3 Tips on Overcoming Poor Aqueous Solubility and Stability

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Rene Holm, Head of Preformulation at H Lundbeck A/S, joins Pharma IQ to discuss the benefits of early stage preformulation, how advances in drug delivery devices have impacted on formulations, and strategies for enhancing solubility.

Pharma IQ: Please could you tell us a bit about your current role?

R Holm: I am currently involved in preformulation, both in discovery and development and troubleshooting based on preformulation things in production, and therefore we have a perspective that covers the entire lifecycle of the compound here at Lundbeck.

Pharma IQ: Early stage preformulation is a hot topic in formulation development. What are the benefits?

R Holm: The benefits of preformulation are to, early on, identify formulation risks; early on help to facilitate and identify a formulation strategy, basically. Those are the two main things. So you need to figure out which strategy to go for and which would work, most probably, and which will not. Furthermore, you need to tell management that you may not be the slacking one here. There may be a scientific reason why this may take longer time. You have to follow the standards, sell the project, perhaps. Preformulation data can actually help with that discussion.

Pharma IQ: How have advances in drug delivery devices impacted on formulations?

R Holm: On devices, I’m not sure if it has done anything. It has done a lot on pulmonary delivery, but not orally, in my perspective. It’s a more specialised delivery form where it has had any impact.

Pharma IQ: And what strategies are companies employing for enhancing solubility?

R Holm: In reality, enhancing solubility is not that difficult. You have two main things you can do: either you can increase the solution rate or you can just present it in that form. That can be done by relatively developed strategies. The well-known way of increasing mobility rate is salt formation, but things that are used much more are the solid solution sensation of amorphous form, lipid based formulations, that kind of stuff. But actually it is relatively well described in literature what can be done for these compounds. The tricky thing, of course, is to do it and also to get it in a GP way and in a commercial scale.

Pharma IQ: In your view, what are the industrial obstacles to the use of lipid based formulations?

R Holm: The main obstacle, as I see it, is encapsability. That’s the one thing. And then solubility in lipids. We would normally use a lipid based formulation where we have a low soluble compound, but there is no link between low… increased solubility and high lipid solubility. So although the compounds are low soluble in water, they may still also have a low solubility in lipids, and we need to solubilise the lipids in order to use that formulation system.

Secondly, in the lipids excipients we see impurities that may lead to degradation and oxidation and that encapsability with the compound is also a major. Lipid based formulations really, really possess huge power to increase solubility on those compounds where it works.

Pharma IQ: How exactly is the industry seeking to overcome these problems?

R Holm: If it’s done right, especially by the excipient deliverance, you can purchase a specialty high purity grade different oils, etc, and that is a way to do it. And then the use of antioxidants, etc. But it is very much to work on the excipient income, in reality, and that’s also what’s been done.

Pharma IQ: And how do you plan a robust formulation strategy?

R Holm: Quality by design. That’s how we would do it normally. First of all, your formulation strategy will be defined by your preformulation input. The knowledge you have about the compound, its behaviour, its solubilities and its physical parameters, they will define what strategy or strategies you think you’ll go for. Then, to get it robust, at least from a pharmaceutical point of view, you would define a design space and that design space can also be transferred into a clinical design space. That’s normally how we would do it. You would use the thinking and the thoughts that are included in quality by design.

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Pharma IQ: What would be your top three tips for overcoming poor aqueous solubility instability, Rene?

R Holm: The best still is to get a soluble compound. Having said that, I’m well aware that whenever you select a compound in pharmaceutical industries, physical parameters normally has a lower rank than pharmacology. This, of course, makes sense, because if it doesn’t work there’s no need to use the time... Internally, in the company, you need to define what relatively generic strategy can be used for these kinds of compounds – what are we going for. Are we going for solidification of the amorphous form, which can be among the different classes of compounds. At least, I would also consider internally which scientific capabilities we have in-house to produce this. We have to have the equipment so we can do it both on a lab scale and on a GP scale. We don’t need to do it on a high scale level. All we need is to identify inventors that can help us to do that. But we need to find what our priorities are and make the formulations.

On solubility it is a bit more tricky because it depends much more what is the instability problem. You need to define the formulation solution to the specific compound, and that is one of the major measures. Look at the compound, look at what you know, and fit the formulation and the work to the compounds.

Pharma IQ: Leading on from that, for anyone interested in attending the Global Preformulation & Formulation Summit, taking place in Amsterdam from the 11th -13th April 2011, what would be your key take-home message?

R Holm: Actually, I will talk about formulations for drug to blood deliverations. Formulation for drugs is normally considered as pushing preformulation to the limit because we need to go way above clinical doses. So I would focus very much on how to achieve this, what experience do we have experience with as safe, and which kind of drug formulation strategies do we actually have for certain compounds.

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