Disappearing polymorph
[3][4] It is hypothesized that contact with a single microscopic seed crystal of the new polymorph can be enough to start a chain reaction causing the transformation of a much larger mass of material.
[5] Widespread contamination with such microscopic seed crystals may lead to the impression that the original polymorph has "disappeared".
In a few cases such as progesterone and paroxetine hydrochloride, the disappearance gradually spread across the world, and it is suspected that it is because earth's atmosphere has over time become permeated with tiny seed crystals.
[3] It is hypothesized that "unintentional seeding" may also be responsible for a related phenomenon, where a previously difficult-to-crystallize compound becomes easier to crystallize over time.
Justus von Liebig and Friedrich Wöhler observed that when a boiling water solution of benzamide is cooled slowly, a metastable morph appears as a "white mass of silky needles".
[note 1] Alternatively, they may try to argue that a new polymorph needs to undergo the same trials as new drugs, potentially delaying release of a generic for years.
In late 1984, while scaling up the production of Paroxetine, a new crystal form (hemihydrate) suddenly appeared at two Beecham sites in the UK within a few weeks of each other.
[14] When the patent for paroxetine anhydrate (the "original" polymorph) ran out, other companies wanted to make generic antidepressants using the chemical.
The Federal Circuit Court invalidated the newer patent concerning the hemihydrates, on the argument of prior public use from the clinical trials.
Scientists who had been exposed to Form II in the past seemingly contaminated entire manufacturing plants by their presence, probably because they carried over microscopic seed crystals of the new polymorph.
Tens of thousands of AIDS patients went without medication for their condition until ritonavir was reformulated, approved, and re-released to the market in 1999.
It is estimated that Abbott, the company which produced ritonavir under the brand name Norvir, lost over $250 million USD as a result of the incident.
[21] Rotigotine (sold under the brand name Neupro among others) is a dopamine agonist indicated for the treatment of Parkinson's disease (PD) and restless legs syndrome (RLS).
[3] The new polymorph did not display any observable reduction in efficacy, but nonetheless, Schwarz Pharma recalled all Neupro patches in the United States and some in Europe.
Researchers have tentatively suggested that form 2 became gradually harder to produce around 1975, based on a review of production difficulties documented or alluded to in existing literature.
[25] Form 2 was eventually successfully synthesized by using pregnenolone, a structurally similar compound, as an additive in the crystallization process.
Multiple theories were proposed for why earlier research was able to produce form 2 from "pure" ingredients, ranging from the possibility that the early researchers were unintentionally working with impure materials to the possibility that seed crystals of form 1 had become more common in the atmosphere of laboratories since the 1970s.
[25] Pfanstiehl Chemical Company in Waukegan, Illinois, was known for isolating and purifying natural substances, including melibiose.
The chemists theorized that tiny traces of the alpha morph in the air or on the lab equipment could be causing this change, but they never found out where the contamination was coming from.
However, since when in solution, alpha- and beta-melibiose rapidly convert to each other, this may still be productively considered a case of crystal polymorphism.
[26] This seems to be because once the stable form has been made in a lab, its "seeds" or nuclei can disperse in air, influencing new crystals to grow the same way.
[7][29] The case hinged on the interpretation of X-ray diffraction data, with BMS arguing it demonstrated the presence of the Bouzard form in patients who ingested Zenith's product.
[15] Ranitidine, a medicine for peptic ulcers sold under the name of Zantac, was developed by Allen & Hanburys (then a part of Glaxo Group Research, now GSK), and patented in 1978 (US4128658A, Example 32[30]).
Originally, its crystals were all in Form 1, but the batch prepared on April 15, 1980 exhibited a new infrared spectrogram peak at 1045
The organic chemist Jack Baldwin, acting as a witness to Glaxo, had two of his postdoctoral researchers, for three times, produce Form 1 according to the 1978 patent procedure.
However, during the prosecution of the first case, Glaxo had already accepted that the 1985 patent covered only products containing chemicals with a specific, 29-peak infrared (IR) spectrum.
This was intended to avoid double patenting—Glaxo had to emphasize the unique aspects of Form 2 to distinguish it from the invention described in the 1978 patent.
Instantly, all the water in the world's seas, rivers, and groundwater transforms into solid Ice-nine, leading to a climactic doomsday scenario.
[38] Ice-nine has been described as a fictional parallel—a seed crystal triggering a chain reaction akin to the disappearing polymorph phenomenon.
[5][39] In an indirect homage to Cat's Cradle, Ice-nine and its doomsday scenario is also mentioned in the 2009 video game 999: Nine Hours, Nine Persons, Nine Doors.
