A reflux in 12 molar HCl
Carefully watched for a frothing,
Painstakingly drained from the reactor,
To strip down and scrub off that gross thing.
My bosses, I tried please believe me,
I’m doing my best as you insist,
I’m ashamed of the material I burned through,
I’m ashamed of the deadlines I missed.
But if you could just see the beauty,
These things I could never describe,
These pleasures of process perfection,
This is my one lucky prize.
refrain: Product isolation…
My apologies to Joy Division
I have been making water-soluble polymers with biomedical applications for the last 16 months and it is quite satisfying: Our macromolecules are usually well behaved – they extract into organic phase. They precipitate as a snow-white fluffy crystalline solid, on a kilo scale. They even have beautiful NMR spectra. Unfortunately, such was not the case with the frothy mixture in the picture. I had to isolate the material from a solution in concentrated HCl (0.3L), with extra sludge of inorganic salts and assorted gunk that included gram quantity of dimethyl sulfide.
The usual process would be: dilute, filtrer, dialyze. But dialysis is a slow and rather frustrating business and we don’t even have bags giant enough for removing few mols of salts and HCl. So I was delighted to learn that tangential flow filtration is a turbo-alternative to a dialysis – instead of steeping a swollen dialysis sausage bag (that can burst overnight) for days and waiting for the diffusion to run its course, the tangential flow filtration setup visibly labors for you: the pump pushes the mixture against a semi-permeable membrane, water and other small molecular weight material leak out, the macromolecular fraction stays in. The purification is done in few hours.
The peristaltic pump in the picture circulates the crude mixture at moderate pressure and high flow rate (20 psi, 1.7 L/min) from the beaker to bottom of the column; the stuff that flows out at the top is fed back into the beaker in a closed loop. The column consist of a bunch of spaghettini-like capillaries that are coated with a semipermeable membrane. The spaghettini are housed in a plastic pipe casing. It is inside these capillaries that the mixture rushes through at high speed over and over again – water and small molecule material that leaks out through the walls of the capillaries collect in the casing and flow into waste (the sidearm and the transparent bottle). One has to keep adding water into the beaker quite often because with a good column + pumping rate/pressure the mixture gets concentrated rather quickly.
The time to end the purification is when chromatography (GPC) can no longer detect small-molecular weight impurities. Of course with a whopping excess of HCl at the beginning, one doesn’t need to run GPC to confirm that all low-molecular weight material is gone – a pH paper will tell you that. (A sniff test for dimethylsulfide presence is also fast … and revolting…)
Five months on – and there is no looking back. With potassium metal freshly cut, with the glassware, solvent and monomer lines pumped down overnight to 20 mTorr, ready or not, macromolecules, here I come.
Credit: Jirí Slíva
I got an e-mail from a patent litigation attorney representing a major pharma company, a company that puts beautiful ads on TV almost every night and whose name rhymes with “Mergers and Massacres”. Turns out, they have a problem with one of their drugs: the drug is selling just over a billion a year and a key patent covering this drug is being challenged by two generic companies. And since I am on the patent (with ten other authors), the company lawyers were eager to prepare me in case I get subpoenaed by the other companies challenging the patent. They offered a free legal representation during the hearings and they proposed to pay me as a consultant (“at my usual rate”).
They mentioned that they are trying to piece together the exact timeline of the project – I suppose questions like who proposed/synthesized what and when are important to the defense. And they are having problems: just one person from the original team is currently employed with the company.
This does not surprise me. I was laid off like everyone else when our research site was closed. (Also, our chemistry director was forced out just before the site closure and I heard that the company has brought some heavy investigation down on him). In the end, only a handful of employees got re-hired by our company and moved to other research sites. I suppose tracking down the patent inventors and interviewing them is somewhat difficult now – and it is possible that not everyone wants to be interviewed…
I did not call the company’s patent lawyers as they urged me to but we had a cordial e-mail exchange and I shared some of the impressions and experiences that I had while being (briefly) a part of their company – from the time they acquired us until they shut us down. I also reminisced on the class-action lawsuit that my ex-colleagues brought against the company because the company tried to cut their severance payments after the layoff. (The class action suit was settled out of court when the company paid in full – about 2 years late.)
I also reached out to the two generic companies involved in this litigation and let them know about this approach from my former employer; I offered to answer questions about the history of this drug discovery and I gave them names of the few key inventors on the patent who could perhaps assist them more than I can. Then I wrote back to the legal team of my former employer to inform them that I contacted the other two companies involved in the litigation. I explained that I do not want money but maybe they could re-evaluate how they are going to treat the R&D inventors in the future. You know, in case they need them again.
Today is my first day with a small privately held biotech company that is developing self-assembling polymers for targeted drug delivery. The group and the projects are awesome – and as much as I am excited about the research and the company, for obvious reasons I shouldn’t be writing about it. So there will be nothing new to add here. This is it – thank you for visiting!
I would like to direct the readers here to the excellent project-and-career story from Bruce Maryanoff in the most recent J. Med. Chem ASAP. It is very illuminating on how the drug discovery and development works, and it describes in some detail what a bright chemist can hope to achieve in this profession -with the necessary motivation and a decent employer (and tremendous amounts of luck).
It is also an illuminating story on how the process does not work. For example, the currently most popular, target-driven rational-design-based approach can be pretty futile in CNS drug projects . The author also suggests that the management mantra about focusing on the discovery of the next “blockbuster drug” actually bankrupts the industry – financially and scientifically; his drug Topiramate (which has been making 2 billions a year for the company) would have not been discovered or developed under the management methods currently prevalent in the industry. Few things stand out: 1) It seems that having a blind luck and testing the compounds in a realistic animal model is more important than having a correct mechanistic understanding how the drug candidate actually works. 2) Few independent-minded individuals in their pharmacology and chemistry have made a good use of their lucky break. They stubbornly kept the research program going – even as their managers were lukewarm and would not support the compound development for a long time. It also goes to the credit of the management that allowed their researchers to pursue this as their hobby. The story shows that the progress in pharma research does not really happen by imposing some management-theory-derived reporting structure on the research department, by drafting the flowcharts and aligning the teams. For medchem research to succeed, the projects should be allowed to self-organize around the bright individuals rather than being planed out from top down, with red tape and micromanagement.
In this context it is entertaining to read rather disingenuous remarks made by the Merck chief strategy officer Merv Turner at the pharma management conference. He explained that they are currently sacking lots of people in research because “Seventy-five cents of every dollar we spend on R&D goes to fund failure” and “the future results must come at a lower cost”.
The actual drug discovery cost makes only few percent of the final drug development cost. By far the most expensive part is the clinical trials and namelly the late-stage clinical trials. What the Merck management poseurs do not tell in public is that it was the Merck top management decisions that cemented their company’s commitment to these “the next blockbuster” projects – which eventually led to a string of stunningly expensive late-stage failures. When the top executives receive massive stock option bonuses, they become mercenaries of the stock prices. Their wishful thinking baloney percolates from top down through the management layers, etc.
There are many parallels between the state of pharma industry and the recent financial sector collapse, and it is always the executives who run their companies to the ground that are rewarding themselves most obscenely. Remember this whenever the pharma companies claim that the freedom to price their drugs is essential for the innovation.
Update: Here are additional two great articles from Bruce Maryanoff on the subject