Formulation Science: Continued

 

In a recent blog post, I discussed the essentials of the Formulation Science discipline, using a long explanation involving cake. I am not a Formulation Chemist, but I quite liked writing this post. For my own enjoyment, and to be more technical, here’s a follow up!

The Role of Formulation Science

So, Formulation is an essential discipline, but specifically why? As a synthetic chemist, I deal with chemicals in their purest forms. And the majority of organic chemicals manifest themselves as unassuming white powders. These are not acceptable as consumer products for several reasons. Namely:

  • Regulation
  • Marketing
  • Storage
  • Consumption
  • Delivery

I’d like to explore all these functions in more detail below.

Regulation

Before a product can go to market, it is regulated by its relevant industry agency – be it the FDA, MHRA or EC. These agencies exist such that consumers know what they are buying is what it says it is, and that it is safe. It’s as simple as that.

Pure chemicals are not good consumer products because they are unlikely to be efficacious. Therefore formulations are necessary to dilute them down to consumable levels. These formulations must be uniform so that the consumer knows exactly what they are getting.

Marketing

If you know of or remember the Herbal Essences marketing campaigns, you will be aware that scent is an attractive attribute for a shampoo formulation to have. You can mount your entire marketing strategy based on it, it seems.

Marketing can also use appearance or texture to sell their food products. Though whether either is actually central to the marketing in my examples is disputable, what is indisputable is that these are desirable qualities.

Storage

Substances, whether they be shampoo, food or medicine, must be storable until they are consumed. The product can smell delicious and have the perfect gooey texture of the perfect shampoo, but if it smells of mould and separates into a liquid and solid after a week it is not acceptable.

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You also want the formulation to afford the stability to maintain those desirable qualities that have been instilled in the property. Loss of flavour or texture is not something we want in foodstuffs. Ice cream, for example, contains anti-freeze molecules to ensure it does not turn into a solid block of ice: instead it maintains a soft, scoop-able texture.

Desiccants are substances that absorb moisture. These are often included in packets to avoid the product absorbing the moisture in transit to the consumer, but they are also included in formulations to ensure, for example, that a laundry powder doesn’t clump up. In solid formulations, products are often spheronised (to form sphere) and coated to aid longer storage and slower release.

Finally, medicines. Indisputably, we want these to maintain their medicinal properties even after we have opened the container. Essential reactive ingredients need to be formulated such that they don’t break down when exposed to heat or moisture. Otherwise, medicines would be far more expensive and equally far less useful.

Consumption

This ties into the marketing section somewhat, as many of the formulated products we buy are for consumption. It is important to instil pleasant scents, textures and flavours into foods and soaps, but also into medicines to enhance patient compliance.

However, it is important that products must be safe to consume as well. Reactive ingredients are included in products simply because they react with the body in some way. But it is undesirable to expose the body to too high a concentration, as they can be irritant or even toxic. Formulations both dilute these chemicals and structure the mixture so that they are released more slowly.

Delivery

This section I have included predominantly to discuss medicine formulations. And this is the area in which drug companies expend most of their research, so I am unlikely to do more than touch upon it here.

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Drugs cannot contain chemicals that are toxic to the body. Unless they need to, for therapeutic purposes.

This is the paradox that drug companies encounter with their products. Any effective drug will alter the activity of a cell, protein or receptor within the body. And therefore we want the drug to do this only where it will help us.

Drug molecules must therefore be formulated to be released only where we need them, and to release at the correct rate so as to be effective. Many tablets are broken down by the acid in the stomach, thereby releasing their drug loads. These drugs are therefore formulated such that they will have a high enough dose to hopefully reach the area of interest even when delivered to everywhere else in the body simultaneously. But equally, they must be formulated such that they will not cause damage when they are non-specifically delivered to areas outside that of interest.

For this, drugs must not have toxic break-down products that will damage the body when they encounter the rest of the gastro-intestinal system or are broken down in the liver. Chemists that know their drug will be broken down in a particular organ can alter them chemically such that only their breakdown product will be reactive (enhancing the slower release profile).

Much of the specificity drug delivery process is covered by the actual structure of the drug lead compound – this is why we have hybrid protein or polymer conjugates on the market. But the role of the Formulation Scientist must not be underestimated.

 

 

References:

(1) An excellent online resource on cosmetic chemistry, which is a form of formulation science.

(2) The RSC subgroups pages on formulation.

“What are all these chemicals for?” – aka, a very basic primer on Formulation Chemistry

Formulation Science?

I’m currently studying for a PhD in Chemistry, and yet never during my Chemistry Undergraduate or Postgraduate career have I come across any modules or even seminars touching on formulation science. This is largely because formulation science is seen as an industry staple, something that doesn’t have a place in more blue-sky, academic research such as university is geared towards. Formulation, outside of industry, is considered more something that a good chemist will be able to pick up on the job.

