In the mid 1990’s I had the good fortune to do a 1-year sabbatical replacement teaching gig at Ft Lewis College in Durango, Colorado. Of the several colleges in which I was lucky enough to be a faculty member, this school was absolutely the best. The chemistry department had a vitality that I had not experienced elsewhere, and sadly, would not be fortunate enough to repeat.

From my office high up on the mesa next to town I could hear the whistle of the steam locomotives of the Durango-Silverton Narrow Gauge Railroad. On friday afternoons a campus Native American group would sit around a single drum outside of Berndt Hall, each striking a hypnotic beat on the preserved skin while chanting and singing in the Ute language. While they were chanting the steam locomotives in the town below would blow their whistles, announcing their arrival for the tourists. The sound of it was an otherworldly experience I have not forgotten.

A prof I got to know at Ft Lewis, Dr. Irwin “Ike” Klundt, was a retired VP from Aldrich. He was to become a mentor and friend. It turns out that Ike was the inventor of the coffee pot kugelrohr that Aldrich offered in its catalog. West Bend, the appliance company, had a coffee pot manufacturing operation in Milwaukee, WI, where Aldrich was then headquartered. Ike learned that they would always have a few off-spec units coming from their mfg line, so he arranged to snag a few of these units. He recognized that these pots were built to contain heat and would be dandy ovens for his application. The large metal coffee pots were delivered to a one man shop somewhere in Milwaukee where the they would be converted to ovens for the Aldrich kugelrohr still, or “bulb-tube” short path distillation device to be more precise.

To provide agitation around the axis of the distillation train, an automotive pneumatic windshield wiper motor provided the needed reciprocating motion. It had a built-in tube that would serve to couple the bulb tube train to the vacuum line. The reciprocating motion of the motor removed the need for a sealed bearing as in the case of a rotary evaporator.

Aldrich sold a geat many of these units. In later years the kugelrohr was modified to enhance safety and ease of use. Aldrich has never been shy about pricing, so the price went way up as well.

I was thinking about this bit of history yesterday as I was operating my home-built kugelrohr. Sometimes shortpath distillation is needed and yesterday was the day for it. Using Ike as my inspiration, I horizontally configured a Buchi rotovap into a kugelrohr distillation unit with a still pot and a bulb tube receiver.

On a hotplate with a temperature indicator, I placed an 8 inch diameter sheet metal 90 degree elbow from Home Depot. The elbow, modified with a bit of aluminum foil, would serve as my hot air bath. The elbow and hotplate assembly is scooted over to the rotovap so that the still pot bulb is isolated in the “oven”.  A dry ice/acetone cooling bath for the receiver bulb was made from the bottom of a plastic jar. It was notched on opposite ends to accomodate the receiver joints.

The setup works just like a Buchi-brand kugelrohr, but doesn’t carry the price of a luxury ocean cruise. I know that larger companies would not allow this kind of thing. They would frown on a chemist using his time to kludge together a piece of improvised equipment. Their safety people would not allow the operation of a device that was not purpose manufactured. But when you work for a small company this is one of the things you have to do, and I enjoy every minute of it.

I ran across this handy pdf file from the website of Prof. Njardason at Cornell. It is a graphic compilation of the top selling drugs (in the USA?). Just click on the image and a pdf will download.  The site has compilations for the last several years as well.

A few of the drugs on the list are protected under patents that will expire in the next few years- Lipitor, Crestor, Lexapro, Advair, Singulair, Plavix, etc. Hours after the license to print money expires, the generic barbarians and visigoths will storm the gates and unceremoniously slaughter these cash cows. The horror, the horror.

I and my assistant have spent the last month devising experiments that are meant to chart out the stability or robustness of a small set of compounds whose manufacture has been problematic. This has been a kind of a process development activity wherein we are trying to understand what the specific sensitivities of this molecule are and how they might impact process stability.

My job these days is reactive hazards analysis and process safety. We have been trying to dream up experiments that tease out particular weaknesses a compound may have in normal or plausible off-normal conditions. While the compounds in question do not have apparent issues with reactive hazards, the skill set needed to find reactive hazards is useful in finding economic hazards as well.

An economic hazard would be something that threatens the profitability of a process. A production instability is simply a low threshold for a transition to off-normal processing conditions. Sometimes a process instability is physically dangerous and sometimes it is only an economic threat.

I have to say that this has been very enlightening so far.

The speakers for the morning of June 8th were Bob Grubbs and Magid Abou-Gharbia. As usual, Bobby Grubbs’ talk was concerned with the latest wonders of olefin metathesis. We saw ATM’s of molecular Cheerios. Pretty cool, actually. Grubbs got the trip to Stockholm for a reason and the work of his group continues to produce molecular wonders.  He was able to demonstrate the production of rings with degrees of polymerization in excess of 5000.  Using NMR and a carefully chosen ring monomer, they could sort out linear polymers from cyclic polymers. Linear polymers will thread a crown ether while the cyclic form will not. By attaching a crown ether (24-crown-8 ??) to polystyrene beads, they could collect and physically separate the linear from the cyclic forms. They were also producing brush polymers.

Prof. Magid Abou-Gharbia, Temple University, gave a talk with lots of fascinating insights into some current thinking on industrial drug discovery. At least from the point of view of a former Wyeth guy. I have been away from the pharma-related work for a number of years now and haven’t really missed it. But his talk has revived enthusiasms in me that have been in a long slumber. 

Anyway, he described the development of the anti-depressant Effexor and their efforts to keep the molecule simple and free of excessive stereocenters. Studies of the metabolism of Effexor lead to the discovery of the des-methyl analog, now called Pristiq.

Concerning High Throughput Synthesis (HTS)-

“… you’re going to get a lot of decorated molecules, but they are not going to be biopharmaceutically useful.”

Abou-Gharbia lamented the languishing of natural products chemistry. He gave some examples of Rapamycin work, which according to his presentation, was originally isolated from a soil sample from Easter Island.  Much productive work apparently has been derived from the modification of this macrocycle. It’s all in the literature.

One of the main take-away lessons from Abou-Gharbia is that workers shouldn’t get too focused on SAR. His advice was that structure-property relationships need an early examination as well. Dual optimization. If the bioavailability is low, then the in vivo activity will not match the in vitro activity- an expensive and time consuming realization.