Solid State Chemistry – Development of Early Tox Formulation

Many teams rely on trial and error, but strategic partnerships can significantly streamline toxicology testing.

by Susan Thompson, Technical Director of VxP Pharma

A number of interrelated factors can have an impact on the delivery of a solid-state drug. Differing crystal forms (polymorphs) of the same drug can also exhibit widely differing solubility and dissolution rates. Varying properties like these can significantly impact the pharmacokinetics and pharmacodynamics of an active pharmaceutical ingredient (API).

Perhaps most dangerously of all, varying polymorphs may have different toxicity levels, due to factors like precipitation, which can alter their bioavailability, absorption rates, and other pharmacokinetic properties. To determine the maximum safe dose of an API, drug development teams perform animal toxicology research, which gives them data on how to create advantageous formulations around the API.

Even so, many labs continue to pursue early toxicological formulation with a trial-and-error process, resulting in wasted time and resources. In order to reduce variability in the testing and production processes, researchers need to adopt robust simulation and screening practices. The more quickly they can understand the system, the more cost-effectively they can bring the drug to market.

Animal toxicology testing

Every drug development program includes an animal toxicology testing phase. In this phase, researchers administer oral doses of the drug to animal subjects, typically in a solution or suspension. As the animals react to the drug, researchers record data on the drug’s uptake, bioavailability, pharmacokinetics, and toxicity.

If the toxicology screen generates poor exposure results, a number of factors could be to blame. Chemical or physical instability may play a part, as may fast metabolic degradation, per permeability, or even physical factors like molecular weight and charge, particle size, and crystal form.

In light of these concerns, a clear understanding of the API’s nature is an absolute necessity for a successful animal testing phase. Polymorphic variations, along with environmental factors like precipitation, can significantly impact the API’s behavior within the animal’s body. One common result of these variations is “muddy” data, which provides unclear or even inaccurate results about the drug’s pharmacokinetics.

While some degree of muddiness might seem to be an unavoidable aspect of animal testing, the truth is that much of this erratic variation can be eliminated with the proper approach.

Variability challenges in toxicology

As is well known, each polymorph of an API may result in widely varying tox test results, as can the solid form in which the API was prepared (e.g., cocrystal, solvate, hydrate, anhydrous, metastable, and so on). The composition and physical properties of the overall liquid formulation can also impact crucial API properties, particularly solubility and uptake. Even small variations in particle surface area can render earlier tox results all but useless.

For all these reasons, many smaller pharmaceutical development firms tend to rely on trial and error in their tox testing. When a given tox test doesn’t yield the hoped-for results, the team may restart the process with a polymorph that seems more promising. However, even if a second (or third, or fourth) tox test yields better results, further studies will still be needed to verify that polymorph’s efficacy and toxicity. Thus, the trial-and-error approach often ends up offering a poor return on investment in the long run.

The good news, however, is that certain approaches to testing, simulation and modeling can streamline much of this phase, while providing even clearer characterization of the API.

Informed toxicology analysis

Since crystalline size, form, surface area and other properties can all impact the behavior of an API, a growing number of research teams are partnering with formulation experts and material scientists before animal testing even begins. These experts can often provide more accurate estimates of an API’s bioavailability and toxicology, helping drug researchers pinpoint and reduce variability much earlier in the testing phase.

These early screenings test not only for varying polymorphs, but also for thermodynamic form relationships, cocrystals, and possible improvements in formulation composition. The more of these “moving parts” can be locked down before animal testing begins, the more cost-effectively solid-state drugs can be characterized, tox-screened, and moved into the clinical trial phase.

In fact, rigorous testing early in the development pipeline can help increase the value of the drug, by reducing risk, shortening the regulatory pathway, and highlighting new opportunities for patents and improvements. Due diligence before the tox testing phase, then, can have significant positive impact throughout the entire design cycle, and long after.

In addition to being an author and speaker, Susan Thompson serves as the Technical Director of Indianapolis based VxP Pharma.

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