Formulation: Using API Powder in a Bottle or Capsule for Clinical Phase I Studies

Sometimes simple dosing with API powder in a bottle or capsule for a clinical Phase I study can be acceptable, and it may be quicker to use API powder in either a capsule or a bottle than to develop a formulation. However, use of such an approach is not always appropriate and may not be quicker in the long run. If you get it wrong, you can cause considerable delay to your project, which most often means that it is dead in the water.

The question almost always comes up when my clients are investigating small-molecule APIs, because some individuals, such as financial backers, often believe that using API powder in a bottle or capsule can reduce the amount of time required to complete clinical Phase I human studies. 

The perceived advantage of using API powder in a bottle or capsule is speed. Time is money, and you can very quickly prepare the few hundred bottles or capsules to cover supplies for clinical Phase I and the necessary supporting stability studies. You might save three or four months for a Biopharmaceutical Classification System (BCS) I drug candidate. But how many modern drug candidates are BCS I? About one in four or five small molecule drug candidates are water soluble by the latest estimates and not all of these are classed as BCS I. 

When I joined the pharmaceutical industry in the early 1970s, the number of soluble drug candidates exceeded 80 percent. So why the change? Several factors are responsible, but a major one is that as industry has moved to adopt high-throughput screening techniques, the medicinal chemists have been able to design drug candidate molecules that interact better with receptors. This change has led to increases in molecular weight and in the number of hydrophobic domains in the molecules. Both these factors generally have a negative impact on drug solubility. 

I do not know how many useful drug candidates pharmaceutical companies have dropped in Phase I because of poor bioavailability, but I suspect that the issue arises regularly. I have worked on a project that a company terminated due to lack of bioavailability. But that was many years ago, before we had sufficient understanding of drug absorption. More recently, however, I have worked on a project that was resurrected after a failed Phase I study using API powder in a capsule! In addition, I have worked on projects that a company has terminated due to lack of efficacy or unacceptable side effects, but those problems are not the same as a lack of bioavailability. 

In my experience with poorly water-soluble drugs, use of API in a bottle or a capsule is a waste of time, effort, and money. If you encounter bioavailability issues using such an approach, it may take up to two years to get to the stage of being able to repeat the clinical Phase I study using a formulation that has acceptable bioavailability. How many small start-up companies can afford or withstand such a delay? My criteria for using API powder in a bottle or capsule are very simple: The drug candidate must be a powder; it must have good aqueous solubility across the physiological pH range—pH 1 to pH 8, particularly, pH 1 to pH 6; and it must have good permeability across the wall of the GI tract (GIT). Realistically, I might accept this approach only for BCS I drug-candidate molecules, i.e., drug molecules that are highly soluble and show high permeability across the wall of the GIT. 

Some of you may ask, “What about BCS III drugs? They’re soluble!” Yes, they are! However, increasing evidence shows that proper formulation can overcome some of the permeability issues encountered with BCS III drugs, especially if efflux is the issue. You can also evaluate permeation enhancers in other cases. So why risk going with an unformulated powder preparation and court failure? 

Assuming you get a good result from your clinical Phase I study using a simple API powder in a bottle or capsule, you and your backers will want to move quickly into clinical Phase II. But now you have a problem. The quantity of unit doses required for clinical Phase II is typically 10,000 or more, rather than the hundreds required for Phase I, and the stability requirements are more exacting. 

From my own experience, I know that you can fill that many capsules by weighing them individually, but it can take several weeks and is very expensive. Even using the newer, unit-dose filling systems, it can take several days. In any event, starting from scratch to manufacture Phase II supplies after the results of the Phase I studies—even continuing with API powder in a bottle or capsule—can take several months by the time you sign the contracts, reserve the manufacturing slot, and design, develop, make, test, and release the supplies. 

To avoid a prolonged delay between the end of clinical Phase I—API powder in a bottle or capsule—and the start of clinical Phase II—tablet or capsule formulation—and to produce follow-on supplies more easily, you need to start the formulation work for the clinical Phase II formulation—and possibly the clinical Phase II and III formulations—in parallel with the work to manufacture the supplies for API powder in a bottle or capsule for clinical Phase I. You will also need to undertake a bioequivalence study comparing the new formulation with the powder in a capsule or bottle formulation, which adds further expense and time. 

Quite simply, the lead time—several months—makes the early formulation for the later clinical phases inevitable if you do not want to have a significant delay between the end of clinical Phase I and the start of clinical Phase II. Thus, how much money can you actually save using an API powder in a bottle or capsule if you want a smooth transition from clinical Phase I to clinical Phase II? 

Many of you will ask, “What if my drug candidate fails in Phase I?” For oral drug candidates in clinical Phase I, the only reason for failure that I have seen was a lack of bioavailability, i.e., a lack of detectable amounts of API in the blood. In clinical Phase I studies, you will discover that failure quite quickly, in the single ascending dose (SAD) study. Then you can terminate the formulation work or put it on hold pending further review of the project findings. 

It is unusual for a new oral drug candidate to fail due to unacceptable side effects in the Phase I study, but it can happen. In my experience, it is more likely that you will not detect an unacceptable side effect until partway through clinical Phase II, and such a failure is always a risk with any new drug candidate. 

Again, you can place any formulation work on hold pending the outcome of a clinical review of the project. I have one exception to that general rule, which concerns ongoing stability studies. If a likelihood exists that a development program will eventually resume, then it can be worthwhile continuing ongoing stability programs because you will need the data. To abandon such studies could complicate the restart of the clinical program by requiring an update of the shelf-life of clinical supplies in the field. 

In conclusion, some individuals tout API powder in a bottle or capsule as a quick way into clinical Phase I. Be careful! Choose the drug candidate for such an approach wisely! If you get it wrong, unless you and your backers have very deep pockets, you will kill the project prematurely.