Tuning in to New Solvents

Tunable solvents, including supercritical fluids and ionic liquids, may not be in your stockroom — yet — but they offer significant environmental and manufacturing benefits.

By Charles A. Eckert, Charles L. Liotta, Christopher L. Kitchens and Jason P. Hallett, Georgia Institute of Technology

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BASF is already using ionic liquids on large-scale chemical processes as part of its Strategy 2015 sustainable manufacturing initiative.

The general public first heard about tunable solvents, although they didn’t know it, when supercritical CO2 (scCO2) was first used commercially in caffeine extraction. The food industry now routinely uses scCO2 and other supercritical fluids to extract valuable chemicals from plants [1], and the solvents are being applied in nutraceutical production.

Supercritical fluids are so named because they are in the “supercritical” state, above the critical temperature and pressure points at which vapor and liquid phases would be in equilibrium. They are part of a new class of “tunable” solvents, whose properties, including density, dielectric constant and solubility, can be easily varied with changes in pressure or other process conditions. The solvents can even “reverse” activity, and function as an acid and base, as needed, within the same synthesis.

Pharmaceutical manufacturers are focusing their evaluation of these new solvents in powder processes [2], which are used to make about 80% of pharmaceuticals on the market. Tunable solvents used in precipitation and collection have been shown to improve particle uniformity and shape. Eventually, however, the fluids could be used outside of powder processing, in virtually every avenue of pharmaceutical manufacturing as a medium for reactions, extractions and separations.

Tunable solvents require specialized and expensive equipment, so validation and other issues challenge their use in full-scale drug production today. However, the solvents offer a number of compelling long-term benefits; they are flexible, safe, inexpensive, inflammable and environmentally benign.

By selectively precipitating catalysts and products or reactants, they offer advantages in chiral drug synthesis and isolation, and chromatography. They also offer flexibility for synthesis and processing. For example, alcohols can be expanded with CO2 to form reversible alkylcarbonic acids, while CO2-expanded amines yield reversible alkylcarbamic acids, for clean, in-situ acid catalysis. These acid catalysts require no neutralization, eliminating disposal issues associated with salt waste generation.

Tunable solvents also offer environmental benefits. Consider phase transfer catalysis (PTC), which has long been used as a technique for the contact of hydrophobic and hydrophilic species and which accounts for more than $20 billion in annual production today [3]. Applying gaseous CO2 to post-reaction PTC mixtures can alter PTC partitioning by up to two orders of magnitude, representing a savings in washwater recovery of over 95% [4], and significant economic savings.

As the pharmaceutical industry moves to new and radically different forms of molecules and modes of delivery, the need for new processing and manufacturing techniques is growing at an exponential rate. Tunable fluids applications in pharmaceutical manufacturing will provide solvent media for synthesis as well as processing that meets GMP requirements and offers distinct advantages over conventional methods.

This article will examine the promise of tunable solvents, focusing on new synthesis routes, solvent types and advantages in heterogeneous catalytic processes. It will also highlight development projects that are now under way at leading pharmaceutical companies (see Going Green: The Spirit's Willing, But… below).

Pharmaceutical applications

The advantages of tunable fluid processing have been studied closely, yielding the following modified drug syntheses, each of which has its advantages and weaknesses:
  • Rapid Expansion of Supercritical Solution (RESS),
      in which a drug is dissolved in an SCF such as CO
2
      and then sprayed into a collection chamber. The solvent is then rapidly removed, resulting in well-defined, uniform drug particles. RESS is a simple and effective technique, but is restricted by the limited solubility of drugs in SCFs.


  • Gas Anti-Solvent (GAS)
      is another popular technique, shown in
Figure 1
      (
below
      ). In this case, a gas such as CO
2
      is added to an organic solution of a desired drug, resulting in the expansion of the organic solvent and the precipitation of uniform drug particles. The precipitation is easily tuned by adjusting temperature and CO
2
      pressure, allowing close control of particle size and morphology. GAS takes advantage of the organic solvent’s strength coupled with the tunable solvent expandability. However, it requires semi-batch operation.


  • Supercritical Anti-Solvent (SAS) and Solution Enhanced Dispersion by Supercritical fluids (SEDS)
    allow for continuous operation and control. In both of these processes, the drug solution is sprayed into the SCF or mixed with the SCF and sprayed into a collection vessel. Nozzle design and inlet stream flow rates can be adjusted to control the process while utilizing the solvent’s tunability.
Unconventional tunables

Conventional tunable solvents, specifically, supercritical fluids, have been shown to improve particle shape and uniformity, and to facilitate new drug delivery systems. But new opportunities are presenting themselves for other types of tunable solvents [5], specifically:
  • Gas eXpanded Liquids (GXLs),
      organic solvents mixed with carbon dioxide gas, which expands their volume by a factor of 10 or more. Nutraceuticals production has moved in the direction of GXLs, by using ethanol cosolvent as a polar modifier with scCO
2
      . This results in a solvent medium that can combine synthesis and product recovery in a simplified and efficient “one pot” system.

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