Determining the influence of particle size of drug compounds on dissolution and absorption using the IDAS system

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 series, we detail on drug-specific characteristics and conditions that can be studied using the IDAS system.

One of the factors influencing the dissolution of a finished drug product, and the subsequent permeation of the API (active pharmaceutical ingredient), is the particle size of the formulation. For drug development, it is essential to investigate various sizes to determine the best possible formulation for a new drug. Particle size is especially crucial for poorly soluble drugs, which have slow and incomplete dissolution in gastrointestinal fluids.

The nanonization of compounds may help increase the bioavailability of a poorly soluble compound. The smaller size results in larger total surface area of the particles, increasing the amount available to permeate. However, testing various particle sizes to identify the optimal formulation can be costly and time-consuming if it is performed in healthy human subjects.

The IDAS system for assessment of the effects of particle size on dissolution and permeation

Our in vitro system, IDAS (In Vitro Dissolution Absorption System), allows for a quick and cost-effective assessment of how particle size affects the dissolution and permeation of a drug. IDAS consists of a dissolution chamber and a permeation chamber, which are separated by a polarized monolayer of human Caco-2 cells. The Caco-2 cell line is a colon carcinoma cell line and serves as a biorelevant barrier, permitting the simultaneous assessment of drug dissolution and permeation through this cell layer. Various buffers can be used in the dissolution chamber to mimic gastrointestinal conditions in the body.

Different formulations can be tested simultaneously, allowing for fast and accurate assessment with a better correlation than standard dissolution tests between the in vitro drug product release characteristics and in vivo performance. The system permits testing of drug products from all BCS classes, including poorly soluble compounds.

Example: Effect of particle size of oral indomethacin formulations

In this example, we assessed the effect of particle size of oral indomethacin formulations on dissolution and permeation. We dosed indomethacin into the IDAS dissolution chamber as nano-sized and micro-sized formulations at equal API levels.

We measured the dissolution and permeation by liquid chromatography–mass spectrometry (LC-MS/MS) to determine the dissolution constant (kd) and the permeation constant (kp) simultaneously, by modeling the concentration-time profiles using a Nelder-Mead simplex algorithm. The dissolution chamber contained Hanks’ balanced salt solution (HBSS) supplemented with 15 mM glucose (HBSSg) at pH 5.75, and the permeation chamber contained HBSSg supplemented with 4.5% BSA at pH 7.4, mimicking blood plasma.

Figure 1: In vitro measurements of indomethacin dissolution and permeation from micro-sized and nano-sized (submicron) formulations using IDAS.

Figure 2: Simultaneous modeling of indomethacin dissolution and permeation profiles.

We found that nano-sized formulation increased the kd by more than 300%, the kp by 30%, and the maximum dissolution by 17% compared to the micro-sized formulation (Figures 1 and 2).

What’s more, in vivo, orally administered nano-sizing increased the plasma Cmax of indomethacin (an index of the rate of absorption) by 25% without changing the total exposure (area under the curve, AUC). These data show that IDAS enables accurate in vitro-in vivo correlations.

Physiologically relevant modeling

As shown in the example, IDAS allows the assessment of the impact of particle size on the dissolution and permeation of drugs. Given that various formulations can be tested simultaneously while obtaining high-quality data that are translatable to the in vivo situation, the system is an efficient and accurate tool for formulation development.

Here to help

Connect with us to discuss your formulation development needs and to see how we can help design experiments that help save you time and money. Determining the effect of particle size is just one of the many uses of IDAS. We previously discussed some other applications of IDAS in previous blogs, with an emphasis on testing the phenomenon of supersaturation, and the effects of increased viscosity due to food intake, on dissolution and permeation.

Does particle size matter to you?