And yet, it is an absolutely crucial discipline. Formulation scientists do exactly what you might expect from the name: formulate the complex mix of chemicals that makes up a tablet, powder, aerosol, gel, cream (etc.). Without them we wouldn’t have shampoos, deodrants, paints, medicines and even some foods.

But why all the chemicals?

Funny how you might ask that, reader, but everything is made up of chemicals. Foods found in nature actually have a colossal number of different chemicals in them. This is because a very delicate balance is required to maintain a stable, pallatable formulation.

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Having a mix of chemicals means you can more finely tune the properties of a particular substance. Think of it like a carrot cake.

Formulating a Carrot Cake

In all cakes, you need butter, margarine or oil to lubricate the mixture and enhance the texture of the finished product. For a carrot cake, you also need self-raising flour and baking powder. Proteins within the flour form a network of gluten when mixed with moisture, which allows the cake to rise. Baking powder creates bubbles of air in the mixture which enhances this rise.

To enhance the flavour of our carrot cake, we also add in some cinnamon, nutmeg and ginger. Sugar also enhances the sweet flavour of the cake – but in addition it absorbs moisture from the mix and thus avoids the cake from getting too hard.

Carrots and orange zest are also needed to tune the flavour of the cake (the former giving the cake its name, after all). However, these ingredients also add moisture to the mix that it would not have otherwise. The quantities of the other ingredients must thus be altered to allow for the inclusion of the wet fruit and vegetables to stop the final product being too dense.

Last but certainly not least: eggs. Eggs are an emulsifier, meaning they can help in the combining of oily and watery mixtures. In cake, they help to combine the liquid and solid ingredients into an even mix. And this is even without thinking about the icing!

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So you see, it is essential to consider the exact properties you need for your final product, and to tailor the ingredients to ensure you achieve this. I’ve found that chemists are well-suited to baking for precisely this reason: they appreciate the complexity and intricacy of a good formulation.

 

References:

(1) An excellent online resource on cosmetic chemistry, which is a form of formulation science.

(2) The RSC subgroups pages on formulation.

(3) Article showing three naturally occurring foods’ chemical “ingredients list”.

Problems in Pharmacology: The Unexpecting Guinea Pigs

 

Clinical trials are the bane of doctors and researchers alike. They are expensive, they rarely pay off, and they take a long time. But of course no one wants a situation where we simply don’t test drugs before we give them to vulnerable patients. The consequences of under-testing are dire, and it still happens that drugs get withdrawn (as a case study, have a look at Benfluorex’s staggered withdrawal in the EU).

Much as it is clear that drug trials are essential before their widespread introduction to a hospital drugs chart, it is also clear that there are risks involved.

On Clinical Trials

The clinical trial process goes something like this:

  • Several months testing in up to 100 healthy volunteers to assess its safety and appropriate dosage (though the latter will vary depending on the patients’ condition).
  • Up to 2 years testing in a few hundred patients with the disease of interest to assess efficacy against the disease and side-effects.
  • Several years’ testing in up to 3000 individuals with the disease of interest to further assess efficacy and side-effects.
  • There may then be a 4th phase of testing to further assess the safety and side-effects if not enough is known.

There are several reasons why clinical trials are expensive, why they fail, why they take so long – these are things I could easily spend a whole post discussing. What we are talking about here is just SAFETY.

waiting-room-1631142So why is it that, after a whole clinical trial, things can still go wrong?

My favourite word to describe patients is “idiosyncratic”. And it fits perfectly here. Patients are idiosyncratic, different, individuals. They have different bodies, different organs, different cells, different DNA, and therefore their reaction to a chemical being ingested or injected is going to differ from another person.

Sure, we can look at measurable variables such as age, height and weight and predict how these affect a patient’s response to a drug. We can even sequence someone’s DNA and look for heritable characteristics that predict a response as well. But there’s an infinite number of non-heritable characteristics, and non-nuclear DNA to account for as well.

So why do we use drug trials, if they’re so very useless? Simply put, it’s the best thing we have. With novel gene-sequencing technology available to us, we may be able to streamline the process quite a lot in the future, but it’s likely to still be imperfect. Especially as so many life-threatening disorders and diseases only manifest themselves beyond the point of no return.

 

Who are the guinea pigs?

At the beginning of the year, the Independent published an article about the three most recent drug trials that led to devastating consequences for the volunteers. I’ll link it here as a summary of what can go wrong for the guinea pigs choosing to participate in drug trials.

Other than these participants, there are two other groups that effectively are treated as guinea pigs: children and pregnant women.

baby-hand-1-1316351It is precisely due to the risks outlined above that we do not include the “at risk” groups of children and pregnant women in clinical trials. Side-effects that could be a minor inconvenience in a healthy individual are exacerbated drastically in unborn children and young people as they could effect their development.

