Disappearing polymorph

labeled photographs showing the differing crystal structure of two different polymorphs
Needles of two different polymorphs of metanilic acid taken under a microscope at ×20 magnification. Figure (a) shows Form II and (b) shows Form III; Form I was unable to be reproduced by researchers, an instance of a disappearing polymorph.[1]

In materials science, a disappearing polymorph is a form of a crystal structure that is suddenly unable to be produced, instead transforming into a different crystal structure with the same chemical composition (a polymorph) during nucleation.[2][3] Sometimes the resulting transformation is extremely hard or impractical to reverse, because the new polymorph may be more stable.[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 is global, and it is suspected that it is because earth's atmosphere is permeated with tiny seed crystals. It is believed that seeds as small as a few million molecules (about grams) is sufficient for converting one morph to another, making unwanted disappearance of morphs particularly difficult to prevent.[3]

This is of concern to the pharmaceutical industry, where disappearing polymorphs can ruin the effectiveness of their products and make it impossible to manufacture the original product if there is any contamination. There have been cases in which a laboratory that attempted to reproduce crystals of a particular structure instead grew not the original but a new crystal structure.[6] The drug paroxetine was subject to a lawsuit that hinged on such a pair of polymorphs, and multiple life-saving drugs, such as ritonavir, have been recalled due to unexpected polymorphism.[7] Although it may seem like a so-called disappearing polymorph has disappeared for good, it is believed that it is always possible in principle to reconstruct the original polymorph, though doing so may be impractically difficult.[3] Disappearing polymorphs are generally metastable forms that are replaced by more stable forms.[3]

It is hypothesized that "unintentional seeding" may also be responsible for the phenomenon in which it often becomes easier to crystallize synthetic compounds over time.[5]

  1. ^ Rubin-Preminger JM, Bernstein J (2005-07-01). "3-Aminobenzenesulfonic Acid: A Disappearing Polymorph". Crystal Growth & Design. 5 (4): 1343–1349. doi:10.1021/cg049680y. ISSN 1528-7483.
  2. ^ Seddon KR, Zaworotko M, eds. (1999). Crystal Engineering: The Design and Application of Functional Solids. Vol. 539. Springer Science & Business Media. ISBN 978-0-7923-5905-0.
  3. ^ a b c d Bučar DK, Lancaster RW, Bernstein J (June 2015). "Disappearing polymorphs revisited". Angewandte Chemie. 54 (24): 6972–6993. doi:10.1002/anie.201410356. PMC 4479028. PMID 26031248.
  4. ^ Lowe D (November 26, 2019). "Perverse Polymorphism". In the Pipeline. American Association for the Advancement of Science. Archived from the original on July 5, 2022. Retrieved 2022-07-04.{{cite web}}: CS1 maint: bot: original URL status unknown (link)
  5. ^ a b Dunitz JD, Bernstein J (1995-04-01). "Disappearing Polymorphs". Accounts of Chemical Research. 28 (4): 193–200. doi:10.1021/ar00052a005. ISSN 0001-4842.
  6. ^ Surov AO, Vasilev NA, Churakov AV, Stroh J, Emmerling F, Perlovich GL (2019). "Solid Forms of Ciprofloxacin Salicylate: Polymorphism, Formation Pathways and Thermodynamic Stability". Crystal Growth & Design. 19 (5): 2979–2990. doi:10.1021/acs.cgd.9b00185. S2CID 132854494.
  7. ^ Prenol A (July 2004). "Disappearing Polymorphs and Gastrointestinal Infringement". Blakes. Archived from the original on 20 July 2012.