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What is drug formulation?
The definition of the drug (pharmaceutical) formulation states that it is the process in which different chemical substances and/or biochemical substances, such as active chemical substances will be combined together to produce a final medical compound i.e., medical drug . The term formulation can however mean not only the inputs and process of manufacturing the drug, but include also the final product dosage form, which is what the patient eventually experiences and what at the same time should not discourage patients to stick to the drug dosage regimen . In practise, the discovery of a new drug is just the beginning of the following long procedure that has to be completed for a new medicine to be developed . Therefore, after the identification of a promising molecule, it is then passed to the formulation scientists. Their task is to find and work out how to create a final formulation that would be the best option for that drug, whether it is injection, a single-shot dose pill or a cream2. However, is it right to name the people that work on this process scientists?
Learning before doing – Preformulation studies
During the drug discovery and development, there are a large number of studies carried out. They involve, among others, pre-clinical in vitro laboratory safety tests, initial volunteer/patient studies and full-scale clinical trials (Fig.1.1 and Fig.1.2 ). For each of them the potential medical substance has to be formulated into an appropriate dosage form. The formulations of the drug, their nature and composition will vary among the stages of the development. However, the formulation prepared for the full-scale clinical trials must be the final one (the same as the product moved to marketing). Pre-formulation studies are conducted to make sure that there are optimal formulations chosen for the intended use, but also to evaluate the characteristics of the candidate drugs and the potential formulation excipients4, which are inactive substances that serve as the vehicle or medium for a drug or other active substance and their interaction with drug substances. Therefore, preformulation studies are essential to determine the appropriate formulation ingredients. An additional function of the preformulation studies is to test the influence of potential conditions of preparation, storage and manufacture on stability, to ensure that the assessment of a candidate drug has the essential reliability during development and post-marketing use. For this reason preformulation studies may be defined as laboratory studies to determine the characteristics of active substance and excipients that may influence formulation and process design and performance4.
What characteristics of a drug substance are assessed by the preformulation studies and why are they importantant?
Pharmaceutical formulation is a process that involves production of drug which can be characterized by two things: it must be a stable product and has to be acceptable to the patient who will use it1. Therefore, the preformulation studies focus on characteristics that can guarantee stability and the most effective and patient-acceptable form of a potential drug. The stability of a drug and the excipients is important in this case to make sure that a patient receives the correct dose of the active ingredient. Also, what can act as a critical factor in achieving a stable marketable product is the stability of the excipients alone and in combination with other excipients and drug substances, for example the stability of antioxidant preservatives in liquid formulations. One of the first assessments usually done on a drug substance is its aqueous and lipid solubility characteristics. These characteristics are of particular importance because they are key in determining whether a drug substance is capable of reaching the sites of absorption, identifying its ultimate metabolism, excretion and interaction with alleged therapeutic targets. When a drug substance reaches the solution in an organ or cell in a biological fluid, it then needs to diffuse to the site of transfer or action. For this reason the rate of diffusion is another characteristic assessed in order to establish the final formulation of a medical product. Another significant factor to consider is the ability of a drug substance to transfer across membranes that depends on its capacity to partition across and into lipophilic substrates, such as the cell wall components. It can be assessed by finding the partition coefficient, which measures the unionised drug distribution between an aqueous and organic (lipid) phase at equilibrium. The partition coefficient is a starting point for understanding the biopharmaceutical properties of a drug substance4. It is also really important to actually assess the proportion of a drug which enters the circulation when introduced into the body and so is able to have an active effect . This property is called bioavailability. The initial estimation of bioavailability is based on the drugs solubility, partition, diffusion coefficient and the nature of the membrane that needs to be permeated. The next factor, called hygroscopicity is a capacity to absorb and desorb water. It must be remembered that during storage and manufacture, there may be many different environmental factors, such as humidity acting on drug substances and excipients. As a consequence, it is important to establish suitable conditions, according to the hygroscopicity, that should be kept in the drugs environment.4
On the other hand, the process of crystallisation, which means a solidification of molecules into a highly structured form named a crystal , causes the molecules of drugs and excipients to arrange in various geometrical configurations, so eventually the structure of crystals formed has different packing arrangements or orientations and these various states are called polymorphs. What is important about the polymorphs is that each form may be different in terms of the physiochemical characteristics, such as solubility which indeed can influence the bioavailability, stability and compression properties of a drug4.
Determining the Formulation
These are just some of the factors taken into consideration while selecting the appropriate excipients and other ingredients of a final medical product. The desired function of an excipient is to guarantee the required physicochemical and biopharmaceutical properties of the medical product. Due to the fact thet excipients play a key role in determining the formulation of a medicine, it is required to test their functionality and control the characteristics that may potentially influence their suitability and consequently the properties of dosage forms prepared. This is possible by conducting a functionality-related characteristics (FRC) test. They are not compulsory and concern only the typical or major uses of excipients, but they also help broaden the knowledge of the pharmaceutical use of excipients .
