Ingredients see a drive for more science

Published: 15-Jan-2016

The need for greater solubility and bioavailability of new medicines, as well as increasing manufacturing efficiencies are driving developments in ingredients. Susan Birks reports on the latest trends

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For many years the pharmaceutical market has relied upon excipients that are safe and available in bulk but are poorly adapted to the purpose of pharmaceutical formulation. As medicinal science has moved on, the difficulties faced by formulators have increased; bioavailability has become a key requisite and the new active molecules coming through are frequently difficult to solubilise. Furthermore, in today’s competitive marketplace where healthcare payers are driving down drug prices, manufacturing costs and productivity have become important drivers for change. At last, suppliers are making serious attempts to understand formulation issues and make excipients really work for manufacturers.

The global excipients market is expected to reach US$5.22bn by 2020, growing at a CAGR of 6.0% from 2014 to 2020, according to the latest report by Grand View Research1 but, on the whole, developments in this market tend to be incremental rather than earth shattering. In this conservative, highly regulated, data-reliant sector, totally new excipients are few and far between. Such materials are, however, increasingly tailored to solve specific issues and contract manufacturers are playing a larger role in tackling the low solubility API issue.

Based in Durham, North Carolina, Patheon’s Vice President of Global PDS Scientific Excellence, Marshall Crew, says: ‘With so few really new excipient launches due to the huge cost of approval, many of the established ingredients were brought to the market for different reasons. Most polymeric materials we use today came through for controlled release and targeted delivery, such as polymers designed to release drugs in specific portions of the gastro intestinal (GI) tract. It just turns out that those materials have the physico-chemical properties that are also well suited to low soluble molecules.’

Crew says the future lies in having a mechanistic and molecular understanding of how these excipients improve the bioavailability and then really designing these dosage forms, rather than merely empirically discovering what works.

If we understood chemically how these excipients improve bioavailability we could be very much more efficient and actually design optimal solutions for the problem

‘The direction in which we need to progress is in the predictability and design of dosage forms. Today, it is an empirical process – we put things together, test them and select the formula that works. This is a pretty archaic way to do it. Most industries have a deep mechanistic understanding and they engineer a solution. If we understood chemically how these excipients improve bioavailability we could be very much more efficient and actually design optimal solutions for the problem.’

He believes the skills required to do this include a ‘computational chemistry component (to understand interactions at a molecular level) and an experimental component’. ‘Another crucial piece required to take us to the next level will be informatics – acquiring large amounts of data, analysing and synthesising it into knowledge,’ he says.

Patheon recently bought Agere Pharmaceuticals, which added spray drying and solid dispersion capability technology to the company’s low solubility drug delivery services. ‘The trick with solubility is to find the right combination of excipients for a particular molecule. They all have their unique challenges and it is important to find the right combination to create a robust formulation that will have the stability, performance and manufacturability to make a commercial product,’ says Crew.

Spray drying is currently the most frequently used path to improving bioavailability, accounting from more than 50% of formulations

So what are the ingredient manfacturers doing to help? Marc Van Gerwen, Global Business Director, Dow Pharma & Food Solutions, highlights the two major trends of improving bioavailability and productivity as areas that the company has been working on. While all kinds of routes are available to improve bioavailability (e.g. spray drying, hot melt extrusion, using lipid technology or micronisation) Van Gerwen believes spray drying is currently the most frequently used path to improving bioavailability, accounting from more than 50% of formulations. Dow offers HPMCAs in the Affinisol range for this purpose, which it can adapt to the API in question.

For producers that want a different solubilisation route, Dow offers Affinisol HPMC, specifically designed for hot melt extrusion (HME). Based on plant material, hydroxypropyl methyl celluloses (HPMCs) make up the single biggest class of ingredients. ‘People like cellulosics as they are innocuous and have no undesirables byproducts,’ Van Gerwen says.

Historically such materials could not be extruded, as they would simply burn during the process but this product is ‘readily extrudable, has improved throughput and processability, it offers a broader processing window and is capable of achieving and maintaining supersaturation with multiple release profiles,’ says Van Gerwen.

Productivity is another big driver, especially for generic producers who really need to operate at lowest total cost. Dow’s direct compression grade Methocel DC, for example, is an excipient typically used in controlled released applications and designed for processing techniques such as dry granulation. Dow has now added Ethocel High Productivity (HP), an ethylcellulose polymer for multi-particulate and taste-masking applications that will enable companies to dry coat barrier membranes in shorter coating times, at higher efficiencies and without the need for solvents.

Water-based processes are a well established route but they create quality issues and require new equipment; in addition there are issues of drying and consistency of release

‘People often want to get away from using solvents. Water-based processes are a well established route to do this but they create quality issues and require new equipment; in addition there are issues of drying and consistency of release. Polymer scientists have produced Ethocel HP, which can be used in a dry technique and can be sprayed directly.’

