Supercritical fluids: realising potential

Strange things happen when chemists increase a substance’s pressure and temperature beyond its so-called ’critical point’. The resulting ’supercritical fluid’ has properties of both gases and liquids but is in fact neither. This unique form of matter is an excellent solvent. Supercritical fluids can be difficult to handle, but they have found numerous roles in experimental and commercial chemistry.

Supercritical fluids have emerged as the basis of a system that optimises the physiochemical properties of pharmaceutical powders. Commercially, the system reduces product development times, lowering manufacturing costs and aiding attempts to implement of green chemistry.

Almost 130 years ago, Irish chemist Thomas Andrews gave a lecture to the Royal Society, reporting for the first time that supercritical fluids dissolve some non-volatile solvents. Andrews described the ’critical point’ as the end of the vapour pressure curve in a phase diagram. At temperatures and pressures above this point, many gases ’dissolve’ certain solids and liquids.

By 1879, Hannay and Hogarth had characterised the behaviour of supercritical fluids in more detail. During another presentation to the Royal Society, they reported results from a series of experiments during which they dissolved solids with a fusing (melting) point much above the liquid solvent’s critical point. The solid remained diffused in the vapour even when they raised the temperature to some 55?C above the critical point and ’considerably’ expanded the volume.

Hannay and Hogarth reported that ’some solutions show curious reactions at the critical point’. Ferric chloride, for example, precipitates from ether just below the critical point but redissolves in the gas when heated by four or five degrees above the critical point. Suddenly reducing the pressure precipitates the solute. They reported that the precipitate from supercritical fluids ’is crystalline, and may be brought down as a "snow" in the gas, or on the glass as a "frost"’. Increasing the pressure redissolved the crystals.

Chemists continued to experiment with supercritical fluids for almost a century, although they remained something of a curiosity until the 1970s, when rising energy costs led chemists to consider supercritical fluids as a cheaper alternative to liquid extraction and distillation.

Today, supercritical fluids are employed commercially to decaffeinate coffee and tea as well as to purify essential oils and flavours from herbs and other natural products.

Natural supercritical fluids also exist. In Iceland, for example, a subterranean water reservoir that contacts magma some five kilometres below the surface forms supercritical steam and could offer a new geothermal power source. Supercritical fluids are also used to address some critical problems in pharmaceutical development.

A glance around any pharmacist’s shelves shows that modern medicines come in a range of formulations, including tablets, aerosols, capsules and suspensions. Drug delivery technology is becoming increasingly sophisticated with systems that can release a precise amount of medicine in a specific part of the gastrointestinal tract, or over a sustained period. More and more devices deliver inhaled drugs - not just for respiratory diseases, but also to circumvent first-pass metabolism, where a drug is removed by the liver before it has been used, or to overcome poor oral bioavailability.

Despite the diverse range of delivery systems, more than 80 per cent of pharmaceuticals are powders - usually crystalline - either in the final formulation or at some point during manufacture. The problems that this raises for pharmaceutical chemists prompted regulatory authorities to scrutinise crystallographic quality in unprecedented detail.

Firstly, the exact crystalline form can influence characteristics critical to formulation and manufacturing, such as dissolution, stability, flow properties and particle size. Secondly, advanced drug delivery systems require precisely defined particle size and properties to ensure, for example, optimal lung distribution or oral bioavailability. Thirdly, particle size can influence a product’s shelf live.

Unfortunately, conventional manufacturing means that chemists have little control over the powder’s physical form and conventional crystallisation can be associated with marked variations in quality. The powder may need additional drying, milling or micronisation to get it to the appropriate size. This could undermine its stability and shelf life. Further processing can influence the powder’s flow characteristics and complicate down-stream processing.

Many pharmaceutical processes can induce transformations between polymorphs. These different crystalline forms reflect alternative ways to pack molecules in a crystal and polymorphs may show markedly different properties, including rate of solution and melting point. As such, polymorphs can differ in stability and bioavailability.

Micronisation using fluid energy or jet milling generates particles that are between one and five micrometres in diameter and can penetrate deeply into the lung. By using these micronised particles, it is possible to optimise the deposition of anti-inflammatory drugs and bronchodilators used in asthma or chronic obstructive pulmonary disease.

