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A disappearing polymorph is a crystal form of a substance that becomes difficult to produce after another form emerges. The substance’s molecules have not changed; their arrangement in the crystal has. Ritonavir’s late-appearing Form II disrupted an established drug formulation, but later laboratory studies recovered the earlier Form I under controlled conditions. The episode shows why the form that crystallizes first is not necessarily the most stable—and why the original trigger for a new form can remain unknown.
What is a disappearing polymorph?
Polymorphism is the ability of the same chemical substance to crystallize in more than one arrangement. Each arrangement is a polymorph. A crystal form can differ from another in properties such as solubility, melting behavior, and stability, even though both contain the same substance.
In pharmaceutical solid-state science, related forms also matter. Hydrates and solvates incorporate water or another solvent into the solid, while an amorphous material lacks the long-range order of a crystal. These are not all strict polymorphs: a hydrate with a different water content is not simply another crystal arrangement of an otherwise identical composition.
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Scan for outdated or missing drivers - takes under a minuteDriver Scan →Clear out junk files and repair common Windows errorsFree Scan →“Disappearing” describes a practical problem, not necessarily an irreversible transformation. A form may become hard to reproduce because conditions that once produced it now favor another form, or because seeds of the competing form make its growth easier. Its apparent absence from later batches does not by itself prove that it can never be recovered.
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Why can one crystal form appear first and another take over?
Crystallization is governed by both thermodynamics and kinetics. Thermodynamic stability describes which form is favored under specified conditions; nucleation kinetics help determine which form appears first. A metastable form can nucleate more readily, so it may crystallize before a more stable form whose initial nucleus is harder to form.
University of Michigan materials scientist Wenhao Sun, quoted in Rachel Brazil’s 2026 Chemistry World feature, describes the nucleation barrier this way: “Once it overcomes this hill, then it can form a crystal and grow continuously,” referring to the barrier a forming crystal must cross. If seeds of a form are present, they can provide a surface for further growth and change which form is easier to obtain. The balance depends on the substance and conditions; there is no single cause that explains every disappearing-polymorph episode.
That distinction helps explain why a manufacturing process can repeatedly make one form for a long time and then encounter another. A shift in conditions or the arrival of a seed could alter nucleation, but the precise trigger in any particular case needs evidence. Environmental dust, process changes, raw-material impurities, or solvent changes should not be treated as proven causes without such evidence.
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What happened to ritonavir’s crystal forms?
Ritonavir is an HIV protease inhibitor developed by Abbott Laboratories. According to Rachel Brazil’s Chemistry World feature, it was approved in 1996. Form I was used in the original capsule formulation; in 1998, a less-soluble, more stable form, Form II, began appearing in manufactured batches. Its lower solubility created problems for the existing formulation, and Abbott temporarily withdrew the product while developing a reformulated refrigerated gel capsule containing Form I.
The episode is a vivid example of stability and ease of formation being different properties. Form I could be produced under the earlier conditions, while the more stable Form II was initially difficult to nucleate. Once Form II appeared, its presence could make it harder to reproduce Form I in the same way. The 2015 PNAS paper on pharmaceutical screening also discusses ritonavir as a major example of a late-appearing stable form disrupting an existing formulation.
The original trigger for Form II’s arrival is not established in the available account. Brazil’s 2026 feature discusses possible explanations including microscopic seeds, process changes, impurities in raw materials, solvent changes, and a stochastic nucleation event. These remain possibilities, not a settled causal explanation. Crystallization expert Roger Davey, quoted in the feature about environmental seeding, says: “There’s dust everywhere – I wouldn’t write it off.” That remark identifies a possibility; it is not proof that dust or contamination caused the ritonavir event.
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Brazil’s feature attributes a cost of over $250 million to the disruption. That figure should be understood as the feature’s reported estimate, not as an independently audited total.
Can a disappearing polymorph be recovered?
