of drug-rich nanodroplets, generated by both solvent-addition and ASD dissolution, resulted in a higher amount of drug transferred across the membrane. Moreover, the mass transfer was further enhanced with increasing concentration above the amorphous solubility, thereby showing correlation with an increase in the number of drug-rich particles. The importance of including an absorptive compartment in dissolution testing is highlighted in this study, enabling coupling of dissolution to membrane transport, and providing a more meaningful comparison between different formulations.

Absorptive Dissolution Testing of Supersaturating Systems: Impact of Absorptive Sink Conditions on Solution Phase Behavior and Mass Transport.

One of the most commonly used formulation development tools is dissolution testing. However, for solubility enhancing formulations, a simple closed compartment conventional dissolution apparatus operating under sink conditions often fails to predict oral bioavailability and differentiate between formulations. Hence, increasing attention is being paid to combined dissolution-absorption testing. The currently available mass transport apparatuses, however, have certain limitations, the most important being the small membrane surface area, which results in slow mass transfer. In this study, a novel high surface area, flow-through absorptive dissolution testing apparatus was developed and tested on a weakly basic model drug, nevirapine. Following optimization of the experimental parameters, the mass transfer attained for a nevirapine solution was 30 times higher in 60 min as compared to a side-by-side diffusion cell. To further evaluate the system, nevirapine powder and commercial tablets were first dissolved at an acidic pH, followed by pH increase, creating a supersaturated solution. Detailed information related to the extent of supersaturation achieved in crystallizing and noncrystallizing systems could be obtained from the combined dissolution-mass transport measurements. Differences in donor cell compartment concentration-time profiles were noted for absorptive versus closed compartment conditions. It is anticipated that this approach could be a promising tool to identify solubility enabling formulations that perform optimally in vivo.