mSAS® Technology

The Crystec team have pioneered the development of mSAS®, a modified SAS process. This unique, multiple award winning platform focuses on ensuring that the process used to generate crystals and particles is thermodynamically stable and scalable.

What is mSAS® Technology?

The SAS in mSAS® stands for Supercritical Anti-Solvent. Essentially this means that a supercritical fluid, typically carbon dioxide due to its low critical point conditions and attractive physical properties, is used to remove solvent rapidly from a drug solution, allowing the drug to precipitate as dry particles. SAS itself has many advantages, particularly in its ability to crystallise drug molecules and remove solvent such that only parts per million can remain in the final product. However conventional SAS approaches have some limitations. Often these processes are unstable, difficult to scale, and nozzles are prone to blockage.

The Crystec team have pioneered the development of mSAS®, a modified SAS process. This unique platform focuses on ensuring that the process used to generate crystals and particles is thermodynamically stable and scalable. The Crystec team have created nozzle designs and configurations which are maintained from the first small-scale research experiments through to commercial GMP scale. The nozzle and vessel assembly encourages ordered crystallisation and particle growth and is not prone to blockage. Generally, it is possible to tune the size of particles from 1 to 25 micron, achieving a tight size distribution.

Crystec’s mSAS® process also allows for the incorporation of processing agents into the system, which can be used to favourably manipulate nucleation, particle growth, crystallinity and habit. Furthermore, a second drug (or drugs), functional excipients or additives are able to be introduced into the precipitation chamber, allowing for the production of composite particles of excellent content uniformity. This effectively enables ‘in-particle design®’ as a single step operation to produce formulated particles enabling product features such as controlled release, taste masking and combination therapy, as well as enhanced bioavailability. Once optimised, the mSAS® process typically achieves yields in excess of 95%.

Crystec’s mSAS® process is proprietary and is generally licensed for use on a specific product basis.

How does mSAS® Compare?


As with micronisation (milling) mSAS® allows the tuning of mean particle size. However, mSAS® particles typically have a much tighter size distribution than equivalent particles manufactured using micronisation.

As our mSAS® process involves a ‘bottom-up’ precipitation approach, rather than a ‘top down’ size reduction approach, our particles are not mechanically damaged. In addition, they typically have much smoother surfaces, without the unstable amorphous content and the high levels of charge generally seen with micronised product. mSAS® products are highly crystalline and often more chemically stable by comparison.

Spray Drying

Whilst there have been notable advances in spray drying systems in recent years, the intrinsic nature of the spray drying process is such that material generated is frequently amorphous, whereas mSAS® material is generally crystalline (unless amorphous material is specifically required).

Amorphous material can cause concerns regarding stability and generally involves a more complex regulatory package. Typically spray drying processes are not as effective as the mSAS® process at removing solvent requiring longer drying times which can lead to phase separation for multi-component formulations. Spray drying also routinely involves higher drying temperatures which can be damaging to sensitive molecules.


Sono-crystallisation is a multi-step process, converting product from the amorphous to the crystalline state. The process generates intense energy which can be damaging (hotspots, degradation) to sensitive molecules.

By contrast mSAS® is a single-stage, rapid and more easily controlled process, carried out at moderate temperatures (typically 40-80⁰C) where the default state of material generated is highly crystalline.


The mSAS® process is a substantially faster process than lyophilisation, a widely used drying operation for biomolecules. Typically dry mSAS® particles are formed in milliseconds or microseconds. Depending on the material used, lyophilisation can take many hours, and often the residual solvent levels remain high.

The duration of lyophilisation provides the opportunity for further reaction, contamination or changes in solid state of the material being dried. The resulting material is often agglomerated or as a cake, which can cause problems with reconstitution.

