The Invisible Science

Introduction: The Unseen Revolution in Your Pocket

Imagine suffering an asthma attack, reaching for your inhaler, and praying for relief. What you might not realize is that the life-saving mist you inhale represents one of pharmaceutical science's most sophisticated achievements—a delicate dance of physics, chemistry, and engineering where millionth-of-a-meter differences determine whether medicine reaches your lungs or sticks to your throat.

As one colleague noted, "Paul's contribution to the science of inhalation drug development, solubility prediction, and service to the scientific community has touched the lives and careers of countless numbers of scientists" ² .

Dr. Myrdal, who passed away in May 2018, stood at the forefront of pharmaceutical innovation for over two decades, making critical contributions that transformed how medicines are delivered to the lungs. His legacy includes developing the world's first CFC-free steroid inhaler and creating sophisticated prediction models that continue to guide pharmaceutical development ² . This article explores how Myrdal's work turned the simple act of pressing an inhaler into a precisely engineered medical intervention.

The Scientist and His Legacy: Tracing a Career of Innovation

Paul B. Myrdal's scientific journey began at the University of Wisconsin Madison, where a freshman chemistry class introduced him to both his future wife and his calling. Transferring to the University of Arizona to complete his molecular and cellular biology degree, he joined Dr. Samuel Yalkowsky's laboratory, where he began his groundbreaking work on solubility prediction ² .

During his graduate studies, Myrdal developed two fundamental tools that would become staples in pharmaceutical research: the Aqueous Functional Group Activity Coefficients (AQUAFAC) and the Unified Physical Property Estimation Relationships (UPPER). These systems allowed scientists to predict how soluble a compound would be in water—a critical factor in drug development—without laborious experimental testing ² . This early work demonstrated Myrdal's unique talent for bridging theoretical chemistry with practical application.

The Particle Puzzle: Cracking the Code of Perfect Inhalers

The Critical Question

Pressurized metered dose inhalers (pMDIs) represent a remarkable engineering challenge: they must consistently deliver precise drug amounts deep into the lungs, where they can exert their therapeutic effects. The effectiveness of these inhalers depends overwhelmingly on one key property: aerodynamic particle size distribution (APSD). Particles that are too large impact in the mouth and throat, while particles that are too small are exhaled back out without depositing in the lungs. The "sweet spot" for lung deposition is remarkably narrow—between approximately 0.5 to 5 micrometers in diameter ⁴ . But what factors determine this particle size, and how could manufacturers reliably control it? This was the puzzle Myrdal and his team sought to solve.

For suspension inhalers (where drug particles are suspended rather than dissolved in the propellant), the relationship between formulation characteristics and final particle size was particularly complex. As Myrdal's research demonstrated, when a pMDI is activated, the formulation is atomized into tiny droplets containing varying numbers of drug particles. As the volatile propellant evaporates, these particles form "multiplets" (aggregates of multiple drug particles) whose size depends on how many original drug particles were in each droplet ⁴ . Understanding and predicting this process was essential for designing effective inhalers.

Methodology: A Digital Laboratory

To tackle this challenge, Myrdal and his colleagues developed an innovative Monte Carlo simulation model that could predict residual particle size distribution from suspension pMDIs ⁴ . This approach allowed them to virtually test thousands of formulation variations without costly physical experiments. The model accounted for multiple critical factors:

• Micronized drug particle size distribution - the original size of drug particles before suspension
• Drug concentration - the amount of drug in the formulation
• Initially atomized droplet size - the size of droplets immediately after activation
• Formulation composition - including propellants and cosolvents like ethanol

The simulation worked by generating virtual droplets with sizes randomly selected from a lognormal distribution, then using Poisson distribution statistics to determine how many drug particles each droplet would likely contain based on its volume and the drug concentration. Each simulated droplet would then evaporate, leaving behind residual drug particles whose aerodynamic diameter could be calculated ⁴ . By repeating this process thousands of times, the model could predict the final particle size distribution that would be produced by a given formulation.

Experimental Validation

To validate their computational model, the researchers prepared experimental suspension formulations with systematically varied parameters. They tested formulations with drug concentrations ranging from 0.01% to 1% and micronized drug sizes between 1.2 and 2.6 micrometers, all suspended in HFA-134a propellant with 8.5% ethanol ⁴ . The aerodynamic particle size distributions of these formulations were then experimentally measured using Andersen Cascade Impactor testing, the standard method for characterizing pharmaceutical aerosols.

Results and Analysis: Cracking the Code

The research yielded crucial insights into what controls inhaler performance. Myrdal's team discovered that drug concentration, micronized drug size, and initially atomized droplet distribution collectively determine the proportion of atomized droplets containing multiple suspended drug particles, which in turn governs the final residual particle size ⁴ . This was a significant advancement in understanding the complex relationship between formulation and performance.

Perhaps most importantly, they developed an empirical algebraic model that could predict residual particle size for a variety of suspension formulations with remarkable accuracy—average error of just 0.096 micrometers ⁴ . This provided pharmaceutical developers with a practical tool for formulation design that could reduce reliance on traditional trial-and-error approaches.

The Scientist's Toolkit: Essential Tools for Inhalation Research

Myrdal's work exemplified the interdisciplinary nature of pharmaceutical sciences, drawing from chemistry, physics, engineering, and materials science. The following table highlights key materials and reagents essential to inhalation research, many of which figured prominently in Myrdal's investigations:

Conclusion: A Legacy That Still Breathes

Paul Myrdal's career exemplifies how targeted scientific inquiry can yield life-changing innovations. From developing the first CFC-free steroid inhaler to creating sophisticated prediction models that continue to guide pharmaceutical development, his work has left an indelible mark on medicine ² . The simulation approaches he helped pioneer have reduced the time and resources needed to develop new inhaler products, ultimately making treatments more accessible and effective for patients worldwide.

As one of his former collaborators noted, "It is through these valuable contributions to science and the careers of so many peers that Paul's legacy will be remembered for years to come" ² .

The next time you see someone use an inhaler, consider the invisible science that makes it work—the precisely engineered particles, the carefully balanced formulations, and the decades of research that ensure medicine reaches exactly where it's needed. In that moment, you're witnessing Paul Myrdal's legacy in action, a testament to how one scientist's dedication can help millions breathe easier.