Implementing Thermal Processing Technologies for the Production of Amorphous Solid Dispersions

Amorphous pharmaceutical materials are now being recognised as an attractive alternative route for solid state development. Dr. Dave Miller, Senior Principal Scientist at Hoffmann-La Roche, speaks to Helen Winsor from Pharma IQ, about the challenges of amorphous solid dispersion production, and explores formulation design principles for thermally processed amorphous systems. To listen to the podcast now go to The Challenges of Amorphous Solid Dispersion Production: A Hoffman La Roche Perspective.

Pharma IQ: To make a start, how would you optimise amorphous form selection, Dave?

D Miller: Optimising amorphous form selection; well, I think the first thing we typically do is go to our list of favourite polymers or excipients that stabilise drugs in the amorphous form. It’s not an extremely long list, so we can typically take an empirical approach where we combine our API with the different excipients, either the single excipient or in combinations of those excipients at various drug loadings. We’ll typically prepare these on a small scale, either by thermal processing means using like a mini hot-melt extruder or by solvent evaporation means through rota evaporation, or perhaps a small spray dryer.

So, we prepare these formulations at different drug loadings, different combinations of excipients, then place these on accelerated stability chambers at varying temperatures and humidities - and we’ll monitor the physical stability and chemical stability as a function of time and conditions. In parallel, we will typically do super-saturating dissolution studies, and so we’ll have two data sets comparing the formulations’ chemical and physical stability against their dissolution performance. Through the analysis of these two data sets, we can typically arrive at a small number of optimum formulations that we’ll then move forward in development with. The next step in development usually involves a small PK study where we’ll evaluate the bio-availability of these formulations.

Pharma IQ: At Hoffmann-La Roche, what techniques do you use to enhance amorphous drug performance?

D Miller: To enhance the performance, well, the techniques and the methods we use for manufacturing amorphous dispersions are - we rely primarily on hot-melt extrusion initially, but we’ve been lately working a lot more with spray drying. In addition, we have a proprietary control precipitation process known as micro-precipitation, the product itself is called microprecipitated bulk powder. By these techniques, and through our formulation experience, the combination of excipients, polymer selection, ancillary excipients, adding things such as surfactants or, perhaps, other water-soluble materials, we can typically tailor the dissolution performance to whatever the particular API needs. So, in terms of achieving extensive supersaturation in a use environment or, perhaps, in some cases with APIs that have rapid crystallisation kinetics, we can through the tailoring of the ancillary excipients, modify the extent of super-saturation as needed. So, by the combination of process and formulation design; that’s how we optimise amorphous formulation performance.

Pharma IQ: Something I’d be interested to get your perspective on, is how do you capitalise on the commercial potential of amorphous forms?

D Miller: In my role in early development, we’re not as concerned with capitalising on the commercial potential, but what I can say is from our past experience, through enhancing solubility by amorphous formulations, we typically reduce - well, substantially reduce the dose and, for most of our discovery compounds in the areas of oncology and inflammation, these APIs are extremely expensive. So, by developing a formulation with modified or enhanced solubility, we tend to reduce the cost of goods that go into each dosage form substantially.In that way, we save quite a bit of money in terms of the overall API cost per dosage form, which therefore would relate to the cost of therapy to the patient.

Looking down the line, I know a lot of companies do a lot of line extension, whereby they improve solubility to reduce dose and introduce a new product - a continuation of an existing product with a lower dose that achieves the same blood levels, and in that way they’re able to extend the life cycle of their product. Here at Roche, we tend to do less of that than other companies; we tend to try to introduce the optimum drug product initially - that’s been our strategy dating back quite a while. We use amorphous systems to optimise the blood levels per dose.

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Pharma IQ: From your experience, Dave, what are the best strategies to stabilise amorphous forms - which is obviously another key question for the industry?

