What is BCS and why it’s quite useful? – Explainer video by Pharma Drama
In this video Pharma Drama aka Prof. Simon Gaisford is going to explain what the BCS is and why it’s quite useful.
See the video and read the full transcript below.
Read the video transcript here:
Welcome to Pharma Drama, the channel where we look at the science of healthcare and healthcare products. You probably know that medicines are extremely expensive to develop and you might also know that most potential drug substances never actually reach the market. If a company has several molecules that might be good candidates for being developed, how does it decide which one to prioritise? There is no clear-cut decision tree, but one good option is to consider the biopharmaceutical classification system, or BCS. In this video I’m going to explain what the BCS is and why it’s quite useful. BCS also stands for black coffee supply; OK, it doesn’t, but I always like to have one and I suggest you get a drink too. And once you have, let’s make a start.
Drug substances are frequently white powders and we don’t give them to patients with a spoon for many reasons; to control dose and taste are the main ones, but there are many others. Instead we formulate them with other ingredients, which we call excipients, into medicines. There are many types of medicine but tablets and capsules are the most common. If you want to know why that is I have videos on that which I have linked to below. That means that pharmaceutical companies don’t just have to find new molecules that could be good drug substances, they also have to develop them into medicines in order to sell them to patients. Finding new drug substances is not easy I have to admit, but developments in computer-design and combinatorial chemistry mean that many companies now have vast libraries of compounds that they can test for efficacy against diseases. It is therefore not super-difficult to identify some molecules that have the potential to be good drug substances. Why then are there not thousands and thousands of new medicines being launched every year?
The answer is because the cost of developing a new medicine, from molecule to market, is astronomically high. Currently it would take around 10 years and upwards of $12 billion US dollars to get a new product launched. To put that into perspective, there are around 6 billion people on the planet, so it would require each and every person to give $2 to get even one product launched! The time and cost are so high because there are many stages of development that a medicine must pass in order to reach the market. The actual dosage form is decided quite early on but there need to be a series of clinical trials to show efficacy and safety in patients before the regulators will grant a licence to a product. It is also easy to assume that once a molecule is selected as a good potential drug substance that it will automatically reach market one day. But again that is not the case! The current estimate is that for every 10,000 molecules screened as a potential drug substance, only 1 will reach the market. That’s quite a rate of attrition!
Given these statistics then, I hope you can see that pharma companies have quite a decision to make when it comes to selecting a molecule for development into a medicine. It is simply not possible to develop multiple molecules simultaneously and see which one is best at the end – that costs too much money and also guarantees the failure of all but one of the molecules. Instead a company must look at the molecules available and make a rational choice of which molecule is the best candidate to develop.
Imagine, therefore, that you are the person with decision-making responsibilities at the company. How might you decide to select one molecule over the others? It might be tempting for you to suggest that you would ask for some data that showed how effective each molecule is against the disease being treated – we call that the efficacy – and then select the molecule with the highest efficacy. BUT, that is often not the best plan. The reason is that in order to be an effective treatment, a drug substance must be able to dissolve in the body once the medicine is taken and then cross membranes into the blood stream. If the molecule can’t do these two actions it will never be an effective treatment because it will never reach its site of action! So a much better plan is to make some measurements so that the likely solubility and permeability can be assessed.
We do these with assays. Solubility is the easiest assay to understand – we simply add an excess of drug powder to water and see what the maximum concentration we can achieve is. I have a video on solubility that explains the idea in much greater detail. And yes, you know very well that I have put a link in the description below.
Permeability is much trickier to determine. Permeability of a drug substance is defined as the fraction of a drug dose given orally that reaches the blood compared with the same dose given intravenously (in other words, it’s the fraction of the dose that actually reaches the blood). How can we measure that in the lab? Easy answer – we can’t! To measure permeability requires giving the drug substance to real humans and taking blood samples. I know that’s not impossible and is in fact done during clinical trials, but it’s not a good idea right at the start of the development process for many reasons. One is that at such an early stage there might not actually be much of the drug substance available (only a few milligrams) and another, which is way more important, is that the toxicity of the compound is not known! So we do NOT round up volunteers to ask them to swallow uncharacterised drug powders – not even students.
