Predicting bioavailability is pivotal in drug development, directly influencing a drug’s effectiveness within the body. A key factor in this process is solubility, which enables the drug to be absorbed and distributed. However, a major challenge we face is the increasing complexity of drugs.
A Historical Perspective
Historically, achieving sufficient bioavailability was straightforward for molecules, which dissolve easily in water and gastrointestinal fluids. This ease of absorption made early drug development direct. However, the landscape began to shift with the rise in computational drug design and the development of more complex organic molecules. These advancements brought about a significant challenge: poor water solubility, which directly impacts bioavailability.
The transition from these simpler times to our current reality highlights the need for innovative formulation techniques. About 90% of newly developed molecules face bioavailability issues. This means, the old and easy world of just synthesizing a crystalline molecule, compressing a tablet matrix, and administering it to patients are clearly gone. Almost each newly discovered molecule requires enabling formulations to enhance its originally poor bioavailability and solubility. This has led to the exploration of various techniques, including ionization, lipid-based formulations and the popular amorphous solid dispersion (ASD) approach.
The Growing Importance of ASDs
ASDs represent a critical advancement in addressing solubility and bioavailability challenges. By converting the active pharmaceutical ingredient (API) into an amorphous state, its water solubility is enhanced. This serves as the first step towards improving bioavailability. The second crucial step is incorporating the amorphous API into a polymer matrix.
Two key properties determine the success of ASD formulations: physical stability and release. Physical stability ensures that the formulation does not recrystallize or undergo phase separation during storage. Equally important is ensuring the timely release of the API out of the polymer matrix in the desired timeframe. Selecting the appropriate polymer and careful fine-tuning of drug load are critical for achieving desired bioavailability outcomes.
Polymers are the Architects of API Release
Polymers play the pivotal role in ASDs, acting as the scaffold within which drug molecules reside. They possess unique properties that profoundly influence drug release kinetics, e.g. via the spring-parachute effect. Imagine a spring-loaded mechanism within the polymer matrix. Initially, the polymer is like a tightly coiled spring, holding the drug molecules in place. However, upon contact with the dissolution medium, the polymer undergoes hydration or dissolution, akin to the spring expanding. This triggers the gradual release of drug molecules—similar to a parachute gently descending from the sky. The shape of this release profile is predetermined by the selection of the polymer, pH, drug load, intermolecular interactions, amorphous and crystalline solubilities, the API crystallization mechanisms and many more factors and need to be mechanistically understood for a successful release design.
Predictive Modeling: The Game-Changer
Building on the advancements of ASDs, predictive modeling has emerged as a transformative tool in the formulation landscape. amofor’s predictive modeling apporach leverages predictive modeling to refine and optimize the formulation process. By employing tools like PC SAFT, we can predict drug solubilities in various aqueous media and physical states, allowing for a tailored formulation strategy that addresses the unique challenges of each molecule. This includes considerations of pH-dependent solubilities and the careful selection of polymers and drug loads.
One of the greatest advantages of predictive modeling is its ability to reduce the reliance on trial-and-error approaches in finding the optimal formulation. Rather than testing numerous formulations in animals, researchers can now shift to in vitro techniques to predict the release profiles and validate the boundaries of formulation efficacy. This not only saves costs but also reduces the number of animal studies, aligning with the industry’s goal of minimizing animal testing.
Challenges Remain
Despite these advances, the path towards optimal bioavailability is complex. Bioavailability itself is a multifaceted process, heavily influenced by the gastrointestinal medium; a complex mixture not just of water, but also various bile salts, various pH levels and many other. Additionally, the task of moving molecules across gastrointestinal membranes introduces further complexity, relying on the nuanced process of membrane permeation. This step is difficult to control and exacerbates already existing challenges with solubility. Simulating and understanding these interactions present a formidable challenge but one that must be tackled to pave the way for successful drug development.
Looking to the Future
Predictive modeling is not just a technological advancement; it’s a paradigm shift in our approach to drug formulation. By focusing on the intricate interactions between excipients, the dissolution medium, and the dynamic changes during dissolution, we stand at the forefront of a new era in drug development.
We invite drug formulators to join us in this path towards standardization and efficiency in drug development. Our commitment to establishing a predictive modeling approach and our goal to standardize drug formulation are steps towards saving time and costs in drug development.
Reach out to us, and let’s discuss your desired release profile. Let’s make drug development simpler and more predictable. Together.