1998

Recrystallization and Polymorphs

Eugene Sun (b. 1960)

Crystallization is a fundamental technique in chemistry and has often been used to purify compounds. A solvent that dissolves a compound while it’s heated but doesn’t do so when it cools down provides the opportunity to recrystallize. When the process is done right, the impurities remain in the solution, and the clean crystals can be filtered off. In the days before chromatography became common, recrystallization of solids and distillation of liquids were the main techniques available for purification.

But there can be complications. The same compound can crystallize out in different ways under different conditions. These different crystal forms (polymorphs, as they’re known) can be laboratory curiosities, but they can also exhibit different characteristics, occasionally putting human lives and hundreds of millions of dollars at risk. That’s what happened with an antiretroviral drug called ritonavir, which was approved by the FDA in 1996 for the treatment of HIV/AIDS. In 1998, a new polymorph appeared (called form II), with a lower-energy crystalline state (with better hydrogen bonding) than the form I found in the original capsules. Since it was more stable as a crystal, form II ritonavir did not dissolve nearly as well, making it ineffective as a drug. The compound’s developer, Abbott Laboratories, had to pull the existing supplies from distribution, since they could not guarantee their crystalline form—an increasing number of sample capsules at the factory were failing to dissolve on testing, as outlined by American clinician Eugene Sun, speaking for the company at a series of press conferences.

A liquid suspension of form I ritonavir was available, but it was foul tasting and hard to tolerate. After much frantic work, the company’s chemists and formulation scientists found that the only way to formulate ritonavir in capsule form was to package it as a thick solution in gel caps, requiring refrigeration. Later, the team (led by Indian-American chemist Sanjay Chemburkar) found methods to produce form I again under tightly controlled conditions, isolated from any traces of form II (which would have converted it back again!). Abbott is far from the only drug company that has experienced polymorph problems, but theirs may have been the most dramatic.

Sodium acetate starting to crystallize out from a solution. Depending on the concentration, temperature, and solvent, even a simple compound, such as this one, can form several crystalline polymorphs.