Here’s an odd story from a group at Bristol-Myers Squibb. They ran into a problem with compound adsorption on to a surface, which is something that many of us have run into once in a while. Generally it’s some protein that likes to stick to a particular type of plastic, and it shows up when you start assay development and realize that you need to watch out for polypropylene, or polystyrene, or what have you, because your biomolecules like to hang on to it. I’ve come across a couple of drug candidates that were pesky that way as well, throwing the assay numbers off because you couldn’t count on them actually being in solution any more when things were run in a given sort of container.
When I think about it, though, all the examples I’ve encountered have been with plastic. This new paper details a problem with a long-chain diamine compound (shown at right) that ended up adsorbing on glass surfaces and causing trouble in a process plant. The methods developed to get to that point had already established that the compound needed to be cleared out of the reaction stream, and the team had set a limit of 150 ppm for its presence to avoid problems with hard-to-remove byproducts in later steps. They ran a step in a glass-lined reactor and washed the product solution with brine to give 90 ppm residual diamine They washed the reactor out with solvent while that was going on and transferred that product stream back to the reactor for distillation. Unfortunately, the product then contained more diamine than it started out with, and the only way that could happen was if there were some of it stuck to the glass surface that couldn’t be removed by simple washing (but which was dislodged during the distillation step).
Now you’d see this and think hey, no problem – instead of a room-temperature wash, I’ll just charge up the reactor with some clean solvent and distill that around for a while, then pump it out to clean the surface. Well, that helped, but not enough: after that round of cleaning, the product would still come back with higher-than-before levels of the diamine, over the limit that could be tolerated. They ended up having to clean up the process stream by first washing with brine and discarding the brine, then with aqueous citric acid (which took the product into the aqueous layer as a citrate salt) and discarding the organic layer, then adding fresh solvent and sodium hydroxide to send the product back into the organic layer as the free base (and discarding the aqueous base), and finally another wash with brine. Pretty much the way you’d do it while shaking a separatory funnel by hand! The NaOH step seemed particularly effective at cleaning things up, since the diamine was probably sticking to acidic silanol groups on the glass surface, so this extraction procedure was also combined with a new cleaning step for the reaction (dilute NaOH, brine, and solvent, sending each to waste in turn).
Finally, after all this, the product stream was fit to send on. I’m actually leaving out some details – the team had to fix a number of problems just in the LC/MS analysis to get accurate numbers on the diamine concentration because the compound would of course stick to glass vessels and syringes along the way! This is obviously a time-consuming and more expensive way to operate (lots of waste to deal with) but the diamine itself was a crucial component of the process and the alternative was to just say that the drug couldn’t be made cleanly, which is obviously not acceptable. The authors noted that this sort of thing probably happens more often that all of us realize (amines have been reported to interact with glass surfaces before), but it’s just that in this case the presence of the diamine couldn’t be tolerated in the next step, while in other cases an amine contaminant might come along at low levels and be removed under normal purification.
