Drug dissolution, a key attribute for determining the bioavailability of a drug, first became official in the United States Pharmacopeia in 1975 for just 12 dosage forms. But now, there are thousands of products which have the dissolution requirement. Further, efficacy is important for any dosage form, and dissolution provides the quality performance phenomena for these. Considered one of the crucial aspects during the drug development process, dissolution comes with a number of challenges, the biggest being simulating in-vivo conditions in toto in an in-vitro dissolution test. Experts suggest we will never be able to simulate it 100 per cent. However, technologies like 3-D printing and automisation, among others, have helped the stalwarts in the industry to cope up to some extent with artificial intelligence (AI) also creating a space for itself. While a lot has been done so far, yet there is scope for more!
By Akanki Sharma
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 only when 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 effects 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.
Professor and President,
Banakar Consulting Services
Another aspect is that we don’t know how much of the drug that gets dissolved in-vivo 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 in-vivo dissolution is slower than absorption. As a result, the quest continues !!
Dissolution test is prescribed in all applicable pharmacopeial monographs
The most important part of drug dissolution is that in-vitro dissolution must mimic the body system. We must come to know what will happen in the body system after tracking this in-vitro exercise. Besides, dissolution is much regulated. All the products, irrespective of the dosage forms, are required to be mandatorily subjected to dissolution studies except certain products like liquid orals and liquid injectables. Dissolution data is an important part of product filing. Dissolution testing is now fairly harmonised– be it USP, IP, BP, JP or EP, though some differences do exist.
There are many challenges though, while performing dissolution test based on a particular formulation. The most critical one is the discriminatory nature of testing methodology which must differentiate between a good bioequivalent product and a bad non-bioequivalent product. You may need changes in the dissolution method prescribed in official pharmacopeial monograph. Next challenge is to fix the specification based on in vitro and in vivo comparison. As far as the role of technology is concerned, dissolution testing is now highly automated with least manual intervention. Future may see application of artificial intelligence (AI) in this area.
Pharma sector is the most dynamic sector and demands continual improvement. What is valid today may not necessarily be valid tomorrow. Who knows that dissolution testing may become redundant tomorrow and we may have some absolutely novel way of determining the in-vitro performance of the product which may involve rapid testing methods.
Training related to proper dissolution testing/bioequivalence/IVIVC is a weak area and SPDS (Society for Pharmaceutical Dissolution Science) is trying to bridge the gap. SPDS, was founded in India and has now become global with the valuable support of pharma professionals all across the world.
There is a huge space for research in the development of newer dissolution technologies
Dissolution testing is a crucial parameter in drug development necessary to screen the optimal formulation.
It monitors two parameters — the rate of solution and the amount of drug going into solution in a defined time period under a pre-determined set of conditions. The dissolution test, therefore, predicts the rate at which a drug would be released from a formulation–be it solid dosage forms like tablets and capsules, semisolids like ointments and gels, and even other formulations like suppositories, implants, etc. Major challenges in the dissolution test include methodologies for complex dosage forms, simulation of sink condition and choice of biorelevant media. Complex dosage forms include suspensions, suppositories, semisolids, ophthalmic, injectables, nano formulations, etc. In case of such dosage forms where no compendial methods are defined, designing a dissolution method that is relevant and can provide requisite and reliable information on dissolution of the drug from the formulation which could relate to the final use of the product, is the major challenge. Some guidance may be available through research publications, nevertheless, their justification and finally convincing the regulators remains an onus. Sink conditions are generally attained through an understanding of the solubility of the drug in various dissolution media. It is important especially when no compendial methods and media are specified. Altering pH, use of cosolvents like alcohols, polyols and surfactants are widely practised to ensure sink.
Biorelevant media is another important criterion in the development of a dissolution method. While this is relatively well-standardised for oral immediate release and controlled release formulations, there is immense scope for research in biorelevant media development for complex dosage forms.
