- 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.
For pharmaceutical manufacturing, the Organic/Aqueous Tunable Solvents (OATS) are very promising. For example, many enzymatic transformations are inhibited by the limited solubility of most hydrocarbon substrates in aqueous enzymatic solutions. In order to overcome this limitation, we have incorporated a series of hydrophilic organic co-solvents (i.e.,THF, acetonitrile, dioxane) that enhance the solubility of very nonpolar organic compounds in aqueous enzymatic systems .
After the reaction has been performed in this mixed solvent, the application of moderate CO2 pressures (~10-20 bar) induces the separation of the organic co-solvent, now containing the hydrophobic product, from the aqueous enzymatic stream, which can then be reused. This technique represents a powerful opportunity to eliminate catalyst contamination of product streams and also recycle highly selective catalytic species. The OATS technique has been demonstrated in many other key reactions, such as the recovery of non-enzymatic aqueous catalysts .
In short, the door is now open for many novel methodologies that are especially applicable to the asymmetric synthesis common to much pharmaceutical production. Though they are a departure from current practice in pharmaceutical manufacturing, such processes have already been applied in a host of other applications, and in each case they give superior products and cost benefits.
|Figure 1. Illustration of Gas Anti-Solvent crystallization for pharmaceutical processing.|
|Figure 2. Comparison of structures of (a) carbonic acid; (b) methylcarbonic acid; (c) peroxycarbonic acid.|
|Figure 3. Alkylcarbonic acids are capable of protonating many molecules. Shown here is an example of the protonation of Reichardt’s betaine dye by addition of CO2 to methanol.|
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.