This means that a paediatrician must rely on their expertise and experience alone to prescribe adult-tested medicines on children: tailoring the dosage to the child’s height and weight. As explained above, this isn’t enough. As adult patients’ bodies are idiosyncratic, a child’s body is an entirely different matter. There are countless chemicals running around that we don’t see in an adult, that may interact with the ingested drug in an adverse way.

In addition to the difficulty in predicting side-effects, adherence to a medicine regime is also more tricky. Children don’t want to take in nasty-tasting drugs (I personally would only take sweet-tasting cough syrups), and they don’t want to have to take several at once (which may be necessary in combination therapy).

 

Teratogens

Pregnant women are also guinea pigs. This means that a gynaecologist must make the same judgement calls as a paediatrician must with children, and these choices affect not only the pregnant woman but their unborn child as well.

As stated many times in this post, it is difficult to predict the activity of a drug in an individual. It is especially difficult to predict the activity of a drug in an individual who has not yet been born. In particular, it would be useful to know just how much of the drug is sequestered by the fetus. The mother and child have a semi-permeable barrier maintaining the separation of their blood systems. As with the testing of a drug’s ability to cross the blood-brain barrier, we need to know how much of the drug crosses this membrane in the placenta to know how much will be taken in by the unborn child.

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This lack of knowledge leads to doctors estimating the appropriate usage of a drug. In fact, it is not unheard of for doctors to prescribe a drug to a pregnant woman for off-label purposes (ie. for purposes other than it has been tested for).

Thalidomide is a terrifying word in chemistry. It has come up in my education separately at least half a dozen times, and with good reason. If you need to brush up, have a look at this Wikipedia article or this article by the Science Museum. Notably, this is a case in which a drug used for morning sickness led to teratogenic effects in unborn children (ie. birth defects).

Inside their mother’s body, the fetus grows from a single cell to form a full baby. This process follows a delicate series of chemical signals within the developing child to ensure that the baby is born fully formed. It therefore follows that anything affecting the chemical environment the developing child is subjected to will have an effect on its development.

The Bottom Line

We need to somehow safeguard child or pregnant patients against preventable adverse effects. There are indeed clinical trials involving children in existence.

We know that clinical testing has an inherent risk, but we do it anyway because the risk in a clinical trial is far lower than going without. That is why it makes sense to test (with due care) in these vulnerable patient groups.

So why are we still lacking data? Unfortunately the issue comes down largely to funding. As with infectious disease drug trials lacking momentum due to less chance for profit from poorer countries, trials that have smaller target patient populations are less common because the final drug brings in less money. There’s less financial incentive to offer trials just for these select patient groups.

The cynic’s bottom line: we need to encourage funding in trials in these essential patient groups!

 

 

References:

  1. European Medicines Agency document recommending Benfluorex withdrawal.
  2. Chemistry world article on Benfluorex.
  3. The FDA’s site on the Drug Development Process: Clinical Rsesearch.
  4. The Independent’s article “The troubled history of clinical drug trials”.
  5. Page on placental transport.
  6. Thalidomide articles: 1, 2.
  7. WHO page on Clinical trials in children.
  8. NIH page on Clinical trials in children.

Images used: 12, 3

Problems in Pharmacology: Clinical Trials and Molecular Markers

This week’s post follows on from something I touched on last week: the issues in the drug design process.

Drug design tends to be stem either from mimicry of molecules the chemist knows that the drug target already interacts with (such as a substrate that binds to an enzyme) or from knowledge of the potential’s drug target’s structure (where computer modelling, for example, can suggest which would be the best structure for a potential drug).Resized

These drugs are synthesized, and then undergo preclinical testing. This involves assessment of their stability and their interaction with an isolated drug target (called in vitro testing), and then testing inside animal models. After these stages, totalling up to 6 years, the drug will go to clinical trials in patients.

Clinical trials are in three stages, with the amount of patients in each stage increasing as confidence in the drug’s capabilities develops. The final stages are then approval by the authorities and marketing. This drug discovery process takes in total anything between 10 and 16 years and will cost the company up to a billion dollars. And yet, there are still issues with drug safety that slip through the net: think of thalidomide as the most popular example! Why is this?

There are a multitude of reasons of course. Once a drug has reached later trials, a company can become invested in it and wish to push it through. There may also be signs that the drug is unsafe missed, which may come from the design of the clinical trial itself.

In clinical pharmacology, a biomarker is a characteristic the patient has that can be measured during clinical trials, and is used as an indicator of their biological state. For example, a biomarker such as glucose or hormone levels can indicate the likelihood that a patient will get better or relapse.

A key issue with clinical trials is that they do not measure all relevant biomarkers. A different drug for the same medical condition will have a different action (mechanism) in the body and therefore will have a different effect on biomarkers. They may effect biomarkers that were unaffected by other drugs.