For drug products where dissolution test is not official in the United States Pharmacopeia (USP), one may refer to the FDA Dissolution Methods Database which is recommended by the Division of Biopharmaceutics, Office of Pharmaceutical Quality of the US FDA. The objective of this database is to provide information on various dissolution methods to assist the industry, specifically in the development of generic drug products. One such USFDA guidance is “Dissolution Testing and Acceptance Criteria for Immediate-Release Solid Oral Dosage Form Drug Products Containing High Solubility Drug Substances”. It is specifically developed to assist manufacturers in the development of new drug applications (NDAs), investigational new drug applications (INDs) or abbreviated new drug applications (ANDAs), specifically for oral immediate-release (IR) formulations containing highly soluble drugs. Attempts at harmonisation are evident in the ICH Q4B Annex 7 Dissolution test submitted by the Pharmacopoeial Discussion Group (PDG), which attempts to enable recognition pharmacopoeial dissolution tests by regulators, especially in the ICH regions.
Technology has addressed the instrumentation with reference to specific dosage forms, specific devices and assemblies to be included in the standard USP II apparatus, the need to maintain sink conditions enabled through Apparatus IV, modifications in Apparatus IV to cater to complex formulations, special assemblies for transdermal formulations, suppositories etc. With rapid developments in drug delivery systems, there is a huge space for research in the development of newer dissolution technologies. As a beginning, AI could probably support decisions on the selection of apparatus based on the dosage form and sink condition, identify outliers during the test and abort, and enable the right time sampling based on drug dissolved etc.
Dissolution is pivotal to determine drug efficacy, safety and quality
Most of the drugs which are available in the market these days are Poorly Water Soluble Drugs (PWSDs) because they have been prepared using techniques like high throughput screening (HTS) and other new drug discovery techniques, which tend to favour the lipophilic molecules that have low water solubility, and which also exhibit the inherent problem of poor dissolution rate. In such cases, their gastrointestinal absorption gets influenced primarily by their dissolution performance. If dissolution is not taken care of, their bioavailability, and eventually, the therapeutic efficacy are going to be hampered. So, dissolution is the major aspect for determining drug efficacy, safety and quality, as stated in the pharmacopeial monographs and otherwise. The quality specifications of the dissolution rate are self-implied, although there is no such harmonisation as far as regulatory parameters are concerned. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) has not come up with any guidelines solely on dissolution, but every other regulatory guidance – be it FDA or Indian Drug Control, among others, has grossly been accentuating on the role of dissolution. Furthermore, there are multiple kinds of commercially available formulations with respect to dissolution – 85 to 90 per cent of which constitute the oral ones. And, amongst the oral ones, it can broadly be immediate release, extended release or modified release.
Currently, there are many challenges coming across with respect to dissolution. In predicting the in-vivo bioequivalence using in-vitro dissolution — appropriate selection of the discriminative biorelevant dissolution medium as well as of the dissolution apparatus — Type 1, Type 2, Type 3, Type 4, etc for different kinds of tests — is a critical challenge before the formulation scientist. As far as AI is concerned, the current status of the introduction of AI in the dissolution equipment is not upto the mark. However, it is permeating rapidly and progressively along with its expanding database. So, there is a tangible scope if somebody wishes to work, though it’s not a day’s job. It will require years of cumulative wealth of analysis and implementation. On the contrary, certainly, the use of other emerging techniques – robotics, automation, fuzzy logic and machine learning – have been duly implemented in dissolution apparatuses. And, recently, there have been some reports (although not yet implemented in commercial manufacturing) that 3-D printing can be used to customise the baskets and pedals, so that biorelevance of the in-vitro data and the consequent prognosis of the corresponding in-vivo data thereof could be established as in-vitro/in-vivo correlation (IVIVC) in a much better manner. Biostudies, essentially carried out in healthy human volunteers, incur a lot of expenditure of manpower, money and time, and these could be rationally waived off or even replaced with suitable in-vitro surrogate, particularly dissolution – using varied combinations of media and apparatus. If scientists can work on piling up the pertinent database and subsequently come up with suitable prognostic strategies, by virtue of which, when one feeds in the requisite input data and the corresponding bioperformance is predicted quite rightly, there would be tangible scope of AI in the times to come.
