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ASK THE LAB EXPERT: The Complex Nature of Drug Formulation: Stories from a Formulation Lab

Drug formulation is and continues to be challenging. Every product is different. Every drug behaves differently based on its physicochemical properties. Understanding those properties through preformulation and in vitro permeability testing is important in designing an appropriate dosage form.

by | Oct 18, 2023

Janice Cacace, PhD, discusses the challenges of drug formulation and how CoreRx helps to address those problems

Expert Bio:

Janice Cacace, PhD, has a BS in Pharmacy from Purdue University and a PhD in Pharmaceutics from the University of Florida. Her career has spanned over 30 years in the pharmaceutical industry in the areas of formulation, product development, consulting, and academia. Over this time, she has gained a unique blend of new drug and generic drug development experience. She is currently the Executive Director of Development at CoreRx where she oversees product and analytical development and preformulation activities. This includes oversight of a diverse group of formulators with expertise in virtually every type of dosage form, including solid and liquid oral, ophthalmic, parenteral, pediatric, and semisolid orals and topicals. She is the co-inventor of 8 drug delivery patents.

Q: What initially drew you to the field of drug formulation?

A: I’m formally trained as a pharmacist, and I always knew I wanted to do research. While I completed my training, I took several industrial and physical pharmacy courses that I enjoyed. I started working in a laboratory as an undergraduate student, and that gave me some experience in chromatography (HPLC). After graduating, I attained a job at a pharmaceutical company doing analytical work for a transdermal development group, applying what I’d learned. One day, the vice president asked my group if anybody was interested in moving into the oral solids formulation development group. I took that opportunity, and have been in the formulations field ever since.

Q: What are some of the primary challenges around drug formulation development that you encounter in your work?

A: One of the primary challenges to drug formulation is the physical properties of the molecule itself as it is scaled up for the different phases of development. This can be a change in morphology or polymorphism. Polymorphs are the same chemical entity that can have different crystalline structures, and these can change during scale-up and stability, altering the drug’s uptake, solubility, and other properties. On top of this, the chemical properties in terms of permeability and solubility are always a challenge.

Once permeability and solubility are feasible and work for the delivery mode, we also have to be aware of bioavailability. The hardest situation to find a solution to is when permeability and solubility problems are paired with bioavailability problems. Each problem on its own is usually fixable, but together, they pose some difficulty for a drug formulation team. There is also what some folks call “the window of absorption”. The drug has to actually get to this area and be absorbed to work. Once it’s outside of the window, which can happen due to sustained release or other factors, the drug won’t be absorbed anymore and is ineffective.

Sometimes the API (active pharmaceutical ingredient) has good morphology and works well for the intended application. But, as we scale it up to a deliverable prototype at the dosage required, a quality change or different morphology can drastically change the outcome. We had this happen at CoreRx a little while ago. The shape of the initial sample of the API used for formulation was nice spherical particles. Upon scale-up, the particles became needle-like in structure. This wasn’t going to work in the direct blend formulation originally designed. It was a last-minute scramble to try to change our processing method to roller compaction, which would compensate for the morphology problem. This also created a much more robust formulation process if additional morphology challenges presented themselves with future API scale-up batches.

Q: Can you give some real-world examples of these challenges in drug formulation that you’ve faced at CoreRx?

A: Absolutely. A client came to us wanting to deliver a high dose of their drug as an oral solution. First, we had to go through and check the solubility. The compound was not soluble enough in an orally acceptable vehicle to deliver the required amount in a reasonable dose volume. We recommended that they consider changing to a suspension to fix this problem. They opted to squeeze the neat API dose into the largest capsule size available instead. But for their study, this would still require that the patient take multiple capsules. When we did that, there was nothing else in the capsule but the drug, so it all compacted onto itself and became a solid mass that didn’t dissolve. So, we reformulated into a powder blend that had acceptable dissolution, and the client ran their trial. But because of the difficulty with patients taking multiple large size capsules, they came back to us asking for development of a suspension. We all had to accept the fact that a suspension was probably the best solution to the problem and came full circle.

Q: How are improvements in technology, available equipment, and drug formulation methods changing the future of effective pharmaceutical delivery?

A: As personalized medicine gains traction, individualized dosages and targeted delivery are being developed, leading to more effective treatments. AI is becoming more widely used to improve screening, which also enables better drug development for patients in terms of reducing side effects and adverse reactions. We’re always searching for new therapeutics with higher potency and more efficient delivery, and advancements like these will make it easier to have a better idea of drug bioavailability and how they work in each individual.

There are also better delivery mechanisms being developed including inhalant devices like asthma treatments instead of pills (which can be difficult to swallow without water) or injections. Some groups are also working on gel pouches so you can take them without water. That’s a big step forward for treatments delivered to developing countries where access to water may be limited. In the case of pediatric and geriatric medicine, delivery methods that are easy to swallow and don’t require water are highly sought-after by healthcare providers.

Q: Can you describe your work at CoreRx?

A: I’ve been at CoreRx for over 10 years, and we’re a drug development and manufacturing company. We’ve gone from being a small drug formulation development company to being a manufacturer of commercial products. We’ve also gotten several New Drug Applications through the approval process, which is very exciting! Last year, we were even involved in an emergency use process, which, while challenging, was a once-in-a-lifetime experience. It’s really interesting to work in drug formulation with the FDA, going through their process on the frontlines of formulation discovery and development.

Not every product is exciting, but each one has its’ challenges. When we encounter challenges with the physical properties of an API, we choose one of several granulation processes. We recently upgraded our roller compaction capabilities to include a Gerteis Minipactor in development and a Gerteis Macropactor in manufacturing. That enables us to scale up dry granulation with minimal effort, and the entire team has loved having that. I’d say it was a great investment for us.

We’ve also brought in in vitro permeability testing. This allows us to identify the factors involved in permeability relating to either solubility or membrane permeability. We use this to identify physical parameters (such as particle size) and formulation variables (such as excipients) that can affect bioavailability in formulations.

Most recently, we’ve brought in a system that combines traditional dissolution testing with permeability testing. This allows testing of the entire dosage form. You can now put the product you want to screen into the dissolution bath and assess the permeability through a membrane simultaneously. This better mimics the dissolution process that would happen when people take oral therapeutics, and helps us develop better, more bioavailable drugs.

Are you looking for drug formulation testing and services?

Drug formulation is and continues to be challenging. Every product is different. Every drug behaves differently based on its physicochemical properties. Understanding those properties through preformulation and in vitro permeability testing is important in designing an appropriate dosage form. CoreRx offers these services as well as full formulation services to get your product into the clinic and beyond. View their services and submit lab requests on ContractLaborary.com.

Author

  • Marnie Willman

    I am currently the Clinical Writer for Today's Clinical Lab Magazine, part of LabX Media Group. In this role, I carry out and summarize Q&A sessions with frontier researchers who push boundaries and uncover findings that challenge all of the knowns. I also write articles on the discoveries that shape our world, and collaborate with research groups whose work impacts every facet of our lives. Prior to joining LabX Media Group, I worked at the Canadian Science Center for Human and Animal Health, honing my skills in research, writing, and team-oriented project execution. My personal research was focused on influenza virus, and I have experience with cell and animal models, professional and lay-audience scientific writing, and statistical analyses.

    View all posts

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