Therefore, in order to fully understand the effect of the drug in the body and truly assess its safety, trials should be randomised with controls (patients taking “placebo” pills with no drug in them to show how biomarkers might change with no drug present). The system currently unfortunately relies on the validation of biomarkers to display patient health, which is both a lengthy and difficult process.

New clinical trial designs are therefore being considered, such as the “I-SPY 2” trial which uses molecular tests to tailor treatment or “BATTLE” which uses biomarkers to tailor the treatment. These new designs are quite new, so unfortunately I am unable to provide more detail than this!

The future of drug discovery seems to be tending towards the more in silico side of research, which uses computational modelling of drug action to suggest how a drug will act in a given system. The future looks bright here, but again that is a discussion for a later post!

I based this post on a talk at the EACPT 2013 conference by Professor Max Parmar (UCL). This post is entirely my own opinion, based on my own experiences – feel free to disagree and share your thoughts in the comments! I’ll be continuing on the “Problems in Pharmacology” theme next week!

 

A note from the author: As my posts sometimes touch on emotive subjects, comments are disabled after 4 days. This is because, at this stage, I feel that ongoing discussions tend to stagnate.

Problems in Pharmacology: Definitions and crossing the Biology/Chemistry Border

I thought a good way to begin this blog was with a series of posts dedicated to defining what exactly pharmacology is, and the inherent difficulties in studying  and practicing it. First of all: definitions!

Chemistry is the study of the composition, properties and behaviour of matter, whilst biology is the study of life and living organisms.Resized

Pharmacology is a boundary science, by which I mean it lies firmly on the border of chemistry and biology, dabbling in both but not really studied by scientists within either of these disciplines. Broadly speaking, pharmacology is the science associated with the study of drug action within a living organism.

And therein lies the problem: in order to truly be a pharmacologist, one must not only understand the structure of a drug, one must also be able to ascertain all interactions with the patient’s cells and biological molecules. This is really, really hard.

As a chemistry student, I have also taken modules in biology. The issue with studying biology as a chemist is that modules designed for chemists differ greatly from those the biologists study – imagine the chemistry student looking through a soundproof viewing window into a biology lecture, unable to hear the words, but being able to see some of the diagrams, and given a description of them by a chemist standing next to them.

It is much the same in biology – having taken modules in the life sciences, chemical subjects are approached as though the subject matter should inherently be treated as alien. Unfortunately, at undergraduate level at least, this is unavoidable.

Students on three or four year courses cannot entirely straddle two departments, where lecture modules later on usually depend on some understanding of several modules taken in earlier years. There is just not enough time to learn every module needed, unless a student decides to specialise in a boundary science at the very onset of their degree. This appears to be a massive commitment, which I personally did not wish to make at the age of 18.

These degrees, such as biochemistry, do not tend to entirely cross the boundary either, they tend to be taught predominantly in one department or the other. Chemistry and biology teaching methods require different learning styles. Having done a variety of these modules myself, I find it awkward to switch between the chemistry style of understanding of process and the biology style of memorising definitions and mechanisms.

As the depth of our understanding in these disciplines increases, such boundaries may only widen. But this is not necessarily a bad thing – it is simply a product of progress, which in science is always good!

Though at undergraduate level it may seem that biology and chemistry are miles apart, upon reaching research level this is not so. More and more research groups contain both biologist and chemist specialists, who may benefit from each other’s knowledge. Many universities recognise chemical biology modules as an essential part of a chemist’s degree, more in silico (computation) research focuses on interaction of proteins and enzymes, and more of the more specific areas of chemistry are opening up to biomedical application.

This is a promising start to widening study of pharmacology and other boundary sciences, but it is not the end. Pharmacology in particular seems to be a specialist science studied mainly in hospitals by clinicians.

Picture1Because the science relies on clinical trials (or in silico research, which I’ll discuss later), it is often overlooked by academic researchers and undergraduates. Although pharmacological research would, ideally, be implemented into the earlier stages of drug design, it is often carried out reactively rather than pre-emptively. I think I’ll leave this discussion for now, though: pharmacology in drug design could fill an entire post by itself!

I feel that a solution to undergraduates being underexposed to the more specific areas of chemistry and biology would be to have lecture series for active researchers just to discuss their specific disciplines. Of course, this sounds very basic, and it is! Different universities tend to churn out scientists specialising in the area the university department itself tends to specialise in. Exposing their students to other areas of research could lead to more well-rounded researchers with a greater understanding of the scientific world as a whole.

This post is entirely my own opinion, based on my own experiences – feel free to disagree and share your thoughts in the comments!

 

A note from the author: As my posts sometimes touch on emotive subjects, comments are disabled after 4 days. This is because, at this stage, I feel that ongoing discussions tend to stagnate.