Water solvable12 April 2021
Pharmaceutical development is a delicate balance of stability, manufacturability and bioavailability. For all the advantages that lipid-based excipients (LBEs) bring to the latter category, weaknesses in other areas have limited their impact. Sharareh Salar-Behzadi, principal scientist at Austria’s Research Centre for Pharmaceutical Engineering, tells Isabel Ellis how she’s using a new chemical group to produce LBEs that can keep poorly water-soluble active pharmaceutical ingredients stable without impacting their uptake by the body.
There are a lot of good things about lipid-based excipients (LBEs). By ‘solubilising’ drug compounds, LBEs can make poorly bioavailable active pharmaceutical ingredients (APIs) viable drug candidates, lower the amount of API required per dose, reduce the variability of drug uptake between patients and minimise the impact of the first-pass effect – all across a variety of dosage forms.
Were you to instil an LBE with language and consciousness, as well as the single, lifelong task of memorising the above sentence, the LBE would even nod along enthusiastically and, for a while, feel confident repeating it back to you.
Then, one day, when you least expected it, for no outwardly discernible reason, the LBE would begin to feel uncomfortable with this arrangement, and start to question it. Why, it might ask, shouldn’t LBEs make previously viable drug candidates poorly bioavailable, and therefore minimise the impact of the API across patients? That’s such a minor change, really – it would cajole – and it would be a lot easier, wouldn’t it?
Before too long, your LBE would have completely reordered its sentence to suit its own predilections, secure and settled in the fact that it had thus made itself utterly useless to you.
In short, properly engineered LBEs are good for all of those things, but you better not give them a chance to consider whether they actually want to do them. Over time, LBEs abandon the nano and microstructures that make them so well suited to delivering APIs in favour of more stable solid states, which may help them feel more comfortable, but compromise the final dosage form.
“It’s really a pain to use them for a formulation because of their polymorphic changes over time,” says Sharareh Salar-Behzadi, a principal scientist focusing on excipients at Austria’s Research Centre for Pharmaceutical Engineering (RCPE). “At first, the molecules are together in a certain arrangement, but they tend to lose energy and then go to the most stable one, and that has an impact on the macroscopic properties.”
Salar-Behzadi doesn’t have a propensity to lose energy, however. From her team at RCPE, an independent company formed to focus on pharmaceutical sustainability as part of a collaboration between the Technical University of Graz, the University of Graz and Joanneum Research, she demands passion. How else could they convince LBEs to remain stable throughout their shelf lives? “Sometimes there are projects that just need to be done, to be finished,” she explains. “But it’s impossible for me to work while seeing things like this, especially research. I need to see my people being passionate and motivated, and that’s how we all were for this LBE project.”
Day of the lipids
Despite their shortcomings, the pharmaceutical industry is increasingly passionate about the applications of LBEs for solving what Salar-Behzadi calls “classical problems of formulation”. As naturally occurring materials that are more or less digestible, with lower toxicity and better biocompatibility than polymers, as well as the ability to improve the solubility or enhance the permeability of APIs, LBEs are, as Salar-Behzadi finds herself saying, “sexier than polymer excipients”.
Indeed, LBEs present more of a chemical problem than a motivational one. Unable to definitively solve it, developers working with them have traditionally tried to pre-empt the issues caused by polymorphism by designing formulations that morph into, rather than from, the optimal structure for delivering the API. Most of these techniques work by introducing a curing or tempering step to prompt a change of structure shortly after manufacture, hopefully removing any uncertainty about shelf life.
“But with this curing step, nothing is controllable,” says Salar-Behzadi. “We assume that it will take the most the most stable polymorphic form after curing, but it means that before having the final formulation, we need to know exactly what the effect of this curing will be in order to design the product in a way that is not really optimal, so that, after the curing, it takes the optimal form.”
It sounds complicated for a reason. Predictive studies of how that process works and how it affects specific formulations are challenging to say the least, and they need to be completely redesigned for every drug. With the amount of labour and expense such an approach requires, it’s a poor fit with RCPE’s sustainability agenda. It also does nothing to prevent the crystallisation process that can also affect LBE performance.
Instead, in their first attempt to sidestep the problem, Salar-Behzadi’s team developed a formulation for hot-melt coating that included an emulsifier, which induced the polymorphic transformation to the most stable form directly after manufacturing. It cancelled out most of the issues around predictability that come with curing, but not all of them. “Then, of course, there was crystal growth on the lipid, which was triggered by the emulsifier in the system,” she says resignedly. “And then, at the end, we also had a phase separation in the coating.”
And so, once again, an attempt to optimise LBEs created another set of problems and a whole lot of extra predictive work. You can begin to see why lipids are themselves so lackadaisical. “Being aware of the problems means you can simulate and predict the conditions they cause, or the polymorphic changes, and the effect they have on the behaviour and performance of the product during its shelf life,” says Salar-Behzadi. “But none of it actually solves the problem. That’s the real issue.”
