Retrospect and Prospects
Transforming inadequate drugs into powerful medicines through crystal engineering
Imagine a life-saving medicine that refuses to dissolve in the human body. This isn't science fiction—approximately 90% of new chemical entities and 40% of currently marketed drugs suffer from poor water solubility, severely limiting their absorption and effectiveness 1 .
For decades, this solubility crisis has been the single greatest barrier to developing effective medications, leaving potentially revolutionary treatments stuck in the laboratory.
Poor solubility affects the majority of drug candidates, creating a major bottleneck in pharmaceutical development.
Salts and cocrystals offer innovative approaches to enhance drug properties without changing chemical structure.
Formed when an API undergoes an acid-base reaction with a counterion, resulting in complete proton transfer and ionic bonding 6 .
Consist of two or more neutral molecular components within the same crystal lattice, associated through non-covalent interactions 1 .
Cocrystal engineering operates on principles of supramolecular chemistry—"chemistry beyond the molecule"—which focuses on how molecules organize through non-covalent interactions 6 .
Form between identical functional groups, such as carboxylic acid dimers 1 .
Connect different but complementary functional groups, like carboxylic acid-pyridine pairs 1 .
The distinction between salts and cocrystals often comes down to the ΔpKa rule:
The primary motivation behind developing pharmaceutical salts and cocrystals lies in their remarkable ability to improve crucial drug properties:
Emerging research shows cocrystals can improve both solubility and membrane permeability simultaneously 7 .
A compelling example of cocrystal potential comes from a 2025 study investigating dihydromyricetin (DMY), a natural flavonoid with multiple pharmacological activities but poor bioavailability classified as a BCS class IV drug (low solubility and low permeability) 5 .
Equimolar quantities (0.5 mmol each) of DMY and CIP were dissolved in 15 mL of 50% ethanol in a round-bottom flask.
The mixture was magnetically stirred at 60°C for 4 hours to facilitate molecular interaction.
The solution was filtered into sealed containers with controlled evaporation and allowed to slowly evaporate at room temperature over approximately one week.
Transparent needle-shaped crystals were obtained and characterized using multiple analytical techniques 5 .
The DMY-CIP cocrystal delivered extraordinary improvements in key pharmaceutical properties:
| Temperature (°C) | DMY Solubility (mg/mL) | Cocrystal Solubility (mg/mL) | Enhancement Factor |
|---|---|---|---|
| 20 | 0.12 | 0.95 | 7.9× |
| 25 | 0.15 | 1.12 | 7.5× |
| 30 | 0.18 | 1.30 | 7.2× |
| 35 | 0.22 | 1.51 | 6.9× |
| 40 | 0.26 | 1.75 | 6.7× |
| Tool/Reagent | Function | Application Example |
|---|---|---|
| Pharmaceutical Salts | Serve as ionic coformers | Ciprofloxacin HCl in DMY cocrystal 5 |
| GRAS Coformers | Generally Recognized as Safe neutral coformers | Nicotinamide, saccharin 2 |
| Ternary Solvent Systems | Facilitate cocrystallization | Methanol-acetonitrile mixtures |
| Hot-Melt Extrusion | Solvent-free continuous production | Twin-screw extrusion for cocrystal formation 2 |
| PAMPA Assay | Parallel Artificial Membrane Permeability Assay | Predicting absorption potential 7 |
The journey from initial discovery to viable cocrystal formulation has evolved dramatically from early trial-and-error approaches to today's sophisticated screening methodologies.
| Method | Principles | Advantages | Limitations |
|---|---|---|---|
| Liquid-Assisted Grinding | Mechanical energy input with catalytic solvent | Rapid screening, high throughput | Limited scalability |
| Thermal Analysis | Differential Scanning Calorimetry of physical mixtures | Detects novel phases through thermal events | Unsuitable for heat-sensitive materials 2 |
| Hansen Solubility Parameters | Thermodynamic compatibility assessment | Predicts formation probability | Requires parameter knowledge 2 |
| Machine Learning Prediction | Algorithmic analysis of molecular descriptors | High efficiency, reduces experimental load | Dependent on training data quality 3 |
The retrospect and prospects of pharmaceutical salts and cocrystals reveal a technology of tremendous potential. From early serendipitous discoveries to today's rational design approaches, these solid form technologies have matured into sophisticated tools for addressing one of pharmaceutical science's most persistent challenges.
Machine learning and artificial intelligence poised to revolutionize coformer selection 3 .
Exciting possibilities for combination therapies with optimized properties 5 .
Cocrystallization can purify structurally similar natural products .