Once a crystal form is lost, it can be nearly impossible to get back.
For decades, a mystery has persisted in the world of pharmaceutical science, tucked away in the crystalline structure of a drug called auranofin. Initially developed to treat rheumatoid arthritis, this gold-based compound has recently seen a resurgence of interest for its potential in fighting cancer, bacterial infections, and parasitic diseases. The mystery, however, lies not in what the drug does, but in what it is—or more precisely, in a form of itself that seems to have vanished without a trace.
In 2025, a team of researchers decided to revisit the crystal structure of auranofin, aiming to solve a puzzle that had been troubling scientists for years. Their investigation would lead them to a phenomenon so elusive that it has been known to halt production in pharmaceutical plants: the case of the disappearing polymorph.
The disappearing polymorph phenomenon was first described by chemist Joel Bernstein and can cause significant challenges in pharmaceutical manufacturing.
To understand the significance of a disappearing crystal, we must first appreciate why auranofin has captivated researchers for nearly half a century.
Auranofin was approved by the FDA in 1985 for rheumatoid arthritis and was found to improve patients' quality of life across multiple measures 6 . More recently, scientists discovered its remarkable potential against various cancers, drug-resistant bacteria, and parasitic infections 1 3 4 .
The effectiveness of any solid drug depends critically on its crystal form—the specific arrangement of molecules in a solid state. Different crystal arrangements, known as polymorphs, can have dramatically different properties.
The drug works primarily by inhibiting thioredoxin reductase (TXNRD1), a key enzyme in regulating cellular oxidative stress 4 . By disrupting this system, auranofin increases oxidative stress in cells, particularly cancer cells, leading to their death 5 .
The gold-based compound has a complex structure that influences its therapeutic properties.
Molecular visualization would appear here
The story of auranofin's polymorphism begins with historical reports suggesting the existence of two crystal forms. The commonly known form, now called Polymorph A, was typically obtained by crystallization from low molecular weight alcohols. A second form, Polymorph B, was reportedly obtained from a mixture of cyclohexane and ethyl acetate and was believed to have enhanced water solubility—a property of significant pharmacological interest 4 .
Historical reports indicated two crystal forms of auranofin with different properties.
In 2025, researchers embarked on a comprehensive crystallographic study to resolve the uncertainty 1 4 .
Multiple crystallization attempts under varied conditions failed to reproduce Polymorph B.
The research team employed X-ray crystallography, a technique that uses X-rays to determine the precise arrangement of atoms in a crystal. They applied particularly advanced methods, including Hirshfeld atom refinement (HAR), which allowed for more accurate positioning of hydrogen atoms in the structure—crucial for understanding the weak interactions that hold the crystal together 1 4 .
| Solvent Systems | Temperature Range | Container Materials | Results |
|---|---|---|---|
| Cyclohexane/Ethyl Acetate | 4°C to 25°C | Glass & plastic of various volumes | Exclusive formation of Polymorph A |
| Various non-polar combinations | Ambient | Different shapes and sizes | No Polymorph B observed |
| Multiple solvent ratios | Controlled variations | Glass vials and plates | Consistent formation of Polymorph A |
| Tool | Primary Function | Role in Auranofin Research |
|---|---|---|
| X-ray Crystallography | Determines atomic arrangement in crystals | Provided detailed molecular structure of auranofin 1 |
| Hirshfeld Atom Refinement (HAR) | Enables more accurate hydrogen atom positioning | Revealed precise weak interaction networks in the crystal 4 |
| Various Solvent Systems | Medium for crystal growth | Tested for polymorph reproduction (ethanol, cyclohexane/ethyl acetate) 4 |
| Hirshfeld Surface Analysis | Visualizes and quantifies intermolecular interactions | Mapped weak hydrogen bonds and dispersive interactions 4 |
Reveals the precise arrangement of atoms within a crystal by analyzing how X-rays scatter when passing through the material.
Provides detailed mapping of intermolecular interactions, crucial for understanding crystal packing and stability.
The researchers successfully obtained a high-quality crystal structure of the canonical auranofin form (Polymorph A), revealing several key features:
| Crystal System | Monoclinic |
|---|---|
| Space Group | P21 |
| Crystal Habit | Acicular or columnar, forming radial clusters |
| Stabilizing Forces | Weak hydrogen bonds and dispersive interactions |
| Asymmetric Unit | Single molecule |
| Diffraction Limit | 0.7 Ã… |
Crystal structure visualization
Radial cluster formation of auranofin Polymorph A crystals
The consistent failure to reproduce Polymorph B led researchers to a fascinating conclusion: auranofin appears to be the first documented case of a "disappearing polymorph" in a pharmaceutically relevant transition metal coordination compound 1 4 .
The disappearing polymorph phenomenon occurs when a previously observed crystal form becomes impossible to reproduce under identical conditions. The term was coined by chemist Joel Bernstein to describe situations where the first crystal form of a compound is joined by a second, more stable form that subsequently becomes dominant—sometimes making the original form nearly impossible to obtain again 4 .
Minute chemical contaminants can selectively inhibit or promote certain crystal forms.
Once a more stable form exists, it can act as a seed that promotes the formation of that form over others.
Tiny changes in temperature, pressure, or atmospheric conditions can affect crystallization.
Slight variations in technique between different laboratories can yield different results.
Polymorph stability comparison chart would appear here
The case of auranofin's disappearing polymorph extends far beyond academic curiosity. It highlights several crucial aspects of pharmaceutical development:
The need for systematic revision of historical crystallographic data in coordination complexes 1 .
Inability to reproduce potentially more soluble crystal forms may limit formulation options.
Other historically reported polymorphs may be worth re-examining with modern techniques 4 .
Scientists are exploring innovative ways to enhance auranofin's efficacy, such as supplementing it with additional thiol ligands to prevent its inactivation in the bloodstream 2 . This approach has shown promise in restoring auranofin's anticancer activity in patient-derived tumor models 2 .
The story of auranofin's crystal structure is more than a technical account of molecular arrangements—it's a detective story with a missing suspect. The 2025 investigation provided a high-resolution picture of the known crystal form while confirming the disappearance of its elusive twin.
This research exemplifies how modern analytical techniques can shed new light on old mysteries, even if some polymorphs remain stubbornly out of reach. The disappearing polymorph phenomenon reminds us that in the solid state, matter has a memory and a will of its own, sometimes defying our attempts at control and reproduction.
As auranofin continues to be investigated for new therapeutic applications, understanding its solid-form landscape will remain crucial. The case of the disappearing polymorph stands as both a cautionary tale and an inspiration—demonstrating that even in the seemingly rigid world of crystals, there remains space for mystery and discovery.
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