Approximately, molecules in the discovery pipeline that are poorly water soluble.
Approximately, the drugs with market approval that are poorly water soluble.
Salar-Behzadi never lost sight of the real issue. Hers is not the way of the LBEs, but she and her team had to grow to understand it. Steadily, the requirements for the optimal LBE became clear.
“By tracking the reasons for the instability in the performance of products with LBEs, we became sure that a stable solid state at the molecular and nano level, with no polymorphic transformations and a one-phase system to avoid phase separation, was the key to having a stable formulation in different pharmaceutical products,” she explains. “So, we started to think about finding a molecule with a stable solid state.”
Strong and stable
The discovery process took longer than an article can convey, but that stability eventually came from an old food and cosmetic additive: polyglycerol esters of fatty acids (PGFAs – marketed under the name Witepsol PMF). Due to their unique chemical structure, PGFAs refuse to settle. “In this chemical structure, we have glycerol moieties bonding to each other between hydroxyl groups that can be partially or completely esterified with fatty acids of various lengths,” says Salar-Behzadi.
“There is space between the fatty acid chains, which weakens their intramolecular interactions, and, because of that, there are a lot of hindrances preventing the molecule tilting to a more structured arrangement, so the polymorphic form remains stable during the whole shelf life.” The closest comparable natural molecules, monoacylglycerols, also have spaces between fatty acid chains that prevent polymorphic transformations, but can’t be altered to serve different purposes as LBEs. “It’s just one molecule with a certain property that we can only use for certain purposes,” says Salar- Behzadi. With PGFAs, by contrast, the number of glycerol molecules moieties bonded to each other, the proportion of esterified hydroxyl groups, and the length of the fatty acid chains can all be tweaked and tuned to create molecules with different hydrophilic-lipophilic balance (HLB), wettability and melting properties to match particular APIs, release profiles and manufacturing processes. “For example, we might want to hotmelt coat one poorly water-soluble API using a PGFA with higher HLB and water uptake for immediate release,” effuses Salar-Behzadi, “Or use a more lipophilic one of these molecules with a lower HLB for an extended release.”
Almost at a stroke, five years of passion and motivation began to pay off for the RCPE team. Salar-Behzadi says her team work so well together because they aim to have fun, but as they spun out their PGFAs for nanolipid suspensions, dry powder inhalations, hot-melt coatings and even macrophage uptake for tuberculosis therapies (for which the team is seeking industrial collaborators), they got other rewards. Every student working on the project had a unique focus for their PhD and master’s theses.
That same flexibility will make PGFA-based excipients perfect for a wide range of patientcentric applications using conventional manufacturing processes, although Salar-Behzadi also stresses that the still uncommon hot-melt coating process will make waves across the industry in the years to come.
“Whether it’s for taste-masking or as a matrix or coating for multi-particulate systems – just coating the API powder itself – for example, we can solve problems with swallowing and adapting to a fixed-dose combination or a flexible dose combination for elderly people that are also dealing with polypharmacy,” says Salar-Behzadi. The message underneath that? Never settle.
Innovation models for formulation and manufacturing
Backed by three separate academic institutions, RCPE works across the areas of pharmaceutical process simulation, molecular modelling, formulation and product development, and manufacturing processing to improve pharmaceutical sustainability. “If I can allow myself to say so,” hazards Salar-Behzadi, “it’s a unique structure. You cannot find these three areas together in the whole of Europe.”
But across the continent, governments are backing research and innovation centres that they hope can prompt pharmaceutical clustering, supporting national economies by attracting industry investment and creating high-skilled local jobs. The UK’s Innovation Centre network is one such example. As mentioned on page 53, the Medicines Manufacturing Innovation Centre is looking to achieve similar breakthroughs to RCPE through its programme of ‘Grand Challenges’.
The first of those projects – which focuses on authorising a replicable commercial model for using continuous direct compression (CDC) for tablet manufacturing – has drawn investments from GSK and AstraZeneca, among others.
“Tablet manufacture has been with us for a hundred years,” says director Dave Tudor, “but the reality of it is that in most tablet processes, you can lose up to 30% of the active ingredient.” By developing and standardising the hardware technology and analytics for CDC, as well as building a digital data twin model that can combine API and excipient data “to predict the success of CDC”, the centre believes it can cut that waste to less than 5% across a huge variety of pharmaceuticals made in the UK – while giving manufacturers far greater control over product quality.
“There are only a handful – less than six, I think – drugs on the market registered with CDC,” says Tudor. “If we can change that paradigm and get 50% of our tablets made through CDC, just look at the dramatic impact that would have on the affordability of medicines and companies’ risk profiles.” The project is almost 18 months old, and Tudor is confident of success.