Issue link: https://www.e-digitaleditions.com/i/1000772
14 July 2018 Tablets & Capsules 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! The revised formulation used a spray-dried amorphous dispersion and increased the oral bioavailablity approximately 12-fold. 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 m u s t h a v e g o o d a q u e o u s s o l u b i l i t y a c r o s s t h e 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