Express Pharma|November 16-30, 2019
Understanding the science of drug dissolution is a must
Drug dissolution is a key attribute for determining the bioavailability of a drug. It’s the one which is least understood, and can affect the quality of the product. Taking the popular dosage form, hard capsules, for instance, when swallowed, it first disintegrates, which is always predictable within a few minutes. After that comes the process of dissolution which can be extremely variable depending on a number of factors.
The failures and problems of some Indian companies with the US FDA authorities are being caused partly due to dissolution failures and variability. This has been serious enough to result in a recall of products from the market. This is not only expensive, but affects the reputation of the company as well. So, the science of dissolution needs to be studied and understood thoroughly. One solution is to consider the use of robotic equipment which are now available, wherein results are recorded online. This brings more accuracy and integrity, and is an effective way to give the inspectors the assurance they look for. Another important trend is the use of artificial intelligence (AI) which is already appearing in the pharma industry. In due course, robotics systems tend to become inevitable. Such work handled by human beings is subject to variability and skill levels.
Interestingly, there has been a system and equipment developed in the Netherlands which mimics the human body. Tests can be done on that equipment instead of doing it on human beings. It takes into account the effect of food ingestion in the body which can affect dissolution. It would be interesting to bring such a system in India for demonstration, possibly in a pharmacy college or, for instance, at the National Institute of Pharmaceutical Education and Research (NIPER), Chandigarh. Financial assistance could, hopefully, be provided by the Government of India. Then, all industry can visit and take trials on this advanced system.
Regulators will believe you onlywhen you provide data
Any product that is administered to the patient must have proven to be safe. Further, efficacy is important for any dosage form, and dissolution provides the quality performance phenomena for such dosage form. If it is a bad or has poor dissolution, the drug will not dissolve, which means it will not be absorbed, and the patient will have no effect. Dissolution first became official in the United States Pharmacopeia in 1975 for just 12 dosage forms (products), but now there are thousands of products which have the dissolution requirement. Long back, it started as a quality control standard. In those times, it would require bioequivalence studies for approval of every generic product. In 1995, we published an article based upon the biopharmaceutics classification system (BCS) which said that if a product has a certain solubility, permeability characteristics, and dissolution characteristics compared with brand name drug product, then there is no need for bioequivalence studies in humans, and the applicant can be given biowaiver based upon the dissolution data. Hence, biostudies are not required. Just the dissolution studies can lead to the approval of a product, and if it is done appropriately, we can say that the product is going to be as good as the brand name drug which was approved with a number of clinical studies and biostudies. That’s how dissolution has evolved. This was only for the solid oral dosage forms. But now, with the advances in science and development of biorelevant dissolution media, we are going beyond these earlier prediction of bioequivalence of simple tablet or capsule dosage forms, we can try to predict the bioavailability of the controlled release preparations. A lot more complicated studies are required to be done for the approval of topical generic drug products like creams, ointments and gels. The work that we are doing now is going to simplify this to such an extent that the topical drug products, not today, but five years from now, would be able to reduce those requirements and regulatory burdens. We started with dissolution in 1975. In 1995, the first publication came out and then we had the BCS guidance that came out in 2000. And five years after that, another publication came out which used the same BCS information from which you can even predict, when you take the drug, whether it is going to be metabolised in the body or not, and how it will be eliminated from the body.
One of the biggest challenges in drug dissolution is generating data to prove your point. You think you can achieve something but when you say that, you have to prove that with data integrity. You have to document that because regulators will believe you only when you provide the data. However, this is not easy because firstly, data generation takes time and then convincing someone with that data is another difficult task.
Simulating dynamic in-vivo environment in an in-vitro test is the biggest challenge in drug dissolution testing
When a drug substance is administered as a formulation to a patient, one critical requirement is that the drug has to appear in blood because unless it appears in blood, it cannot circulate to all parts of the body in order to exert its response. The formulation can contain the drug which is in solid state. Drug appearing in blood to elicit a response is in molecular state, where the molecularisation takes place in a solvent (biological fluid) outside blood. The process of molecularisation of the free drug substance in a solvent is called solubalisation. The moment one takes this free drug and puts it into a composition, it is no longer in its free state because the formulation effectsâ€‹ will come in, such as, processing effects, equipment effects and so on and so forth. So, molecularisation through the process of releasing and solubilising it into the medium from a formulation is dissolution. The end point in both cases is the same, but the starting points are different. In one case, it is purely the drug alone in its free state and in the second case, it is processed.
Another aspect is that we don’t know how much of the drug that gets dissolved invivo gets into the blood, i.e., it is bioavailable. We only know what we see as drug in blood. If I want to predict what would be my in-vivo bioavailability from a formulation, theoretically, I could take every formulation I make and conduct a biostudy or a clinical trial in humans. However, it is ethically wrong, expensive and too much time-consuming. So, I need some measurement in-vitro to screen my formulations in order to get to the one that I would like to take forward. In addition, while doing this, I also want to have my in-vitro dissolution tests to give me an assurance that my chances of failing biostudy are decreased. Nobody can predict 100 per cent bioavailability from dissolution but one can enhance the chances of getting that prediction.
The challenge associated with the process of dissolution is trying to really simulate in vivo conditions in toto in an in vitro dissolution test. We will never be able to simulate it 100 per cent. The biggest challenge is how close we can get to in-vivo process as possible and the second one associated with it is, 'no matter whatever drug dissolution we do, it will be a stagnant test while the in-vivo environment is dynamic.' The solutions are then getting into the advanced understanding of the factors that dictate the in-vivo performance like, combined understanding of in-vitro dissolution with permeation as opposed to either one independently. This is because the first realisation is the chances of predicting bioavailability post in-vivo dissolution is highly possible only when invivo dissolution is slower than absorption. As a result, the quest continues !!
Dissolution test is prescribed in all applicable pharmacopeial monographs
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November 16-30, 2019