Enhancing Stability

There are many factors which effect drug stability (e.g. temperature, light, pH, oxidation etc.) and both chemical and physical stability are vital to ensuring that therapeutics can be manufactured, stored, transported and administered to patients without a loss of efficacy or safety.

Some pharmaceutical processing technologies expose drug substances to damaging environments, such as high temperatures, mechanical stress and shear forces, which can lead to chemical and physical degradation, and leave them susceptible to further instability.

Crystec’s mSAS® supercritical fluid (SCF) technology can be applied to a range of approaches to provide enhanced stability for small and large molecule therapeutics.

mSAS® strategies for enhancing the stability of pharmaceutical products

Highly crystalline material

mSAS® has the ability to produce highly crystalline material, and by tuning the precise crystallisation environment it is possible to screen for, and selectively generate, a preferred solid state form. This process allows strong selectivity of crystalline structure, typically resulting in material with very high solid-state purity. As a result, mSAS® material is generally more stable against solid-state transformation than material which has been produced through more conventional means, where localised areas of instability can seed conversion.

Low amorphous content

Amorphous content is a common feature in drug development and many pharmaceutical processing technologies are known to induce the formation of amorphous regions (e.g. through mechanical grinding or high temperature processing). Amorphous content can leave pharmaceutical products vulnerable to both physical and chemical degradation, often driven by uncontrolled crystallisation or increased affinity for moisture. Because mSAS® is a single step process combining crystal and particle engineering, highly crystalline powders can be generated with a targeted particle size, without the need for subsequent size reduction, resulting in inherently higher stability.

Eliminate residual solvent and impurities

Supercritical fluids have been used widely for extraction purposes for many decades. The unique and tuneable solubilisation properties of SCFs enable selective removal of certain components from complex mixtures. This provides a wide range of applications, from isolating active ingredients from plant extracts, to removing caffeine from coffee, and even in recycling components of electronic devices.

In mSAS® crystallisation, the SCF acts as a powerful anti-solvent, efficiently stripping solvent from an organic drug solution, while simultaneously extracting components with inherent solubility in the SCF. These properties can be exploited to precipitate pure drug particles with low levels of solvent and impurities, which could otherwise supress crystallisation and leave products susceptible to physical and chemical instability.

Further information about employing the solvent and impurity scavenging benefits mSAS® to optimising natural products can be found here.

Particles coated to protect against moisture

Where drug substances are hygroscopic, exhibiting a tendency to absorb moisture, eliminating exposure to water throughout the manufacture and supply chain can be a challenging but necessary step to avoid agglomeration and degradation. Despite innovation in packaging and the use of low humidity environments, formulation is often key to mitigating exposure and enabling commercialisation of such products.

Crystec routinely apply mSAS® technology to co-formulate Active Pharmaceutical Ingredients (APIs) with enhancing agents for a range of purposes (e.g. improving dissolution, absorption, dosing and stability). One such example includes the coformulation of a hygroscopic and strongly cohesive inhalation API with a regulatory approved excipient to protect against water absorption. Such an approach results in coated particles which remain stable, free flowing and aerosolisable throughout the lifetime of the product. This provides opportunities to reduce processing, packaging and supply costs, while ensuring delivery of a high quality and efficacious product to patients.

Ambient biotherapeutics

With an increasing number of biologically derived therapeutics (e.g. proteins, peptides) entering the market, a key barrier to development is ensuring adequate stability throughout manufacturing and supply chains. Distribution can often prove challenging due to low temperature storage conditions that are often required to prevent degradation. In many cases, water is removed from biotherapeutics in order to reduce cold chain requirements, but these processes often result in reduction in activity, reducing potency and potentially impacting safety.

Freeze drying (or lyophilisation) is frequently used to remove water and provide powders that can be reconstituted prior to administration. However, the shear forces and temperatures used in the system, as well as the long and complex cycle times, mean that fragile biomolecules are often damaged. mSAS® offers an attractive alternative, where low processing temperatures (close to body temperature), lack of shear forces and interfacial stresses, and short contact time, result in a relatively benign process whereby biomolecules can be precipitated with high levels of retained activity. mSAS® is a single step process that can incorporate additional agents where required, such as pH buffers and stabilising agents to further enhance stability post processing, and can also provide opportunities for alternative routes of delivery (e.g. dry powders for nasal or inhaled delivery).

Further information about mSAS® biomolecule processing can be found here.

Find Out More

Improving Dissolution

40% of marketed drugs and up to 90% of those in development exhibit poor solubility1. mSAS® provides different ways to address this challenge, including through increasing surface area, reducing agglomeration, new solid-state forms, co-crystals or stabilised amorphous forms of drug molecules.

Optimised Inhaled Therapies

mSAS® enables the design of drug particles of precise size and shape, that aerosolise even in patients who may struggle to breathe. As well as treating lung disease, inhaled therapies can be designed to enter the bloodstream, providing opportunities for fast onset and an alternative to painful injections.

Enhancing Stability

Chemical and physical stability is vital to ensure that therapeutics can be manufactured, stored, transported and administered to patients without a loss of efficacy or safety. mSAS® enables manufacture of highly pure, residue-free drug particles, capable of resisting moisture, and able to withstand higher temperatures.

Simplified Formulations

Formulation is often a complex, multi-step process, adding considerable time and cost to development. The mSAS® process involves a single step, and enables design of particles which contain all the components required for a medicine to perform, reducing the need for downstream processing.

Biomolecule Processing

Biotherapeutics such as peptides, proateins, antibodies and oligonucleotides are often delicate and easily damaged. mSAS® provides a gentle way to process biomolecules as free-flowing powders, retaining high levels of activity, reducing cold chain and enabling easier reconstitution.

Natural Products

Natural products are often highly complex and conventional approaches to their extraction, purification and formulation can be inefficient and often result in a poor-quality product. mSAS® simplifies production of natural products, allowing fine tuning of the components of a medicine and improvements in quality and consistency.

Green Manufacturing

Improvements in human health should not come at the cost to the planet, yet traditional approaches to medicines manufacturing carry a high environmental burden. mSAS® enables the production of medicines with lower waste, reduced emissions, using less solvent, and greatly improved energy efficiency.

Intellectual Property

Innovation in medicines development often requires robust protection of intellectual property (IP). The mSAS® process provides numerous opportunities to enhance IP, whether through novel solid-state forms, improved formulations or new routes of delivery.