What is a disappearing polymorph? It is a crystal form of a substance that becomes difficult to produce after a different form appears and begins to dominate crystallization. The form has not necessarily become impossible to make: experiments have recovered the original ritonavir form under controlled laboratory conditions. The episode shows why “first to crystallize” and “most stable” are not the same—and why an unexplained change in crystal form can disrupt a medicine.
What does “disappearing polymorph” mean?
A polymorph is one of two or more crystal structures made from the same chemical substance. The molecules are the same, but their arrangement in the solid differs. That arrangement can affect properties such as solubility, melting behavior, and stability. In a drug, a difference in solubility can matter to how a formulation performs.
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The term “disappearing” describes a practical problem: a form that was once made reliably becomes hard to reproduce because crystallization now favors another form. It does not mean the earlier structure has ceased to exist or that it can never be made again.
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Repair common Windows errors and clear accumulated junk for a smoother, more stable PC - no reinstall needed.Free scan · no reinstallSome related solid forms are not strict polymorphs. Hydrates and solvates incorporate water or another solvent into the crystal, so their composition differs as well as their arrangement. Amorphous material, by contrast, lacks a regular crystal structure. FDA-hosted ICH Q6A discusses these as related solid-state forms, but the distinctions matter when describing a particular case.
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Why can a less stable form appear first?
Thermodynamic stability is not the same as ease of formation
Thermodynamics describes which form is more stable under specified conditions. Kinetics describes how quickly a form can nucleate and grow. A metastable form can have a lower barrier to nucleation, so it appears readily even when another form is thermodynamically more stable. The more stable form may have a higher nucleation barrier and take longer to emerge.
Materials scientist Wenhao Sun describes the barrier this way: “Once it overcomes this hill, then it can form a crystal and grow continuously.” If a crystal of the later form is present, it can provide a seed for further growth. Conditions that once produced the earlier form may then yield the later one instead.
What might change the outcome?
Solvent, temperature, concentration, raw materials, process conditions, and the presence of tiny seed crystals can influence crystallization. Environmental particles are one possible source of seeds; crystallization expert Roger Davey said, “There’s dust everywhere – I wouldn’t write it off.” That is a possibility, not evidence that dust caused any specific industrial event. Random nucleation can also be a possibility. No single trigger is established as a universal explanation for disappearing forms.
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Why did ritonavir’s crystal form change?
Ritonavir, an HIV protease inhibitor developed by Abbott Laboratories, became the best-known pharmaceutical example. Chemistry World’s Rachel Brazil reports that the drug was approved in 1996 and that a less-soluble, more stable form—Form II—began appearing in manufactured batches in 1998. The original capsule formulation depended on Form I. Form II’s lower solubility created a formulation problem; Abbott temporarily withdrew the product and developed a reformulated refrigerated gel capsule containing Form I.
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The reason Form II emerged when it did remains unresolved. Brazil’s feature, published on 13 April 2026 and updated on 22 May 2026, discusses possible microscopic seeds, process changes, raw-material impurities, solvent changes, and a stochastic nucleation event. These are proposed explanations, not a proven account of the original trigger.
The same feature attributes a cost of more than $250 million to the disruption. That is the figure reported by Chemistry World, not an independently audited total established here. A 2015 PNAS paper also cites ritonavir as a major example of a late-appearing stable form disrupting an existing formulation.
Can a disappearing polymorph be recovered?
Yes, at least in laboratory research: experiments published in 2024 recovered ritonavir Form I using controlled crystallization approaches. These demonstrations show that a form’s apparent disappearance does not prove it is unrecoverable. They do not establish a ready-to-use manufacturing process, a clinical recommendation, or a reliable recipe for non-specialists.
| Approach | Reported result | What the result establishes |
|---|---|---|
| Ball milling | A 2024 PNAS study used choices of solvent and milling time to reveal Form II and recover Form I. Chemistry World reports that liquid-assisted grinding first produced Form II, while later milling in water returned Form I. | A controlled mechanochemical experiment can access different forms. It does not show that consumer grinding equipment can safely or reliably reproduce the result, or that the procedure is suitable for production. |
| Solution crystallization | A 2024 Molecular Pharmaceutics study reported metastable Form I at high supersaturation with rapid cooling to 283.15 K from acetone, ethyl acetate, acetonitrile, and toluene solutions. Under the reported conditions, ethanol produced stable Form II. | Solvent and process conditions can change which form crystallizes. The reported laboratory conditions are not, by themselves, a validated pharmaceutical manufacturing method. |
The different outcomes underline why a recovery method cannot be separated from its conditions. A form obtained through milling is not evidence that the same form will appear in a solvent crystallization, and one solvent’s result cannot be assumed to hold for another.
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How do manufacturers identify and control solid forms?
For a medicine, the question is not simply which form is most stable in isolation. It is whether the solid form affects drug-product performance, bioavailability, or stability. FDA-hosted ICH Q6A states: “In cases where differences exist that have been shown to affect drug product performance, bioavailability, or stability, then the appropriate solid state should be specified.” This is regulatory guidance for pharmaceutical specifications; it does not explain why a particular form appeared in a historical batch.
Q6A lists several analytical approaches for evaluating solid forms:
- Powder X-ray diffraction
- Solid-state infrared spectroscopy
- Raman spectroscopy
- Thermal analysis, including differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA)
- Solid-state nuclear magnetic resonance
- Melting-point methods
The guidance treats a polymorph-content test and acceptance criterion as a last resort when product-performance testing can serve as an adequate surrogate. In other words, a specification should address a solid-form difference when that difference matters, without assuming that measuring polymorph content is always the best control.
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What do other cases show—and what do they not show?
Cefozopran: a related solid-form change, not strict polymorphism
Brazil’s Chemistry World feature recounts a Takeda episode in which an alpha trihydrate was followed by a more stable gamma heptahydrate that spread across facilities. Because the two forms contained different numbers of water molecules, this is a hydrate change rather than a strict polymorph example. It illustrates a related manufacturing challenge but should not be treated as the same kind of case as ritonavir.
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Ranitidine hydrochloride: disputes over patents and proof
The feature describes litigation involving Glaxo’s patents on ranitidine hydrochloride Forms I and II and Novopharm’s generic product. In a second dispute, Glaxo could not prove that Novopharm’s product contained the patented form, and Novopharm proceeded with its generic. This is a historical summary of particular disputes, not legal advice or a statement about current patent status.
Paroxetine hydrochloride: an argument made in litigation
SmithKline Beecham argued that an older paroxetine hydrochloride anhydrate could convert to a more stable hemihydrate, including in the gastrointestinal tract. Brazil recounts trial and appeal outcomes that affected the later patent. The “gastrointestinal infringement” position was an argument in that litigation, not a generally accepted scientific or legal rule.
A cocrystal example illustrates seeding, but is not a disappearing polymorph
A 2013 Chemical Science study showed that heteronuclear seeding enabled formation of a previously elusive caffeine–benzoic-acid cocrystal. A cocrystal contains more than one chemical component in the crystal structure, so this is not a strict example of one polymorph displacing another. It is a separate illustration of how seeding can help direct crystallization.
What the ritonavir story establishes
The central lesson is narrower and more useful than a claim that crystals simply “turn into” a more stable form: different crystal structures can compete, and a form that is harder to nucleate may emerge late and alter the reproducibility of a process. Ritonavir shows that such a change can affect a drug formulation. The later laboratory recoveries show that the earlier form can still be accessible under selected conditions, while leaving the original trigger and the production-scale implications unresolved.
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