However, the preformulation tests fixing the drug substance properties also enable the scientists to use these properties later in order to determine the optimal drug delivery technology, which is a technology that optimally enhances drug absorption, efficacy, and patient experience . As a starting point to this process there is often the Developability Classification System (DCS) used which classifies the molecule based on its dose-solubility ratio and effective permeability properties. It is then plotted on a chart (Fig. 2 ). The position of the active ingredient is a guide to the most suitable drug delivery technology to obtain a successful, efficient (usually oral) product . Molecules described as Class I have both good solubility and permeability. They are quite straightforward to develop and the delivery preferred in their case is by solution, suspension, tablet, capsule and even injection. Class III molecules on the other hand are characterised by good solubility but poor permeability. They may need the permeation to be enhanced by the special technologies but it is possible to design a suitable tablet or capsule with an active ingredient in this class. Class IV molecules (possessing poor solubility and permeability) may be acceptable in some formulations overcoming these characteristics, but it would not be reasonable to assume that these molecules are characterised by particularly high bioavailability. Therefore, in this case of a Class IV substance it is probable that there will have to be another candidate drug evaluated that possesses better properties. Around 70% of drugs in development are classified within Class II, which means that they have good permeability but poor solubility. Class II is divided into two groups and the distinction between Class IIa and Class IIb is based upon a molecules solubility limited absorbable dose (SLAD), below which all the dose could dissolve, and above which the fraction dissolved will be negatively correlated with dose11. Molecules from Class IIa have a limited dissolution rate, which is the rate of the process in which molecules are separated from the surface of the solid drug and enter into the surrounding solution phase , rather than the actual solubility. Therefore, a simple particle size reduction or solutions can be applied to determine optimal drug delivery technology. In the case of the Class IIb molecules, it is not expected that the full dose will dissolve before leaving the small intestine, so a lipid-based solution is usually a beneficial choice for development11, as it enhances the bioavailability of poorly soluble compounds .
A science or not?
Once we understand what a drug formulation actually is, we can think if it can be classified as a science. However, initially it is essential to define the term science and to find out what it covers. The problem is that it is actually quite difficult to define science, since it applies to a very broad set of human endeavors, from for example developing lasers, to analyzing the factors that affect human cognitive processing . The word science comes from the Latin term scientia ( knowledge ), meaning knowledge based on demonstrable and reproducible data (according to the Merriam-Webster Dictionary) . On the other hand, the Oxford Dictionary states that the English word science means the intellectual and practical activity encompassing the systematic study of the structure and behaviour of the physical and natural world through observation and experiment . There are some key features that join together these various activities from a large spectrum encompassed by science. Therefore, even though the boundaries of science are not clearly defined, if something does not meet most of the typical characteristics, it should not be treated as science9.
First, and probably one of the most important features is that a science focuses on the natural word. It studies and asks questions about the components of the physical universe like atoms, plants, ecosystems, human beings, but also the natural forces at work on those things. Therefore, science cannot study supernatural forces and explanations, because they are not classified as a part of the natural, physical world that we, as people directly see, investigate and experience9. To my mind, there is no doubt, that a drug formulation focuses on the natural world. While determining the right formulation, the chemical substances, their properties and interactions are investigated, which means that the process of drug formulation studies the chemical components of the physical universe around us to find the best way to combine them in order to form suitable, acceptable and efficient medical products. In addition, it is completely certain that drug formulation does not expect answers that are beyond the natural word, like the explanation based on supernatural forces.
However, science not only studies the natural world, but also aims to explain it. The sciences main goal is thought to be building knowledge and understanding and producing more accurate natural explanations of how the physical world works, how it got to look as it does now and what it consists of. But this theory also states that science is aiming to broaden the knowledge and understanding regardless of its potential applications9. And that causes a question: can we consider science a process that from the beginning is investigating something which a clear application wanted to be achieved? The main goal of a drug formulation is to find the right combination of ingredients in order to form a final medical compound with desired properties, not to explain and understand the natural world or its components. Interestingly, science does not exclude any research undertaken with the aim to solve a problem or develop a technology. That is because along the path to that goal new explanations and knowledge can be discovered9. In this case, while trying to produce a final medical product and combining the active substance with excipients, a formulator can for example discover new unusual properties of some substances combined together. That knowledge can be subsequently applied to create other chemical substances with desired characteristics. The drug formulation is therefore considered to be applied research. The difference between the pure and applied research lies exactly in the aim. The nature of pure (also called fundamental) research is explanatory, so it is conducted without any end-use considered. In addition, it is called fundamental because it may act as a foundation for applied research. In comparison, applied research is conducted in order to solve a practical problem or answer a specific question . Science aims to increase the understanding of how the natural world works either way, using pure or applied research9, so drug formulation is still scientific according to this criteria.