Yes, at least in laboratory demonstrations. Two 2024 studies recovered or produced ritonavir Form I using different approaches. Their results establish that the form can be obtained under selected experimental conditions; they do not establish a production-ready manufacturing fix or a recipe for use outside a laboratory.
| Approach | Reported result | What it demonstrates | What it does not establish |
|---|---|---|---|
| Ball milling (2024 PNAS study) | Carefully chosen solvent and milling-time conditions revealed Form II; later milling in water returned Form I, as summarized in the Chemistry World feature. | Mechanochemical conditions can affect which ritonavir form is obtained, and Form I was recovered in the experiment. | A simple or safe consumer method, or a validated production-scale process. |
| Solution crystallization (2024 Molecular Pharmaceutics study) | At high supersaturation and rapid cooling to 283.15 K, the study obtained metastable Form I from acetone, ethyl acetate, acetonitrile, and toluene solutions; ethanol produced stable Form II under the reported conditions. | Solvent choice and crystallization conditions can change which polymorph forms. | That these laboratory conditions are appropriate for pharmaceutical manufacturing or will transfer unchanged to other settings. |
The two studies illustrate different controls: one changes conditions during milling, while the other selects a solvent and cooling path for crystallization from solution. A separate 2013 Chemical Science study used heteronuclear seeding to form a previously elusive caffeine–benzoic-acid cocrystal. That is a cocrystal example, not a strict case of a single compound’s polymorph disappearing, but it shows how seeding can help access a difficult-to-obtain crystalline material.
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Why do pharmaceutical manufacturers care about solid form?
A change in crystal form can affect a drug’s physical behavior and, in some cases, product performance. Ritonavir’s Form II mattered because its lower solubility caused trouble for the formulation already in use. The practical concern is not simply that two forms exist; it is whether their differences matter for the drug product’s performance, bioavailability, or stability.
FDA-hosted ICH Q6A guidance 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.” The guidance identifies possible analytical techniques for characterizing solid forms, including melting-point methods, solid-state infrared spectroscopy, powder X-ray diffraction, thermal analysis such as differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), Raman spectroscopy, and solid-state nuclear magnetic resonance.
Q6A also treats a polymorph-content test and acceptance criterion as a last resort when product-performance testing can serve as an adequate surrogate. This is regulatory guidance for pharmaceutical specifications; it does not identify why a particular form appeared in a historical manufacturing event.
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Screening for solid forms is therefore part of managing uncertainty, not a guarantee that every possible form has been found. Process scientist Joop ter Horst, quoted by Brazil, describes the challenge: “There is a broad screen of solid states of the chemical compounds, and then they select one … and of course, then hope in the development process that this is not going to disappear.”
When “disappearing polymorph” enters patent disputes
Crystal-form disputes can turn on what a patent claims, what an earlier process actually produced, and whether evidence establishes that a product contains the claimed form. The historical cases summarized in Brazil’s 2026 Chemistry World feature illustrate different arguments; they do not create a simple rule that a later-appearing form is, or is not, patentable.
Ranitidine hydrochloride
The feature recounts litigation involving Glaxo patents on Forms I and II and Novopharm. 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, not a statement of current patent status or legal advice.
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In litigation concerning paroxetine hydrochloride, SmithKline Beecham argued that an older anhydrate could convert into a more stable hemihydrate, including in the gastrointestinal tract. The feature recounts trial and appeal outcomes that affected the later patent. The gastrointestinal-conversion position was an argument made in that litigation, not a generally accepted legal or scientific principle.
Cefozopran: a related solid-state episode, not a strict polymorph case
Brazil’s feature describes a Takeda episode in which an alpha trihydrate was followed by a more stable gamma heptahydrate that spread across facilities. Because these forms contained different numbers of water molecules, they were hydrates with different water content, not strict polymorphs of identical composition. The example broadens the solid-state story but should not be used as though it were chemically identical to the ritonavir case.
Quick Recap
What the ritonavir episode does—and does not—show
- It shows that a more stable form can emerge after a different form has been used in manufacturing, with consequences when the forms differ in a relevant property such as solubility.
- It does not establish a definitive cause for Form II’s late appearance. Proposed triggers remain hypotheses.
- Laboratory studies show that Form I can be recovered under carefully selected milling or solution-crystallization conditions.
- Those demonstrations are not evidence that the same procedures constitute a validated manufacturing process.
- The case is prominent, but the sources cited here do not provide a reliable industry-wide count of such events or a comprehensive estimate of their total cost.
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