Drug dissolution a vital parameter to understand batch-to-batch consistency
Drug dissolution is a process in which segregation of molecules from the solid drug surface occurs and the same enters into surrounding solution. Rate of drug release, which in turn is determined by drug dissolution is important for effectiveness/efficacy of a dosage form. It is a vital parameter to understand batch-to-batch consistency/repr
CEO and MD, Sparsha Pharma
oducibility and to make formulation and optimisation decisions, equivalence decisions, product compliance and release decisions. However, there are many challenges associated with this process. These comprise equipment-related challenges, which can be overcome by choosing appropriate equipment that suits particular formulation, usage of filters to avoid undissolved materials in the sample solution, suitable calibration. Then, the problems related to process can be resolved via suitable dissolution medium, minimising error in sample introduction and deaeration of medium. Understanding the Active Pharma Ingredient (API) physicochemical properties is another challenge that one can solve by having knowledge of drug solubility, pH, crystallinity and preparation of clear standard solution. Further, recognising drug formulation properties can be made easy by maintaining content uniformity, anticipating or analysing reactions, and avoid drug and excipient interactions. Lastly, having well-trained analysts to pinpoint and address observations like swelling, capping, sticking, etc can also help perform drug dissolution better.
Over the years, automisation, fiber optic technology, and more sophisticated equipment have helped in the drug dissolution activities. Besides, research conducted using AI such as artificial neural network, three- or four-layered models to predict dissolution profile exhibited their upper hand over linear regression models.
Dissolution testing plays a major role in the decision-making process
The purpose of dissolution testing for a commercial pharmaceutical product is routine use for QC-QA purposes, to ensure consistency between production batches, and justify scale-up and post approval changes made to the manufacturing process. It is primarily carried to assess product stability, monitor formulation changes over time and study drug release pattern in the presence of various excipients used in the formulation, and finally establish in-vivo-in-vitro correlations. In cases where in-vivo-in-vitro correlations have been demonstrated, dissolution test can be used as a surrogate test to predict the in-vivo performance of the drug product. From a regulatory perspective, dissolution testing plays a major role in the decision-making process, particularly in the development and approval of generic dosage forms, where unnecessary human clinical studies can be avoided without compromising the quality of generic drug products.
SME Committee
The overall variability of a dissolution method might not be fully understood at the time of regulatory approval, given that method reproducibility via an inter-laboratory trial is not required to be thoroughly assessed as part of the marketing application in accordance with ICH Q2. It is common that dissolution testing might be performed routinely at only one laboratory during product development, usually the laboratory that also conducts method validation. But once the product is approved for commercialisation, there are multiple drivers for needing to conduct analytical method transfers for dissolution testing including outsourcing of commercial stability activities.
In recent times, the regulatory perspective of dissolution has shifted due to improved knowledge and understanding of dissolution science and mechanisms. FDA’s guidance for industry on the Biopharmaceutics Classification System (BCS Guidance) emphasises how the dissolution test can be used to grant biowaivers for highly soluble and highly permeable drugs formulated in rapidly dissolving IR solid oral dosage forms.
Till now, not too much importance was given to the aspect in terms of providing the right apparatus necessary to ascertain the appropriate dissolution profiles studies in most of the colleges of pharmacy in India. Even in most of the pharmaceutical companies too, the later evolved models of dissolution apparatus have not been procured by many companies in order to upgrade the dissolution profiles. However, now that CDSCO is harping on stability studies, bioequivalence studies and appropriate validated data on both for licensing, these have become essential to get the license renewed even for older already approved formulations, as the regulator feels that these are utmost essential parameters for establishing the quality of products and their predictable therapeutic efficacy for patients.
