- Rapid Expansion of Supercritical Solution (RESS),
- in which a drug is dissolved in an SCF such as CO
- 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
- ). In this case, a gas such as CO
- 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
- 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.
- 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
- . This results in a solvent medium that can combine synthesis and product recovery in a simplified and efficient “one pot” system.
- Near-critical Water (NCW),
- which offers organic solubilities and the potential for reversible acid/base catalysis.
- Organic/Aqueous Tunable Solvents (OATS),
- or water-soluble catalysts (including both aqueous organometallic complexes and enzymatic biocatalysts) that can perform difficult transformations on highly hydrophobic substrates.
- Miscible water/organic systems,
- where a catalyst is modified for aqueous solubility;
- Miscible poly(ethylene glycol)/organic systems,
- where a catalyst is modified for PEG solubility;
- Immiscible fluorous/organic liquid/liquid or solid/liquid systems,
- where the catalyst is modified for fluorous solubility;
- Immiscible water/organic systems
- involving phase transfer catalysts.
We know the party line on green chemistry: renewable reagents and cleaner processes lead to reduced environmental burden. But what do risk-phobic pharmaceutical companies really hope to gain from alternative solvents and processing?
“It depends on whom you ask,” says David J.C. Constable, Ph.D., team leader at GlaxoSmithKline’s (King of Prussia, Pa.) Environment, Health and Safety department. “Going green has been shown over and over again to save money. I have stacks of literature about this.”
Early on, during GSK’s assessment of what constitutes green and what does not, the company evaluated “an enormous number” of chemistries and chemical process technologies and published its results widely. But even with senior management’s blessing, adopting green chemistry is anything but a walk in the park. There are the usual objections of loss of time, regulatory hurdles, revalidation, and the “if it ain’t broke don’t fix it” mentality.
It’s not that much easier during early R&D, either. Not only do preclinical and clinical projects leave little time for chemical or process development, but many synthetic organic chemists are reluctant to try new syntheses and processes. “There is a need for greater collegial collaboration between the chemist, chemical engineer and biotechnologist,” Constable says.
Constable also believes the regulatory trajectory of new chemical entities severely inhibits process innovation. “FDA's approach to marrying process to product, as opposed to just a rigorous product specification, locks bad processes in place,” he says. “It is enormously difficult and expensive to change.”
The more far-out the change, the less likely it will be taken seriously. For example, ionic liquids are a hot topic in green industrial chemistry, but have received scant attention from pharmaceutical chemists (no less a change agent than Constable described GSK’s forays into ionic liquids as “unproductive”).
Ionic liquids are organic salts formed from an almost infinite combination of imidazolium or pyridinium cations, and select anions, mixed in any quantity. Ionic liquids have no measurable vapor pressure and are nonflammable, so they are potential substitutes for volatile organic solvents. At the same time, they dissolve almost any organic compound and catalyze reactions, thereby serving as agents of process intensification.
What more could a pharmaceutical chemist ask for?
According to a 2004 Chemical Week article, Novartis (Basel, Switzerland) has replaced six chemical steps in an established process with a two-step Friedel-Crafts alkylation in an ionic liquid. Not only is the process run at pilot scale, but the use of ionic liquids was deemed patentable. Other major manufacturers are also investigating ionic liquids, according to chemical suppliers quoted in the article.
K.R. Seddon, Ph.D., chair of inorganic chemistry at Queen's University (Belfast, Northern Ireland), a leading authority on ionic liquids, sees “no great obstacles” to adopting liquids in drug-making.
He dismisses the notion that these solvents are toxic. “The knock on ionic liquids is more a result of image than of fact. Ionic liquids consist of mostly simple ions, many of which have already been designated as safe for ingestion.”
BASF (Florham Park, N.J.) is already using ionic liquids on large-scale chemical processes as part of its Strategy 2015 sustainable manufacturing initiative. The company’s BASIL (biphasic acid scavenging using ionic liquids) process is applicable to about one-third of all industrial chemical processes that require acid scavenging.
Normally, acidic by-products are scavenged with amines, which results in viscous, white slurries that are difficult to remove from the product. BASF’s work-around uses methyl imidazole, whose hydrochloride salt happens to be an easily-removable ionic liquid. According to Calvin J. Emanuel, Ph.D., manager of new business development, benefits include easier product isolation, higher yield, and an 80,000-fold improvement in operating efficiency (you read that right). “Without all those solvents around, the process requires less energy to overcome heat transfer issues,” he explains. After the reaction, the ionic liquid is converted back to imidazole and reused.
BASF sees ionic liquids as more than simple solvents. “Calling them solvents doesn’t do them justice,” Emanuel says. “It’s impossible to compare the utility of a simple solvent like THF with ionic liquids.” Prof. Seddon agrees. In his estimation, ionic liquids’ true benefit is their ability to provide greater selectivity and higher yield than traditional solvents.
Since BASIL was introduced in 2002, chemical companies have used it in production of alkoxyphenylphosphines on a multiton scale. An “important” pharmaceutical industry customer has also licensed the process, says William Pagano, a BASF spokesman. BASIL’s potential applications include chlorinations by nucleophilic HCL, azeotropic distillations, and extractions. In addition to using ionic liquids, BASF offers a broad portfolio of them in bulk quantities through its BASIONICS product line. Investigators can purchase development and laboratory quantities through Sigma-Aldrich.
Dr. Jason P. Hallett is a Research Engineer in the Eckert-Liotta Joint Research Group at Georgia Institute of Technology. He received a B.S. in Chemical Engineering from the University of Maine and a Ph.D. in Chemical Engineering from Georgia Institute of Technology, where he worked on novel methods for homogeneous catalyst recycle.References
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