In trials conducted by Dow, use of Ethocel HP reduced overall coating times by 60% compared with aqueous or methacrylate systems and by 40% relative to solvent systems. Trials with the excipient have also shown a step improvement in barrier membrane coating efficiency compared with solvent or aqueous ethylcellulose systems with opportunities for raw material cost-savings. Beyond its productivity attributes, Ethocel HP also offers environmental and sustainability benefits because it is designed to operate solvent-free in rotor coater systems. By using it, product formulators can avoid high solvent costs, eliminate capital expenditure for solvent-rated equipment and remove operational safety concerns associated with solvents.

Security of supply and sustainability

In recent times, stricter legislation has brought pressures to bear relating to product purity and security of supply chains. Van Gerwen notes: ‘A drug can be five years in development and companies need to be sure that a supplier will be around in 5–10 years’ time and that they can grow with the security of ingredient supply.’ As a result, Dow is preparing to expand its regulated manufacturing network. ‘We are the largest HPMC supplier and we are looking to ensure our regulated grades are available on a continuous basis from multiple sites.’

Dow also has a drive towards sustainability. But for pharma companies a balance has to be struck between the requirement to have reproducible, consistent quality using ingredients that are chemically pure and the need for greater sustainability. ‘Natural ingredients don’t always have that reproducible nature; they can be variable,’ says Van Gerwen. ‘However, increasingly, quality and compliance require that drugs have no off-coloured particles,’ he says, ‘such requirements cost a lot of money, but we are doing it.’

Ashland Specialty Ingredients is another provider looking to advance drug delivery through engineering and design. ‘We have medicinal chemists and pharmaceutical specialists looking to make excipients more intelligently,’ says Thomas Durig, Ashland’s Senior Director, Pharma and Nutrition Specialities R&D. ‘Fundamental polymer design is our approach,’ he adds.

A holistic, science-based approach to excipient selection rather than a traditional empirical approach affords the pharmaceutical industry the ability to consider the impact of polymer excipients in key areas of drug development

Direct compression Benecel DC hypromellose, for example, is designed to control the release of complex drug molecules in solid-dosage forms. Where the products already available did not have the right flow characteristics to make large volumes at high speed, Ashland looked at how it could re-engineer this polymer to make it more robust in manufacturing.

‘A holistic, science-based approach to excipient selection rather than a traditional empirical approach affords the pharmaceutical industry the ability to consider the impact of polymer excipients in key areas of drug development, including manufacturing, bioavailability and stability,’ says Durig.

One of the latest products in its armoury is AquaSolve hypromellose acetate succinate (HPMCAS), a solid dispersion polymer for bioavailability enhancement of poorly soluble APIs. ‘Originally conceived for capsule manufacturing, we have developed new analogues that are able to deliver poorly soluble compounds that would otherwise fail in clinical testing due to poor bioavailability.’

Like others, the company is having to adapt to a changing industry landscape where there is greater therapeutic focus on drugs to treat cancer, diabetes and rare diseases. This provides challenges because such drugs are more complex and difficult to deliver, especially in respect to bioavailability, and they are more potent. Durig says the company has built a strong knowledge centre and has expertise in high potency active pharmaceutical ingredients (HPAPIs) and HME. It is, for example, building a solubilsation database, in addition to the already established controlled release database which can be used to predict how its polymers will work in silico.

On the productivity side, Durig highlights the drive towards continuous manufacturing, which involves the design of continuous systems for agglomeration, HME or coating. ‘Having moved from a novel concept to commonplace, continuous agglomeration is extremely versatile and makes for better controlled release,’ he says.

But Durig also believes that the introduction of new manufacturing technologies and new ingredients is slowed by the time-consuming regulatory procedures required by change. ‘More innovation could be stimulated, if there were a regulatory framework that would allow for new excipients through a new approval process,’ he suggests.

Lipids and softgels

True innovation can be a long and expensive process, thus some 80% of products still use the main two dosage forms – solid dispersion or lipids and softgels. Compared with solid dose technologies, Patheon’s Crew says: ‘Lipids interactions at a molecular level are even more complex but we are expanding the role of the science by bringing molecular modelling into the softgel space. So there will be more advances in future.’ He says the company has seen positive interest in that space, partly because there is an increasing number of low soluble molecules, and secondly, it is a robust and economical process with an attractive presentation.

The challenge is to find a combination of excipients that will create a robust formulation

The challenge is to find a combination of excipients that will create a robust formulation

Also expert in lipids, Abitec has expanded its portfolio of Capmul bioavailability enhancers, which are medium-chain mono- and di-glycerides and propylene glycol esters. These functional lipid excipients act as solubilisers and emulsifiers in oral, topical, transdermal and parenteral drug delivery systems. The company believes these excipients are an ideal starting point when formulating poorly water soluble and poorly permeable molecules. Abitec also recently introduced Injecta, a parenteral grade lipid excipient that improves the solubilisation and permeation of injectable APIs.

