Natural Products

Current techniques used to generate formulations of complex natural product mixtures are time consuming, complicated and often result in a low-quality product. Typically, numerous steps are involved, often including a combination of extraction, concentration of the extract by solvent evaporation, drying and finally milling to generate powders. These powders are then formulated in to the required dosage form, e.g. tablets, capsules and granules. In addition, the limited ability to control the quality and uniformity of the product can produce high levels of inconsistency between batches. The content of active constituents can also be greatly diminished due to complicated, high temperature processing steps.

Crystec’s mSAS® technology is a powerful tool which can facilitate the transition to a more uniform, regulatory acceptable product, providing an attractive alternative to conventional processing techniques.

mSAS® strategies for the development of natural products

Remove residual solvent and impurities

In mSAS® crystallisation, the supercritical fluid (SCF) acts as a powerful anti-solvent, efficiently stripping solvent from a drug/active in solution, while simultaneously extracting components with inherent solubility in the SCF. One of the key advantages of SCFs is the effect that relatively small changes in process conditions have on phase behaviour, meaning that a relatively small change in pressure, for instance, can have a significant impact on the dissolution properties of the SCF. As a result, iterative changes to the processing environment can be exploited to provide a high level of control over particle composition. This allows the ratio of components in complex mixtures, a common feature of natural products, to be tuned to achieve optimal levels of active components.

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

Benign process conditions

The most common choice of supercritical fluid employed by mSAS® is CO2. This is principally due to the relatively low critical temperature (the temperature above which supercritical behaviour can be exhibited) at 31°C. This means that mSAS® processing can be conducted at low temperatures, reducing the propensity for chemical degradation to occur. The mSAS® environment is also free from light and air, which in some case can cause chemical instability, and the lack of surface tension in the system means that sensitive components are not exposed to damaging shear forces.

Controlled particle formation

In addition to controlling the composition of natural products, mSAS® also allows a high degree of control over particle formation. Properties which are critical to product performance, such as particle size, shape and solid-state form can be targeted to meet a pre-determined Target Product Profile. By designing performance into particles, a diverse range of outcomes are achievable, from improved dissolution and enhanced stability, to enabling novel routes of administration (e.g. inhalation).

Dry, free flowing powders, suitable for complex mixtures

As described above, one of the benefits of using mSAS® technology is the rapid extraction of solvents and impurities from a complex mixture of components in a single step process. This rapid extraction combined with the high degree of precipitation control resulted in a highly uniform, free-flowing powder with low levels of residual solvent and high levels of active ingredient. The video below demonstrates the transition from a crude slurry to engineered mSAS® particles, in a single step.

Product consistency facilitates regulatory approval

Overall, an mSAS® approach allows a range of particle characteristics to be precisely targeted in a highly controlled and reproducible single-step process. By designing performance into particles, ensuring consistency of particle size, shape, solid-state form, and composition, as well as low levels of residual solvent (below ICH limits), between batches and across process scales, mSAS® can be readily scaled for commercial GMP manufacture, while ensuring that product quality and regulatory compliance is maintained.

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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.