D Miller: Yes, the best - as I referred previously - the best strategy is to determine the carrier formulation that is most miscible with your API. Ideally you have inter-molecular interactions between your API and the excipient carrier, and these intermolecular interactions, these hydrogen bonding forces, these dramatically help to stabilise the amorphous form of the API. There are different ways of predicting this kind of interaction, or miscibility between a drug and a polymer. We typically take an empirical approach, where we produce compositions at various drug loadings with various polymers and other ancillary excipients. We put them in stability chambers and monitor them with time - monitor physical and chemical stability. So, in my opinion, the most effective way of optimising a formulation for stability is a high throughput screening approach, whereby you just produce a lot of different compositions and monitor their stability at different temperatures, humidities, over time.

Pharma IQ: Dave, what do you think the future holds for the development of amorphous forms as viable and profitable drug candidates?

D Miller: I see amorphous formulations becoming more and more relevant, particularly here at Roche, Nutley. We are working with primarily oncology inflammation metabolics, so most of the drugs coming out of discovery into our shop are very poorly soluble. Most of these compounds, even through extensive particle size reduction; you can’t achieve the kind of dissolution that’s necessary to achieve acceptable exposure. So we’re relying more and more on amorphous technologies to improve the blood levels of these types of APIs. I think we’ve found ways of dealing with the inherent instability of amorphous forms. We have a portfolio of process technologies, by which we’re able to take just about any given API and produce a viable amorphous form of the drug. So I see here at Roche, very amorphous formulations are being utilised more and more, from early pre-clinical studies into the clinic, and eventually into the market. But I think what’s critical is understanding the factors that influence stability, as well as having a portfolio of technologies that enable you to produce viable amorphous forms for any given API, irrespective of its physio-chemical properties.

Pharma IQ: Thank you, and finally, just to round off. I understand that you’ll be presenting at the upcoming Amorphous Pharmaceutical Materials conference, which will be taking place from the 27th-29th September 2010 in Amsterdam. Now, for anyone interested in attending the event, what would you say is the key learning point to be gained from your presentation?

D Miller: Well, I’ll be going through two techniques - thermal processing techniques for producing amorphous formulations. Hot-melt extrusion obviously is a technology that is becoming more and more popular, so I will basically be going over the basics of hot-melt extrusion. I’ll be looking at when to use hot-melt extrusion, some of the key process parameters to focus on and the formulation aspects of hot-melt extrusion. I’ll be presenting some case studies as well. The audience should be able to take some key learnings from some case studies that we’ve recently completed here at Roche. In addition, I’ll be presenting a new technology called KinetiSol®  dispersing; it’s also a thermal process, similar to melt extrusion in that it’s an anhydrous thermal process for making amorphous solid dispersions. It’s got some key advantages to hot-melt extrusion.

Pharma IQ: Yes, and what are the advantages, just in summary?

D Miller: Mainly, there’s no external heat supplied. The materials are rendered molten through the DU kinetic energy so there’s no external heat. So typically, the heat exposure to your drug is quite low in that regard. Also, processing times are substantially reduced; typically processing times are less than 20 seconds to render an amorphous formulation, and that is constant through scale-up. So the processing time required to produce 50 grams of material is the same processing time used to produce 100 kilos of material. So, scale-up is a little more straightforward with KintetiSol® .

Primarily, the advantages are more aggressive mixing which tends to allow you to produce a more homogenous amorphous dispersion with polymers, particularly with cellulosics that have high melt viscosity and you can have issues with mixing with a typical hot-melt extruder, and also the reduced processing time for thermally sensitive actives. Processing time can be critical and with KintetiSol®  dispersing - with typical mixing times less than 20 seconds - you’re definitely reducing the heat load that those actives see. But it’s definitely a complementary technology to hot-melt extrusion. There are certain applications for which KintetiSol has some key benefits; like I said, with using polymers that typically went through mixing issues with hot-melt extrusion and heat-sensitive actives.

Pharma IQ: Well, we look forward to learning more at your presentation. Now, Dave, thank you so much for your time today; it’s been a real pleasure talking to you.

D Miller: Thank you very much. It was my pleasure.


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