But micronised particles can be highly charged. This undermines flow rates and makes it harder to make aerosolised and dry powder inhalers. Micronisation can also alter crystal structure, which in turn can undermine stability, partly by increasing susceptibility to moisture. Supercritical fluids offer a potential solution to these and other problems.

While supercritical fluids have found numerous commercial applications, several problems have hindered attempts to use the technique in pharmaceutical manufacturing. For example, many pharmaceuticals’ solubility in supercritical fluids is poor. In traditional systems supercritical fluids are bubbled or injected through a solution of the drug. This means that solvent extraction occurs during laminar flow, which can undermine purity and solvent recovery. If solvent extraction happens during turbulent flow instead, both purity and solvent recovery are improved.

Against this background, in the 1990s, UK company Bradford Particle Design (now Nektar) developed the Solution Enhanced Dispersion by Supercritical Fluids (SEDS) system to control powder formation from a diverse range of chemicals, including inorganic and organic substances, polymers, peptides and proteins.

SEDS allows simultaneous dispersion, solvent extraction and particle formation. This single step simplifies manufacturing, quality assurance and regulatory approval. The highly turbulent flow creates continuous and uniform crystallisation using carbon dioxide - which has relatively low critical temperature and pressure, is non-toxic, inexpensive and non-flammable. Changing the conditions makes it possible to control the size of the resulting particles.

The drug solution meets the supercritical carbon dioxide in the coaxial nozzle of the SEDS apparatus, producing a supersaturated solute. The turbulent, high-velocity flow speeds both mixing and particle formation. The supercritical carbon dioxide disperses and mixes the drug solution, acting as an anti-solvent at the same time. Decompression separates the supercritical fluid from the organic cosolvents, which can be recycled, and powders. The crystalline precipitate stays in the vessel. Because supercritical fluids are gases under ambient conditions, SEDS often removes the need for harvesting and drying.

SEDS offers a precision and consistency that is difficult to achieve with conventional pharmaceutical powder production processes. Technologies based on supercritical fluids help prevent batch variation, crystal damage, processing inefficiencies and out of specification products. SEDS produces free-flowing micrometre-sized particles that are not highly charged and are therefore less cohesive than conventionally milled powders.

Nektar has used SEDS to produce powders of numerous drugs, including nicotinic acid, paracetamol, budesonide, salbutamol sulfate, salmeterol xinafoate, fluticasone and terbutaline.

For instance, SEDS produces microfine crystals of salmeterol - a bronchodilator - that are between two and five ?m in diameter, the ideal size for lung delivery. By altering the operating conditions, SEDS can produce particles sized 2-17?m. Many pharmaceuticals are 0.1-10?m in diameter. Unlike other approaches, Nektar’s SEDS produced pure polymorphs of several chemicals, including terbutaline and salmeterol xinafoate. This polymorphic purity helps ensure stability and consistent bioavailability.

SEDS offers several commercial benefits. Firstly, it typically gives at least 95 per cent yield. Conventional multi-step manufacturing can waste up to 30 per cent of the drug. Secondly, SEDS manufactured powders are usually more stable, pure and consistent than powders made by conventional processes. This may translate, for example, into longer shelf life.

SEDS is an enclosed system. This vastly reduces risk of contamination, which can be a problem with some manufacturing processes, potentially making quality failures and product recalls less likely. As SEDS is a single-step, self-contained process, it tends to use less solvent than conventional approaches. The system also allows solvents to be recycled. As companies face increasing public and legislative pressure to be aware of their environmental impact, SEDS can help them strive towards ’green’ chemistry.

Nektar is proud of SEDS. Not least because it overcomes many of the limitations of conventional processing in producing consistent, pure and high-quality powders. But also because it has potential to reduce waste, extend shelf life, reduce the risk of product recalls, simplify manufacturing and avoid problems with solvents. More than 125 years after Andrews first characterised the critical point, supercritical fluids are set to realise their potential in pharmaceutical chemistry.

Peter York works at the Institute of Pharmaceutical Innovation, University of Bradford and Nektar Therapeutics

Further Reading

• T Andrews, Proc. Roy. Soc. 1875, 24, 455-63
• S Beach et al, Organic Process Research and Development 1999, 3, 370-6
• J B Hannay and J Hogarth, Proc. Roy. Soc. 1879, 29, 324-6
• P York, PSTT 1999, 2, 430-40