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Improving Dissolution

Poor aqueous solubility is a recurring and increasing challenge for drug developers. With 40% of marketed drugs and up to 90% of those in development exhibiting poor solubility(1), finding solutions to overcome this challenge and increasing the bioavailability of compounds is as important now as it ever has been.

Crystec have experience in overcoming solubility challenges across a range of molecule classes (small and large molecules, natural products) and routes of administration (e.g. oral, inhaled, injectable). Crystec’s mSAS® (modified Supercritical Anti-Solvent) platform enables a range of strategies to be implemented, in isolation or in parallel, to improve rates of dissolution.

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mSAS® strategies for addressing poor drug solubility

Novel solid state forms

Polymorphic forms differ in internal structure (solid state) and can exhibit changes in packing, kinetics, mechanical, spectroscopic, surface and thermodynamic properties. Each of these dimensions can greatly influence the bioavailability of the API, and it is often possible to selectively generate solid-state forms which are more readily dissolved than the ‘stable’ form. Crystec’s mSAS® technology is a highly effective tool in isolating known ‘stable’ and metastable polymorphs, as well as in identifying polymorphic forms unique to the high-pressure SCF environment. As such, mSAS® is often used as an enhanced polymorph screening technique for both new chemical entities and currently marketed APIs, not only to optimise performance but also to secure new intellectual property (IP) positions and ensure robust IP protection.

Because mSAS® is a controlled ‘bottom-up’ precipitation process, particles are highly crystalline and do not exhibit amorphous regions that are often created as a result of conventional size reductions techniques (e.g. milling). As such, mSAS® metastable polymorphs tend to exhibit a high degree of stability, even under accelerated stability conditions.

Further information about mSAS® solid-state screening can be found here.

Particle size and surface area

It is known that increasing surface area through decreased particle size is an effective way to improve rates of dissolution. While mean particle size is important to enable rapid dissolution, so too is particle size distribution (PSD) as larger particles may not dissolve sufficiently, reducing overall bioavailability. Crystec’s mSAS® technology typically generates particles with a targeted size, often in the low micron range, with a very high level of control over PSD. Data shown below represent mSAS® particles with D90 = 3.67μm, with a narrow PSD reproducibly generated (n=10).

Manipulating particle shape

In addition to particle size, particle shape can also significantly influence surface area, resulting in improved dissolution performance. For example, mSAS® has been applied to produce ‘platy’ particles which, in addition to tuning particle size, enabled surface area to be maximised. In doing so, it is possible to substantially increase dissolution compared to conventionally micronised products. Furthermore, because mSAS® particles are precipitated directly from solution, they have smooth, low energy surfaces that are less prone to agglomeration than micronised material. This reduction in agglomeration can increase the apparent surface area, allowing improved dissolution of an API by the surrounding medium.

Scalable co-crystals

Co-crystallisation is an increasing area of interest in the pharmaceutical industry, offering the potential for improved product performance in areas such as enhanced solubility, dissolution rate and bioavailability, as well as additional benefits such as improved compressibility and stability.

For ‘standard’ co-crystallisation approaches, scalability remains challenging. Solid state grinding is often used for co-crystal screening at laboratory scale, where mechanical agitation is applied to induce a transformation from a physical mixture into a co-crystal. In addition to poor consistency on scale-up, potential drawbacks with this method include instability to mechanical/thermal stress. By contrast, the mSAS® platform is a thermodynamically stable, single-step process and is a fully scalable approach to generating co-crystals. The scavenging power of the supercritical CO2 enables removal of impurities and solvents to trace levels, which greatly improves the potential for co-crystallisation. It is also possible using mSAS® to isolate different polymorphic Forms of the co-crystal, providing additional opportunities to tune the pharmacokinetic properties.

Further information about mSAS® co-crystals can be found here.

Active-enhancer composites

Applying mSAS® to generate composite particles containing API and enhancing agents (e.g. surfactants/wetting agents, sugars and polymers) has been shown to substantially increase dissolution rates of poorly soluble products. Unlike physical mixtures generated through blending, mSAS® enables the generation of composites with a uniform mixture of API and enhancing agent distributed throughout each particle. This intimate association of components can allow efficient reduction in the surface tension between API molecules and aqueous media, further enhancing dissolution. A major strength of the mSAS® platform is in generation of these ‘intimately mixed’ composite particles, using a commercially scalable process.

Stabilised amorphous particles

Amorphous formulations are routinely explored as a means to overcome poor aqueous solubility. However, with conventional processes, this is often not a preferred means of development given frequently encountered stability issues. The mSAS® process exploits the benefits of supercritical CO2 to generate powders with low levels of residual solvent and impurities, resulting in amorphous product with intrinsically higher stability. Where necessary, amorphous particles can be co-formulated with regulatory acceptable excipients (e.g. a polymer or sugar) to further improve stability, or to modify drug release profiles.

A Crystec case study demonstrating this approach can be found here.

References:

1. Kalepua. S, Nekkantib. V, Acta Pharm Sin B. 2015 Sep; 5(5): 442–453

  • Novel solid state forms
  • Particle size and surface area
  • Manipulating particle shape
  • Scalable co-crystals
  • Active-enhancer composites
  • Stabilised amorphous particles

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Improving Dissolution

40% of marketed drugs and up to 90% of those in development exhibit poor solubility. 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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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