Another characteristic feature of science is that it only works with testable ideas. The ideas have to logically generate specific expectations, so there are clear, defined observations expected to support an idea and similarly a different set of observations that can reject it9. In this regard, the drug formulation is truly scientific. During the stage of the preformulation studies, when the specific properties of a drug substance are assessed, the formulators ideas can be tested in various different ways. For example, by finding the partition coefficient they test the ability of a drug substance to transfer across membranes. The idea in this case is how able the substance is to transfer across the membranes (what is its capacity to partition across and into lipophilic substrates) and it is tested using this technique: A known concentration of the assessed compound is dissolved in an aqueous solution and then shaken together in a flask with an equal volume of the lipid. The phases separate and subsequently the remaining amount of the drug in aqueous solution is determined. It can then be used to calculate the amount of a drug substance that has partitioned into the lipid4. During the process of drug formulation there are only testable ideas present, because if they were impossible to assess, the health and even the life of a person using a medical product would have been in danger.
The testability of science is closely related to the next, very important characteristic science relies on evidence. The acceptance or rejection of a scientific idea is possible only in the light of relevant evidence, not opinion or belief. Therefore, scientific ideas not supported by any evidence are rejected9. Again, drug fromulation is based upon nothing else, but evidence. All the properties of drug substance alone, excipents or the final medical product are assessed by carrying appropriate tests (as it was for example in the case of partition coefficient explained in the paragraph above). The final drug formulation, is therefore determined only after obtaining significant results of appropriate tests, that act as the evidence, confirming that a particular formulation has all the required properties to become a manufactured drug.
Often, this evidence rely and is based on observations. While conducting a test researchers look for particular outcomes that can be observed and measured. As previously described scientific ideas generate specific expectations, defined observations expected to support an idea and similarly a different set of observations can reject it. The observations that are scientific have to remain constant across repeated experiments and measurments . It is this idea that for a scientific outcome to be reliable it has to be repeatable (the same findings after repeating an experiment and the following conditions must be in place: the same location; the same measurement procedure; the same observer; the same measuring instrument, used under the same conditions; and repetition over a short period of time) and reproducibile (refers to the degree of agreement between the results of experiments carried out by different individuals, at different locations, with different instruments) . Scientists conduct the same experiment several times in order to confirm their findings. In drug formulations all tests are repeated and replicated and only reliable findings are taken into consideration in this process.
All of these factors explained above support the view that drug formulation is a science. However, what may make us think that it is not? What are the other options that drug formulation can be considered to be? To my mind, the other possible option is to classify drug formulation as art, but only to a certain extent. In fact, determining the proper combination of ingredients, while balancing product quality, stability, cost, and many other factors can be sometimes considered a puzzle. Art can be defined as the expression of human creative skill and imagination, typically in a visual form such as a painting, producing works to be appreciated primarily for their beauty or emotional power . In my opinion, determining a suitable drug formulation reqiures a dose of creativity. This process is based on arranging and combining certain elements to form a final product and it is the researchers job to think of appropriate ingredients that can potentially possess the desired properties while combined with the active substance to form a final medical compound. Therefore, the drug formulation actually is an application of human creative skills. On the other hand, a characteristic of art is that it requires skills developed through experience which can be applied to drug formulation. The more experience a formurator has, the more able he is to come up with an idea of what excipients would be potentially suitable for a certain drug substance. However, although apparently there are some features that art and drug formulation have in common, it has nothing to do with creating something with the aim for it to be appreciated primarily for its beauty or emotional power. Therefore, drug formulation can be considered art but only to some extent. However, does it mean that it cannot be considered science anymore? Drug formulation may be both art and science. Both are interdependent and inseparable16. Different parts of the formulator scientists work require different skills, some of them are more related to science and others to art. The process on his own is science without a doubt, but would be impossible without the human beings that conduct it and their creativity and skills gaind through experience.
Final verdict
Drug formulation possesses all the essential scientific features, from the fact that it focuses on the natural world, through the use of testable ideas and evidence to repeatable observations. For this reason, it can be said with full confidence that it is a right and confirmed idea to call people working on this process formulation scientists . However, it is also important to bear in mind that these scientists are also human beings. Human beings that bring to the work their own creativity and skills, making a drug formulation an artistic process. These artistic features are not in opposition to the conclusion that drug formulation is a science, but are necessery in this process. In my opinion, it is therefore right to consider drug formulation a science, but it is also worth remebering a quote from Albert Einstein: The most beautiful thing we can experience is the mysterious. It is the source of all true art and science. He to whom the emotion is a stranger, who can no longer pause to wonder and stand wrapped in awe, is as good as dead his eyes are closed .
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