Q&A: Scientific Advances Address Challenges Posed by Poor Solubility of Drug Candidates

At Metrics Contract Services, Dr. Michael DeHart manages all aspects of personnel and operations relating to formulating and manufacturing a client’s pharmaceutical materials for Phase I, II and III clinical trials. In this article, Dr. DeHart discusses how scientific advances are addressing challenges posed by the poor solubility or stability of drug candidates.

Tell us about new strategies or technologies that are optimizing bioavailability and solubility.

Nanoparticulate formulations can increase bioavailability in multiple ways. Due to the high surface area-to-volume ratio associated with decreased particle size, nanocrystals of poorly dissolving APIs can provide faster drug absorption and higher bioavailability by increasing the API’s dissolution rate. Amorphous nanoparticle dispersions also can increase the absorption rate of drug due to the same enhancement in surface area and dissolution described above while simultaneously stabilizing the amorphous state of the API and its higher solubility. Still other forms of nanoparticles can achieve high drug loading of poorly soluble compounds (e.g. polymeric micelles and liposomes) by providing a suspending vehicle capable of transporting their drug payload across the permeable intestinal wall. On the other hand, localization to the permeable tissue may forego the need for API to reach a higher bulk solubility in the intestinal fluid. This can be accomplished by the incorporation of adhesive excipients into the nanoparticle’s composition.

What specifically is Metrics Contract Services doing to address solubility and bioavailability?

We offer clients the ability to manufacture spray-dried material or to micronize the API that we receive through jet milling. Both of these technologies work well within our business model because the resulting material still will be formulated as a capsule or a tablet. In addition, these technologies fit well within our scientists’ skill sets as they have a firm understanding of amorphous material and nanoparticles.

How can a CDMO like Metrics Contract Services help accelerate the development of these challenging compounds?

In my opinion, communication is the best way to accelerate the development of these challenging compounds. It helps to know if the client has already performed some preliminary solubility studies, any kind of simple animal PK studies, or even what the critical quality attributes are (e.g., modified release, specific delivery in the small intestine). This allows us to move the project forward without having to redo, or in some cases relearn, information that may already be known.

What roles do excipients, formulations and drug delivery play when it comes to improving drug performance?

Excipients and formulations play a critical role in improving drug bioavailability and solubility. For example, an IR tablet of a poorly water-soluble drug may not have much bioavailability at all. Converting that same molecule to a controlled release product may help improve bioavailability by reducing the amount of drug released over time. One challenge with excipients is that there are so many of them on the market and several different grades (e.g, hypromellose, polyethylene oxide). We work intimately with our vendor’s sales teams and technical support groups to make sure that the right excipients are chosen from the beginning to ensure that the development time is minimal.

Can you describe a time when Metrics Contract Services resolved a client’s bioavailability/solubility issue?

A client brought us a pro-drug that was susceptible to acid degradation and general hydrolysis. This meant that the drug had to be protected from stomach acid. In addition, the exposure time to the intestinal fluid of the small intestine should be minimal. We took a combination approach to this type of drug delivery. First, we knew that an enteric coat was essential to provide acid protection. Second, we incorporated muco-adhesive polymers into the core tablet to help the tablet adhere to the walls of the small intestine. This allowed the pro-drug to permeate across the small intestine where it was then hydrolyzed to the active drug. Despite the daunting challenge of preventing hydrolysis throughout transit in the stomach and small intestine, animal studies confirmed that we were able to provide bioavailability of the molecule of interest.

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