Advantages of mSAS® Technology

Crystec’s mSAS® technology compared
to conventional processing methods

mSAS® – modified Supercritical Anti-Solvent technology
Hot melt extrusion – mixture of drug and polymer (* consequence of subsequent milling)
Lyophilisation – sublimation process of iced solutions
Spray drying – typically an aqueous system using elevated temperatures
Micronisation – conventional crystallisation followed by mechanical size reduction (e.g. milling)

Supercritical Fluids

General Principles

Although discovered over 120 years ago, the potential of supercritical fluid (SCF) technologies have only been partially realised for the controlled formation of particulates over the last decade. Whilst the SCF technologies have been established at large scale operations for other industrial applications, including controlled reactions for fine and speciality chemicals and extraction processes, securing confidence and experience with pilot and large scale processing, the great potential of SCF methods for meeting ever increasing demands of particulate properties for medicinal and health care products remains relatively untapped.

Essentially the formation of particles by SCF processing involves using a supercritical fluid either as a solvent or an antisolvent under supercritical fluid conditions of temperature and pressure. In most cases for pharmaceuticals, supercritical (SC) carbon dioxide is used, and as most therapeutic agents have very low solubility in this fluid, the antisolvent option is preferred, with this SCF having unique properties of liquid-like solvent power combined with gas-like transport properties. However, there is currently an inhalable monohydrate molecule in late stage clinical trials, which two members of the Crystec team had a lead role in developing.

Supercritical Carbon Dioxide

A fluid is defined as supercritical when its temperature and pressure exceed critical values (Tc and Pc respectively). In the supercritical domain, the SCF increases in density as the pressure is raised whilst other physical properties, including diffusivity, change but remain gas-like.

For the pharmaceutical and health care industries SC carbon dioxide is particularly attractive, since temperature and pressure values at its critical point are relatively mild and readily attained (Tc = 31.5C; Pc = 75.8 bar) and has GRAS (Generally Regarded as Safe) status at regulatory agencies. Additionally, SC carbon dioxide is readily available in pure form, inexpensive, non-flammable and, unlike many organic solvents used in large quantities for preparing drug particles, is environmentally acceptable, can be recycled during processing, and can be readily disposed. Other attractive features of SC carbon dioxide include its non-toxicity, does not cause oxidation and its solvation properties can be customised by the addition of co-solvents.

Antisolvent SCF Based Particle Formation

The basic process involves preparing a solution of the therapeutic agent of interest in a suitable solvent, such as ethanol or acetone, and introducing this solution to an SCF environment, typically SC carbon dioxide, in a pressure vessel.

With the aid of atomisation of both fluids using a proprietary nozzle arrangement, rapid extraction of the solvent into the SCF occurs creating a high level of supersaturation of the material of interest in the diminishing level of solvent causing rapid precipitation of solid particles. As most common solvents are completely miscible with SC carbon dioxide, any remaining solvent is quickly extracted into the SCF stream, to produce fine, dry particulate products The product is retained in the pressure vessel and the SC solution (now SC carbon dioxide and solvent) passes out of the vessel. Solvent recovery can be implemented (by returning the SC carbon dioxide to a gaseous state) and the now virtually solvent free carbon dioxide gas can be recycled.

Particle Characteristics

It has been recognised that a particular attractive feature of the ‘one step’, totally enclosed particle formation process, delivering dry particles, is the generation of well controlled particulate products with well defined physical, chemical, structural and surface characteristics.

In many cases, directed changes in these characteristics can be achieved by modifying the processing conditions and environment, such as temperature or pressure and fluid flow. Typically, micron sized particles with well defined crystalline morphology are produced, with minimal residual solvents. Opportunities also exist for co-introduction of regulatory approved formulation excipients or other small molecules e.g. antioxidants to yield composite particulates with uniform drug content.

An additional attractive feature for pharmaceuticals is the impressive inter- and intra-batch consistency of product which can be achieved when processing with SCFs.

Scaled Equipment & GMP Processing

The operation of scaled-up equipment, operating under GMP conditions for SCF processes, has been demonstrated. Furthermore, staff at Crystec have experience with international tech-transfer, with a plant used for production of material for clinical studies.

Pharmaceutical Applications

With this versatile platform technology, a range of applications for pharmaceutical and biopharmaceutical materials have been reported. Some of the challenging areas of crystal engineering and particle design for therapeutic agents which have been addressed by SCF processing are listed below: