In the world of pharmaceuticals, a tiny architectural change at the molecular level can be the difference between a life-saving drug and an ineffective pill.
A cocrystal is a sophisticated crystalline material composed of two or more different molecular species—typically an Active Pharmaceutical Ingredient (API) and a "coformer"—arranged together in a specific, repeating pattern within a single crystal lattice. Unlike salts, where protons are transferred between molecules, the components in cocrystals share protons and connect through non-covalent bonds, creating an entirely new solid structure with unique properties2 3 .
Think of it this way: if traditional drug crystals are like a neighborhood built with only one type of house, cocrystals are a carefully planned community with multiple complementary architectural styles, creating something more functional and stable than either could achieve alone.
The significance of cocrystals extends far beyond academic curiosity. They represent a powerful tool in the pharmaceutical industry's quest to overcome one of its biggest challenges: poor bioavailability. When a drug doesn't dissolve properly in the body, it cannot reach its target effectively, rendering it less potent or completely useless. By forming a cocrystal, scientists can enhance a drug's solubility, stability, and absorption characteristics without altering its fundamental chemical structure or therapeutic activity3 .
of new drug candidates face significant challenges due to poor solubility
global norovirus cases annually with no approved treatments
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The process of creating pharmaceutical cocrystals combines the precision of crystal engineering with the practical art of formulation science.
Traditional mechanical approaches where solid ingredients are physically ground together. While useful for initial screening, these methods often produce materials with low purity and are difficult to scale up5 .
A solvent-free method where components are heated until melted, then cooled under controlled conditions. This approach is valuable for compounds that tend to form solvates in solution5 .
Modern approaches that use automation and miniaturization to rapidly test thousands of possible cocrystal combinations with minimal material4 .
Researchers at Newcastle University in collaboration with AstraZeneca developed a groundbreaking approach called Encapsulated Nanodroplet Crystallisation (ENaCt) that addresses one of the most significant challenges in cocrystal development: the exhaustive exploration of an enormous experimental landscape with limited material4 .
The ENaCt method employs liquid-handling robotics to set up thousands of parallel crystallization experiments in 96-well plate formats. Each experiment uses mere nanoliters of test solutions—containing both the pharmaceutical compound and potential coformers—encapsulated in inert oils that mediate the rate of concentration through controlled evaporation and diffusion.
| Parameter | Experimental Conditions | Results |
|---|---|---|
| Substrates | 4,4'-bipyridine, caffeine, nicotinamide | 3 substrates tested |
| Coformers | 6 compounds with H-bond donors | 6 coformers tested |
| Solvents | MeOH, DMF, MeNO₂, 1,4-dioxane | 4 solvents screened |
| Stoichiometries | 2:1, 1:1, 1:2 substrate:coformer ratios | 3 ratios tested per combination |
| Total Experiments | 3,456 individual crystallisation trials | 18/18 possible binary combinations accessed |
| Novel Structures | All conditions | 10 new binary cocrystal structures |
The ENaCt method demonstrated extraordinary efficiency in cocrystal discovery. Of the 18 possible binary combinations between the three substrates and six coformers, the researchers successfully accessed all 18 combinations—including 10 novel binary cocrystal structures that had eluded previous discovery attempts using traditional methods.
12 new higher-order cocrystals discovered from 13,056 experiments
All 18 possible binary combinations successfully accessed
The discovery and implementation of pharmaceutical cocrystals are already producing tangible benefits in medicine.
Using melt crystallization, scientists discovered a novel cocrystal formed between molnupiravir and caprolactam that demonstrated superior tableting properties compared to the pure drug, exhibiting enhanced tabletability, compressibility, compactibility, and plasticity—critical improvements for large-scale pharmaceutical manufacturing5 .
Cocrystals of cannabigerol (CBG), a promising non-psychoactive cannabinoid, have shown remarkable improvements in dissolution rate compared to the pure compound. Advanced surface analysis revealed that this enhancement strongly correlated with the crystal's distinctive electrostatic charge distribution6 .
| Property | Improvement | Example |
|---|---|---|
| Solubility & Dissolution | Enhanced bioavailability | CBG cocrystals showed significantly increased dissolution rates6 |
| Stability | Extended shelf life | Cocrystals can resist hydration and oxidation better than pure APIs |
| Tableting Performance | Improved manufacturing | Molnupiravir-caprolactam cocrystal demonstrated better compactibility5 |
| Melting Point | Better processing | Cannabigerol cocrystals with higher melting points than pure CBG6 |
As computational prediction methods become more sophisticated and high-throughput experimental techniques like ENaCt continue to evolve, the systematic design of cocrystals is transitioning from serendipitous discovery to rational engineering. Researchers can now explore complex multi-component systems with unprecedented efficiency, opening doors to pharmaceutical formulations that were previously inconceivable.
The ongoing development of continuous manufacturing processes and advanced process analytical technologies promises to bridge the gap between cocrystal discovery at the nanogram scale and commercial production at the kilogram scale, ensuring that these molecular marvels can reach patients who need them2 .
In the relentless pursuit of better medicines, cocrystals represent a powerful testament to how reimagining the architecture of molecules can unlock their full therapeutic potential—proving that sometimes, the smallest structural changes can make the biggest difference in human health.
For further reading on cocrystal discovery methods, see the original research article "High-throughput encapsulated nanodroplet screening for accelerated co-crystal discovery" in Chemical Science (2025) and the review "Prioritizing Computational Cocrystal Prediction Methods for Experimental Researchers" in the International Journal of Molecular Sciences (2024).