The exact dissolution technique is determined by the dosage form characteristics and the intended route of administration
The dissolution of a drug is important for its bioavailability and therapeutic effectiveness. To properly evaluate the dissolution of drug products, it is critical for procedures to be standardised, which helps to show consistent quality in production and may serve as a predictive measure of efficacy. A dissolution test uses an apparatus with specific test conditions in combination with acceptance criterion to evaluate the performance of the product. There are four standardised apparatus: basket, paddle, reciprocating cylinder, and flow-through cell.
The exact dissolution technique employed is determined by the dosage form characteristics and the intended route of administration. For solid dosage forms, the industry standard dissolution testing methodologies are the United States Pharmacopoeia (USP) Apparatus I (basket) and USP Apparatus 2 (paddle). Immediate, modified and extended releases are usually tested in standard dissolution baths with USP 2 paddles. For oral dosage forms that are prone to floating, USP 1 (baskets) would generally be required. Besides, other techniques are also available, like USP 3 (reciprocating cylinders), USP 4 (flow-through-cell), USP 5 (paddle-over-disc), USP 6 (cylinder) and USP 7 (reciprocating holders).
When developing a dissolution method, it is important to take a logical, systematic approach to the process, and ensure that both the scientific and regulatory principles are borne in mind. A robust dissolution method should be free of significant interferences (e.g. matrix effects due to excipients), give low variability (precision) and produce a good profile shape. The method should also be challenged to discriminate between batches of material with different quality attributes. However, the major challenges associated with drug dissolution that will always remain are: mimic in-vivo situation of drug safety, and efficacy into in-vitro technique and procedure, repetitively, consistently with accuracy; predictable in-vitro in-vivo correlation; predict impact and effect of various events happening during manufacturing, storage and handling during shelf life and at patients end; determine the effect on safety and efficacy; and design and development of robust predictably, safe and efficacious bioavailable product.
In the past few years, medical advances and breakthroughs have included new technologies including 3D printing, implanted and remote-controlled devices. Graphene, an extremely flexible material 200 times stronger than steel, is now being produced at a lower cost and can be used to develop revolutionary medical devices used in biomedical applications like tissue engineering, an artificial pancreas, etc. Predictive medicine is a major focus of start ups. In the past, formulators tended to use statistical techniques to model their formulations, relying on response surfaces to provide a mechanism for optimisation. However, the optimisation by such a method can be misleading, especially if the formulation is complex. AI is a technology that is going to revolutionarise the treatment – safety and efficacy of medicines. Dissolution testing, as always, will remain a bridge to achieve this perpetual objective.
A discriminating medium plays an important role in routine dissolution evaluation tests
Dissolution process depends on two consecutive steps: liberation of the drug from the formulation matrix (disintegration), followed by its dissolution in the liquid medium. The overall rate of dissolution depends on the slower of these two steps. Dissolution testing over the last half-a-century has emerged as a highly valuable and powerful tool for assurance of drug product quality and drug product performance. It basically started as a tool to test the quality of a solid oral dosage form like a tablet. However, it has now expanded to all areas in the pharmaceutical industry,
Society for Pharmaceutical Dissolution Sciences
drug development as well as quality control. Its applications and usefulness have clearly expanded in regulatory arena of bioequivalence, to provide biowaiver and to reduce regulatory burden in drug approval process, and maintaining the product quality and performance.
A discriminating medium plays an important role in routine dissolution evaluation tests by aiding to differentiate between good and bad formulations. Dissolution profiles generated by use of discriminating media can be used to compare the performance of two formulations in vivo. If the dissolution profile generated for a sample formulation matches with the dissolution profile of the standard formulation, it can be predicted that both the sample and standard formulation will exhibit similar performance in vivo. Dissolution profiling is a laborious and time-consuming procedure. However, advancement of automation in entire dissolution technology, has made it easier and unattended procedure.