kilomentor

An article entitled “Pharmaceutical Manufacturing Goes Green” appeared in the recent March 1 2008 issue of Genetic Engineering & biotechnology News (GEN). It was stated that “advances in enzymatic catalysis of synthetic reactions, solvent substitutions, and recycling of by-products and waste may not only reduce the environmental impact of pharmaceutical processes but, with the potential to have a positive effect upon synthetic efficiency and overall productivity, can also decrease waste streams, lessen energy input, and minimize the need for hazardous reagents”.

It is only human nature that academic scientists who have hitched their career aspirations to green chemistry will advocate the greenness of a process as the essential basis for process evaluation; but realistically all that can be hoped for is that industrial process chemists will increasingly include green technology and its potential advantages to the corporation among all the basis upon which a preferred process is selected. There is, however, good reason to expect that this will happen.

As the GEN article notes realistically, ‘This may be a particular challenge in organic chemistry, in which many of the classical chemical reactions have been in use for decades to produce small molecule drugs”.

The industry does have an advantage in this re-education program since at this time there is a particularly rapid turnover of chemists because so many of them are reaching retirement age. The ranks must necessarily be quickly filled up with younger more environmental conscious and hopefully trained in universities very aware of the need for green chemistry.

Because of the patent laws and health regulations in the main, world pharmaceutical markets, the emphasis in the pharmaceutical industry must be on the synthetic route which is overall the most rapid, inexpensive, scaleable and rugged. The high risk of failure and the cost of even a successful development necessitate that pharmaceutical companies maximize the number of years that they have a monopoly in the marketplace before patent expiry. This forces these organizations towards using the first dependable, economic and scaleable process that will deliver a product that can satisfy the health regulatory authorities. Once product from this early process has been used in successful clinical trials, there are bureaucratic hurdles created that make it very expensive to “green up” steps of the process or to replace whole portions of the process with ecologically more friendly alternatives. Pharmaceutical companies will never introduce process retrofits that require the repeating of clinical trials because these human tests are the most expensive part of drug development.

Green chemistry will typically be unsuccessful as a retrofit strategy for old products but they can be immediately introduced into all new processes. All that is required is awareness that it is wanted. When a process step is optimized, the entire reaction space is not explored. Decisions are made at the beginning of the project concerning the values of discrete variables (variables that cannot change continuously like time or temperature) that will be included in the optimization study. An example is useful to understand this. Suppose in a process step an alcohol is converted to an acetate ester. Only a few acetylating agents will be chosen to examine: say acetic anhydride and acetyl chloride. If transesterification with ethyl acetate or isopropenyl acetate is not included at this stage, no transesterification process has any chance of becoming the optimized method. To exemplify again, an auxiliary base may be include in the optimization study and the candidates will be preselected: say pyridine, and triethylamine. If a recyclable base such as polyvinylpyridine is not included among these discrete variables in the study, it has no chance of becoming part of the optimized process step. If chloroform or methylene chloride are included among the discrete solvents selected for the optimization, they have a good chance of becoming part of the optimized process step. If the choices at the outset for building the process step are greener, the resulting optimized step must be greener. It is only when this ‘greener’ study cannot come up with an adequate process step that chemists may need to fall back on the traditional ungreen methodologies.

In the GEN report, David Constable of GlaxoSmithKline teaches that the cost of new solvent, combined with the cost of disposal of both the used solvent and the water contaminated with organic solvent constitute about 75-80% of the environmental impact and energy use in the life cycle of a pharmaceutical compound. If Kilomentor translates this into actionable terms, it means: learn the effect the solvent/substrate ratio upon yield and purity during process optimization.

The selection of the reagents, catalysts and solvents to be tested in the optimization of new process steps is going to be done within industry. The work is being performed on drug intermediates that are secret at the time the work is going on. Where academia can contribute to the green revolution is to provide a literature, which suggests green alternatives that industrial project manager can use in their optimization studies. Publish a more atom economic acetylation. Publish and popularize a readily recyclable trap for hydrogen chloride gas to replace triethylamine. Put it in your text books. Teach it in your lectures. Make it top of mind.

The GEN article reported that David Constable of GlaxoSmithKline iinformed a conference that in the past five years his company had achieved a 50% per kg API reduction in use of methylene chloride for final processing, where it had been replaced with either methyl isobutyl ketone or ethyl acetate. He also reported a 95% decline in DMF use.

The GEN article also mentions the solvent tetrahydrofuran as a solvent of concern to EPA for emission of toxins to air and water. Tetrahydrofuran is an important solvent for organometallic reagents and 2-methyltetrahydrofuran appears to be a good replacement. This needs to be made more widely known. 2-methyltetrahydrofuran is not completely miscible with water and so can be recovered more easily.

Atom economy is being popularized as an important aspect of green chemistry. Atom economy measures the amount of a reagent that gets incorporated into the final product versus the portion that goes into waste. For example in making an acetate product from an alcohol using Ac-OAc, the Ac goes to make the acetate product and the OAc goes into waste. Using AcCl, the Ac goes into product, the Cl goes into waste. The goal of atom economy is to reduce the percentage weight that goes into waste for any reagent.

It is important for process chemists to understand the concept of atom economy but Kilomentor’s assessment is that the idea is overhyped. Reagents typically contribute very little to the waste burden compared to solvents, and reagents are very much more likely to be critical to the particular reactivity of a substrate because the reagent is a very important part of the activated complex for the reaction transition state. The result is likely to be that a small positive influence of reagent structure is going to be difficult to counterbalance by arguments about relative atom economy. If a less atom efficient reagent gives a more cost effective process, the latter will win out.

Neal Anderson of Anderson’s Process Solutions identifies oxidation/reduction reactions as among the least atom economic which is rather automatic given that most oxidations or reductions only add or remove a couple of hydrogens. Kilomentor has already provided a blog discussing the more promising oxidation technologies, including a method using only catalytic amounts of chromium. Anderson’s good suggestion to design processes avoiding unnecessary changes in oxidation state is a worthy repetition of what he taught in his superb book, Practical Process Research & Development, Academic Press. , This book is still the best process chemistry book available.