Chemistry in its element · Chemistry World

Ritonavir

·12 min·1 clip

Abbott Laboratories discovered a new, more stable polymorph of ritonavir that made their capsules insoluble and forced a production shutdown.

This episode of Chemistry in its Element explores the drug ritonavir, an HIV treatment, through the lens of a scientific phenomenon called polymorphism. Host Alexander Whiteside is joined by John Morris, a senior director at AbbVie who worked on ritonavir in the 1990s. The narrative connects the drug's history to a classic science fiction concept introduced by chemist Irving Langmuir to writer H.G. Wells. Langmuir imagined a hypothetical "warm ice," a polymorph of water that could seed and convert all liquid water at room temperature. Polymorphism describes how molecules can pack into different solid forms, or polymorphs, with distinct properties. Ritonavir was launched in 1996 as a breakthrough antiretroviral that helped transform HIV into a manageable chronic illness. The original liquid formulation had a foul taste, so Abbott Laboratories developed a more palatable gel capsule filled with a concentrated ritonavir solution. In mid-1998, production of these capsules failed because a new, previously unknown polymorph of ritonavir, called Form 2, spontaneously appeared. Form 2 was half as soluble as the original Form 1 and acted as a seed, templating its own formation wherever it was present. This new polymorph quickly contaminated manufacturing lines in Chicago and, later, Italy, making the production of the soluble Form 1 impossible. John Morris compares the containment efforts to working with a virus, due to Form 2's pervasive seeding ability. Abbott had to publicly halt capsule production in October 1998, forcing patients back to the disliked liquid formulation. The company ultimately developed a new, lower-dose soft gelatin capsule compatible with Form 2's solubility, which launched in 1999. The entire episode cost Abbott an estimated $250 million. A 2018 study suggests a more stable polymorph awaits discovery for 15-50% of all drugs, though few cases have such dramatic consequences. The story concludes by revealing that Langmuir's "warm ice" idea inspired Kurt Vonnegut's novel *Cat's Cradle* and its fictional substance, Ice-9. The episode is educational and narrative-driven, weaving together historical anecdote, chemistry, and pharmaceutical drama. Listeners interested in material science, pharmaceutical history, or intriguing scientific mishaps will find this compelling. Those seeking a purely technical discussion of ritonavir's current medical use might find the historical and narrative focus less relevant.

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