Use of the IDAS system to assess supersaturation

The pharmaceutical industry is feeling the acute effects of disruption caused by the COVID-19 pandemic. With most human trials on hold, drug developers and generics companies will be looking for new ways to progress product portfolios. This series of blog posts aims to highlight BCS and BCS-based biowaiver applications as such an opportunity.

In our previous blogs, we highlighted BCS and BCS-based biowaivers. Furthermore, we discussed experimental approaches to guide drug development of complex compounds. In this blog and the next, we will detail drug-specific characteristics, such as supersaturation and viscosity, and conditions that can be studied using the IDAS system.

Our in vitro tool IDAS is a dissolution vessel, which uses the Caco-2 colon carcinoma cell line as the biorelevant barrier to evaluate the dissolution and permeation of new drug compounds simultaneously. In each assay, a test compound can be dosed into the buffer solution in the apical chamber to assess apical-to-basolateral (absorptive) transport. As the system allows for the use of intact, clinical size dosage forms (tablets or capsules) and the volume of dissolution medium in the system is 500 mL, two dose units in IDAS is representative of human intake of a single dose with a glass of water (250 mL).

The system accurately predicts human outcomes and assesses how the critical quality attributes (CQAs) of formulations affect the local and/or systemic pharmacokinetics and pharmacodynamics of new drugs.

Supersaturation

Drug formulations with poor solubility may take advantage of gastric supersaturation to enable or increase intestinal absorption. The IDAS2 system can be used to assess the effect of supersaturation of poorly soluble weak base drugs on their intestinal absorption.

To assess supersaturation, experiments are performed in a biorelevant medium to mimic gastric (pH 1.6) and intestinal conditions (pH 6.5). Furthermore, these can represent fasted or fed states to assess the effect of food intake on drug dissolution, absorption, and permeation.

We have developed an IDAS2 procedure with a pH shift to explore the drug supersaturation phenomenon. This protocol includes a two-stage setup that mimics the route of drug intake through the gastric and intestinal environments.

In this two-stage setup, the tablets or capsules are first exposed to simulated gastric fluid (SGF, pH 1.6) for 20-30 minutes. After this, the composition of the medium is modified to mimic the intestinal contents by adding a concentrated buffer to increase the pH to 6.5 and introduce bile acids and lecithin at appropriate concentrations. This adjusts the dissolution medium to fasted state simulated intestinal fluid (FaSSIF, pH 6.5). Dissolution is measured in both solutions, and permeation is measured using chambers containing Caco-2 cell monolayers with their apical surface facing the dissolution chamber.

The two-stage conditions induce supersaturation by the rapid dissolution of basic drugs in the gastric acidic medium (pH 1.6). After adjusting to the intestinal environment (pH 6.5), the dissolved concentration declines, indicating nucleation and precipitation. Weakly basic drugs with low solubility at neutral pH show higher dissolution in the pH shift protocol compared to the one-stage setup, modeling supersasturation in vivo. And some weak base drugs such as dipyridamole (see below) maintain higher dissolved concentrations, even after the switch to pH 6.5, and correspondingly higher permeation, in the pH shift protocol compared to FaSSIF (pH 6.5) without the initial low-pH stage.

All experiments are performed using multiple dissolution and permeation replicates collected at predefined time points. After each permeation sample collection, the receiver medium is replenished. Dissolution samples are filtered to remove undissolved particles, and all samples are analyzed using reverse-phase high-performance liquid chromatography-mass spectrometry (LC-MS/MS).

Examples: dipyridamole (Class II weak base) and minoxidil (Class I soluble weak base)

In this experiment, we tested drugs with the two-stage (pH shift) protocol and the one-stage setup, in which dissolution and permeation are measured in FaSSIF (pH 6.5). At predefined time points, samples were collected and analyzed by LC-MS/MS.

Data for the Class II drug dipyridamole (with limited solubility at neutral pH) and the Class I drug minoxidil (with high solubility throughout the physiological pH range) show that the dissolution and permeation of dipyridamole significantly increases in the two-stage setup.

Figure 1: Examples of the dissolution and permeation time profiles of dipyridamole (basic drug) and minoxidil (soluble weakly basic) as measured using the pH shift (●) and pH 6.5 (▪) IDAS2 assays.

Here to help

The pH shift procedure can correctly convey dissolution in the gastric environment, as well as supersaturation and precipitation processes in intestinal media. This allows for the detection of minor changes in dissolved drug concentrations with high sensitivity under various dissolution and absorption conditions. For more information on how this technique can be used for your drug development processes, check this page or contact us.

In our next blog, we will highlight the use of the IDAS system in evaluating the effects of food intake (viscosity) on drug dissolution and permeation.