Ritonavir is the active ingredient in Norvir®, a protease inhibitor used to treat HIV/AIDS. It was launched by Abbott Laboratories in 1996 in what was, at the time, the only known solid form of the drug. In 1998, approximately 18 months after launch, a second, more thermodynamically stable, polymorph of ritonavir appeared in one of Abbott’s facilities, and, despite Abbott’s best efforts at containment, spread to each of Abbott’s other facilities. This polymorph (form II) was 50% less soluble than the original form in the marketed drug, and caused the drug to fail its regulatory dissolution specifications. The drug was withdrawn from the market in all but the bad-tasting liquid solution form while Abbott tried, unsuccessfully, to reproducibly recover the original solid form of the drug. The drug was eventually relaunched with the form II polymorph, in a soft gel formulation that required refrigeration, but not before Abbott suffered considerable economic loss, including a significant drop in its stock price, lost sales, the write-off of a manufacturing facility and substantial amounts of inventory.
Employing our CrystalMax® technology on just a few grams of ritonavir that had been purified from the commercial solution, TransForm performed over 2,000 crystallization experiments within a four-week period. We discovered not only the original form, and form II, but also three other previously unreported forms. Interestingly, one of these newly discovered forms was an intermediate by which the “disappearing” form I could reproducibly be made.
Had TransForm been involved in the development of ritonavir, perhaps the outcome would have been different. The most popular theory about ritonavir is that, although form I was kinetically the most stable, an impurity introduced during the manufacturing process may have templated the thermodynamically more stable form II which, once seeded, thereafter contaminated all of Abbott’s facilities. For this reason, TransForm recommends that, once final process scale-up steps have been “locked down,” it is prudent to conduct an additional comprehensive CrystalMax® screen, adding whatever impurities may be introduced during scale-up or manufacture, in order to minimize the likelihood of repeating the ritonavir story.