Rather, we make a measurement that we can do in a laboratory, which uses small amounts of material, does not involve humans and relates to likely permeability; it’s called the partition coefficient. It’s measured by adding the drug substance to a mixture of immiscible solvents – one is water and the other is an organic solvent, usually n-octanol but it doesn’t have to be. Water is a polar (or hydrophilic) solvent and n-octanol is a non-polar (or lipophilic) solvent. Usually, drug substances have some affinity for hydrophilic solvents and some for lipophilic solvents, so when added to a mixture of both some of the molecules dissolve in the water and some dissolve in the n-octanol. I hope you can see that if a compound has a greater tendency to dissolve in a hydrophilic solvent then more molecules of it will dissolve in the water than the n-octanol and conversely if a compound has a greater tendency to dissolve in a lipophilic solvent then more molecules of it will dissolve in the n-octanol than the water. Thus, is we measure the concentrations of drug substance in the two solvents after letting them reach equilibrium can see how hydrophilic or lipophilic it is. We determine this as a number by simply taking the ratio of the two concentrations and we call the resulting value the partition coefficient. Amazingly I also have a video on that. Now where would you find that…?
The partition coefficient is useful because if we want a molecule to cross a biological membrane (which is lipophilic) it needs to dissolve in a lipophilic environment. Similarly, to dissolve in the gut and the blood we need it to be soluble in water. Thus, we want a potential drug substance to be soluble in both water and lipophilic phases – if it heavily favours one over the other it will either not get absorbed (if it favours water) or get stuck in membranes (if it favours lipophilic phases). Since the partition coefficient tells us the relative affinity of a compound for water and lipophilic phases it’s a great indicator of likely permeability in-vivo (although I note it’s only indicative – there are other factors in the body, such as active transport mechanisms, that might increase permeability).
Once we have made these measurements we have two values – solubility and partition coefficient (which we link to permeability). Since either value can be high or low, we have 4 potential ways in which we can classify a drug; high solubility and high permeability, low solubility and high permeability, high solubility and low permeability and finally low solubility and low permeability. This method of classifying drugs is called the biopharmaceutical classification system, or BCS (you knew I’d get there eventually!)
A molecule with high solubility and high permeability is termed BCS class 1, and unsurprisingly should be relatively easy to develop into a medicine.
A molecule with low solubility and high permeability is termed BCS class 2; these classes of compounds should also be relatively easy to develop into medicines, because we can often improve poor solubility with clever formulation (such as making a salt form or dispersing in an amorphous polymer) and once it’s in solution it should be absorbed well.
A molecule with high solubility and low permeability is termed BCS class 3. Compounds in class 3 could be tricky to develop. It’s possible to use formulation strategies to improve solubility but not much can be done about permeability – that’s something inherent to the chemical structure of the drug candidate – but if the solubility is high enough then it may well be the case that enough of the drug is absorbed that it can have an effect, especially if it’s a highly potent, so low dose, drug.
And that leaves molecules with low solubility and low permeability, which you might be surprised to discover are termed BCS class 4. These are clearly tricky, because they neither dissolve well nor absorb well, so their development is likely to be tricky.
The upshot of this is that by making two relatively simple measurements on our range of potential drug candidates, we can easily assign them to a BCS class, and we can then use the assignment to inform the decision-making process as to which is easier to develop. For instance, if the drug candidate with the highest efficacy turned out to be BCS class 4, while another compound with lower efficacy turned out to BCS class 1, it is likely that the latter molecule will be MUCH easier to formulate, and so is likely to be a better choice for development.
Of course, there are many other factors that feed into such a big decision, but I hope you can see that the BCS is at least a useful way of categorising compounds early in the development process.
Right, that’s all we need to know about the BCS – it’s a simple way of classifying the likely developability of compounds based on solubility and permeability and there are 4 classes – molecules in classes 1 and 2 should be relatively easy to develop, those in class 3 might be OK, especially if they are highly potent and molecules in class 4 might best be avoided. I hope you found that helpful; if you did, please hit the like button and consider subscribing as it really helps the channel. Otherwise, I hope you enjoyed your drink as much as I did and I’ll see you again soon.
Read more on Binder – Pharmaceutical Excipients here:
