Predicting Physical Stability of Amorphous Solid Dispersions

Stéphanie Greco, Analyst Scientist, Pharmaceutical Science Department, Sanofi-aventis, joined Pharma IQ to discuss predicting physical stability of amorphous solid dispersions.

Pharma IQ: Please could you tell us about your previous achievements and current work at Sanofi-aventis?

S Greco: I've been working for Sanofi for seven years, just after my PhD, and I spent six years in the Physical Quality Service where I was in charge of a laboratory of physical analysis. My main task was to support the teams developing processes of drug's physical treatment, such as milling, micronisation, nano-milling and amorphisation by spray drying. One of my projects has been to actively participate to the development of an amorphous dispersion, and particularly in the screening of a polymer carrier, to improve the stability of this amorphous form. So this project gave me the opportunity to study extensively the physical stability of amorphous dispersions.

One year ago I moved to the Pharmaceutical Engineering Service, and I'm now developing formulation and processes for extremely poorly-soluble drugs in the nanotechnology domain. For instance, I'm specialised in processes like nano-milling or nano-precipitation.

Pharma IQ: Commentators have suggested that the number of poorly-soluble drugs on the market is increasing. Why do you think this is?

S Greco: Indeed it is one of the most important challenges we are facing in the Pharmaceutical Science department for the development of new drugs. I have heard that 40% of candidates in development are stopped because of the lack of solubility, but it was some years ago, and this number might be under the reality now.

Pharma IQ: At the 7th Annual Improving Solubility Summit in June, you are going to be delivering a talk on practical methods to predict physical stability of amorphous solid dispersions. Why did you choose amorphous solid dispersions as a method of improving solubility?

S Greco: It is well known for a very long time, that a drug isolated in its amorphous state gets a much higher dissolution rate in water, than its most stable crystalline form. So it seems very interesting to use this property in order to improve the bio availability of poorly-soluble drugs. Unfortunately the development of amorphous drugs was blocked, I think during a long time, because of some technical challenges, such as the poor physical and chemical stability of amorphous compounds. But during the past several years, high improvements have been made to withdraw these technological locks, for example, with the use of a polymer carrier to increase the stability, or the addition of surfactants to improve solubility. And the number of drugs developed as an amorphous form has increased significantly.

But the amorphous dispersion is not the only way to increase drugs solubility, for example reducing the drug’s particle size to the nano scale can also give good results. For the project I will present at the conference, in-vivo pharmacokinetic studies demonstrated a better exposure with an amorphous dispersion, compared to the micronised drug or even a nano-suspension. And that was the reason why the amorphous dispersion was the formulation selected for the development of this drug. There are several criteria that are important to discriminate different formulation strategies for poorly-soluble drugs, but I think that the direct measurement of bio availability, by in-vivo studies, must always be the crucial point for the final choice.

Pharma IQ: What would you say are the main challenges that you face with using amorphous solid dispersions, and how have you overcome them?

S Greco: As I've just said, I think that the main challenge that is usually faced when developing amorphous dispersion is the lack of physical stability of such formulations. Indeed the better solubility is directly linked to the metastability of the amorphous form. An amorphous drug is more soluble because it is less stable.

The solution to overcome this problem is well known: it is to make a solid solution between the amorphised drug and an excipient, generally a polymer that is called a polymer carrier. The main role of this polymeric matrix is to prevent the crystallisation of the drug, but not only. During the screening of best polymer carrier for a given drug, it is important to keep in mind that it must be selected according at least three criteria

• this polymer has to improve the chemical stability of the drug, so there must be a good compatibility between the drug and this polymer.
• Secondly, it has to improve the long-term physical stability of the drug, since the final amorphous dispersion has to be stable at least two years.
• At last, it has also to prevent the recrystallisation of the drug in the stomach, or in the gastrointestinal tract, and this can be determined by appropriate in vitro biopharmaceutical tests.

It is only when all these criteria are evaluated at the same time that a good choice will be made for the polymer carrier.
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The process of amorphisation by spray drying can also pose technical difficulties. Handling organic solvents, for instance, in a pharmaceutical environment is not straightforward. It requires double skills between chemical and pharmaceutical areas.

So to conclude, the development of amorphous dispersion is a quite complex technology, but all the technical difficulties can find appropriate solutions.

Pharma IQ: At the 7th Annual Improving Solubility Summit, what do you expect will be the most valuable discussion points, and what do you hope to gain from being there?

S Greco: All the presentations seem to be very interesting, and will give a broad overview on this issue of low solubility. Especially I expect that the session dedicated to the very latest developments in this topic will highlight some innovative strategies and technologies of formulation and drug delivery. And as there’s some time kept for exchanges, I am sure that very fruitful discussions will take place between all the experts, and I hope that some new idea will come out.

Interview conducted by Andrea Charles

IQPC

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