Capsugel, a global leader in dosage forms and solutions, utilises its technologies and manufacturing capabilities to solve its customer’s most pressing drug delivery challenges. For years, the industry has been searching for a fully enteric dosage form that does not require functional coatings. Capsugel recently launched enTRinsic, a drug delivery technology platform that provides full enteric protection and targeted release of gastric acid- and heat-sensitive active ingredients to the upper GI tract, without the need for functional coatings. Produced using pharma-approved enteric polymers, the technology enables oral delivery of a variety of compounds – including vaccines, proteins and peptides.

Stephen Brown, MD of Encap Drug Delivery, a division of Capsugel Dosage Form Solutions, says: ‘The formulation of the shell used in enTRinsic technology makes it enteric, so it doesn’t require functional coatings. This has particular advantages for moisture- or heat-sensitive materials, many of which may be destined for the GI tract.

Liquid-filled soft or hard capsules provide better operator safety compared with powder. Getting the drug into liquid form is the first requirement in making the process more manageable

The industry is also intent on expanding its capabilities in developing pharmaceutical products containing HPAPI ingredients. Capsugel’s Edinburgh, Scotland facility set up HPAPI facilities in 2008, and these were expanded last year. The expansion allows the company to increase its liquid- and semi-solid-fill hard capsule manufacturing capacity for drug products containing HPAPIs and to further diversify the technology platforms offered at the facility.

Liquid-filled soft or hard capsules are ideal for HPAPIs, says Brown. ‘They provide better operator safety compared with powder,’ he explains, adding: ‘Getting the drug into liquid form is the first requirement in making the process more manageable.’

Additionally, the industry is focused on developing drug delivery technologies that employ non-animal, naturally derived (e.g. vegetarian) raw materials. Brown notes that in terms of dissolution, some new capsules are getting towards the technical capabilities of gelatin. Two-piece hard shell capsules made from hypromellose HPMC have typically been used as an alternative to conventional gelatin capsules for oral drug delivery for ingredients that are chemically incompatible with gelatin, hygroscopic, or sensitive to moisture. Capsugel’s Vcaps Plus capsules, which are relatively new HPMC polymer capsules produced without secondary gelling agents, have shown dissolution profiles without any statistical difference to those of conventional hard gelatin capsules, according to a recent in vivo bioequivalence study.

Capsugel is exploring use of capsules for inhalation of asthma drugs, and formulations for paediatric use – something that the regulators are pressing for. ‘We develop hard capsules containing multiparticulates, which can be easily opened and sprinkled onto soft food or drinks,’ says Brown, adding: ‘We can make lipids with multi-particles that can be used to improve mouthfeel and mask any bitter taste.’

Improving the understanding of solid state science

One of the companies looking deeper into solid state science with a view to helping pharmaceutical manufacturers is Johnson Matthey Fine Chemicals. In 2015, the company saw further expansion and rebranding as part of a multi-million pound investment across the business. The acquisition of Pharmaphix (Cambridge, UK), for example, has provided Johnson Matthey with a technology that fits well with the company’s strategy of offering enhanced customer development in solid state science.

Recently appointed Managing Director Antoine Bordet says: ‘It fitted into the technologies we wanted to acquire as it links into the development studies we do for medium to small businesses.’ He added: ‘It is becoming a necessity to understand those solid state characteristics of products and with it Johnson Matthey can add value to its API offering. Also the technology can help us to optimise our processes so that we can manufacture APIs more efficiently and make them more consistent and robust.’

Larger companies are more focused on cost than they used to be so getting efficient and sustainable processes is becoming more acute

In its catalyst business, the company is also gaining a better understanding of how a catalyst will work in a particular process and how this process can be scaled up and used in a production plant.

Productivity is an important driver here. ‘Biocatalysis is employed to save costs across the whole process, so even if the catalyst is more expensive it should save on the overall process by reducing the number of steps to end products, Bordet says, adding: ‘Larger companies are more focused on cost than they used to be so getting efficient and sustainable processes is becoming more acute. Big pharma is doing less of the research, more of it is being led by smaller biotech companies in the emerging markets and they really need to get those assets through the development system quickly. So we are really focused on how can we help those innovators to drive those products through.’

As a manufacturer of controlled substances, Johnson Matthey is also looking at ways of bringing in new technologies during the growing phase of plant materials that will give a higher content of specific narcotic chemicals to ultimately make the extraction process more efficient. ‘These products are derived around opiates and cannabinoids so we look to see where we can bring our chemistry strengths to bear,’ he says.


1. Report 431843 from

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