Engineering Molecular Alliances to Revolutionize Medicine
Imagine a life-saving drug that refuses to be absorbed by the human body. A compound with perfect therapeutic properties, rendered useless by its stubborn inability to dissolve in bodily fluids. This isn't a hypothetical scenario—it's a daily reality for pharmaceutical scientists worldwide. In fact, approximately 40% of marketed drugs and 90% of drug candidates struggle with poor solubility, significantly limiting their effectiveness 5 .
What if we could solve this problem not by changing the drug itself, but by reimagining its crystalline form? This is where the fascinating science of cocrystals enters the picture.
Scientists are now moving beyond simple two-component systems to engineer sophisticated 'higher-order cocrystals' (HOCs) that contain three, four, or even more molecular components in an organized crystalline lattice 1 3 . These advanced molecular architectures represent the cutting edge of crystal engineering, offering unprecedented control over drug properties without altering the therapeutic compound's chemical structure.
of marketed drugs have solubility issues
of drug candidates face bioavailability challenges
At its simplest, a pharmaceutical cocrystal is a sophisticated crystalline structure containing an active pharmaceutical ingredient (API) and one or more 'coformers'—generally recognized as safe molecules—in a specific stoichiometric ratio, all assembled within the same crystal lattice through non-covalent bonds 2 4 . Think of them as molecular alliances where each component maintains its chemical identity while cooperating to create a material with superior properties.
The true innovation lies in what scientists term crystal engineering: deliberately designing these molecular arrangements to enhance specific drug characteristics. Unlike traditional chemical modification, cocrystallization doesn't alter the covalent bonds of the active ingredient—it simply gives it better molecular neighbors 5 .
While binary cocrystals represent a significant advance, higher-order cocrystals (those containing three or more molecular components) open up even more possibilities. The transition from binary to ternary and quaternary cocrystals is not merely additive—it's transformative. With each additional component, scientists gain new variables to fine-tune drug properties, creating increasingly sophisticated solid forms with precisely optimized characteristics 3 .
| Solid Form | Components | Bonding Type | Key Characteristics |
|---|---|---|---|
| Pure API | Single active compound | Covalent lattice | Unmodified inherent properties |
| Salt | API + acid/base counterion | Ionic bonds | Improved solubility for ionizable compounds |
| Binary Cocrystal | API + one coformer | Non-covalent bonds | Modified properties without chemical change |
| Higher-Order Cocrystal | API + multiple coformers | Non-covalent network | Multi-property optimization |
Creating these sophisticated molecular architectures is no simple task. The challenge stems from the fundamental process of molecular self-assembly—the spontaneous organization of molecules into structured arrangements without external direction. As more molecular components are introduced, the possible arrangements multiply exponentially, making it increasingly difficult to achieve the desired organized crystalline structure 1 .
Professor Ashwini Nangia, a leading researcher in the field, compares this to organizing a complex dance with multiple partners: "The self-assembly process of multiple molecular components to an ordered and organized crystalline structure becomes increasingly difficult and complex as more than two molecules are present" 1 .
Most cocrystal formation methods rely on creating supersaturated solutions—conditions where the concentration of dissolved components exceeds their equilibrium solubility, creating a driving force for crystallization. In the Reaction Crystallization Method (RCM), for instance, scientists carefully control solution conditions to make the environment supersaturated with respect to the cocrystal while remaining saturated or unsaturated for the individual components 4 . This encourages the molecules to come together in the crystal lattice rather than forming separate crystals.
Spontaneous organization of molecules into structured arrangements
Driving force for crystallization through concentration control
Organized structure where molecules arrange in repeating patterns
Traditional cocrystal screening methods require substantial amounts of material (grams) and resources, making the exploration of higher-order cocrystals particularly challenging . Recently, a team of researchers from Newcastle University and AstraZeneca unveiled a groundbreaking approach that dramatically accelerates this process: High-throughput Encapsulated Nanodroplet Crystallization (ENaCt) 3 .
This innovative method uses liquid-handling robotics to prepare thousands of nanolitre-scale crystallisation experiments in 96-well plate formats. Each tiny droplet contains potential cocrystal components in specific ratios and solvents, encapsulated in inert oils that control concentration rates through evaporation and diffusion . What makes this approach revolutionary is its incredible efficiency—it can perform 13,056 individual experiments using only micrograms of material per trial, allowing researchers to explore vast experimental landscapes with minimal substance requirements .
Researchers prepare stock solutions of substrates and coformers near their solubility limits in selected solvents like methanol, DMF, nitromethane, and 1,4-dioxane .
Using automated liquid handling, 150 nL of each test solution—containing both substrate and coformer in a single solvent—is dispensed into 96-well plates .
Each sample droplet is encapsulated with 200 nL of inert oil, which mediates the rate of concentration through controlled evaporation and diffusion .
The sealed plates are left for 14 days, during which slow crystal growth occurs. The resulting crystals are analyzed using single-crystal X-ray diffraction (SCXRD) .
| Experimental Variable | Options Tested | Impact on Results |
|---|---|---|
| Substrates | 3 (4,4'-bipyridine, caffeine, nicotinamide) | Different hydrogen bonding capabilities |
| Coformers | 6 acids with complementary functional groups | Determined possible molecular interactions |
| Solvents | 4 (MeOH, DMF, MeNO₂, 1,4-dioxane) | Varied polarity and solubility parameters |
| Encapsulating Oils | 4 different oils + no-oil controls | Controlled crystallization rate |
| Substrate/Coformer Ratios | 3 (2:1, 1:1, 1:2) | Explored different stoichiometric possibilities |
The ENaCt method yielded spectacular results, successfully identifying all 18 possible binary cocrystal combinations between the three test substrates and six coformers. Even more impressively, the team expanded their approach to higher-order cocrystals, discovering 8 novel ternary cocrystals and 4 novel quaternary cocrystals—remarkable achievements given the complexity of these multi-component systems .
The power of this method lies not only in its efficiency but in its ability to navigate what the researchers describe as "the highly complex experimental landscape that must be navigated" for higher-order cocrystal discovery 3 . By testing thousands of conditions that would be impractical with traditional methods, ENaCt provides unprecedented access to previously inaccessible crystalline forms.
| Cocrystal Type | Number of Molecular Components | Experiments Conducted | Novel Structures Discovered |
|---|---|---|---|
| Binary | 2 | 3,456 | 17 |
| Ternary | 3 | Part of 13,056 total experiments | 8 |
| Quaternary | 4 | Part of 13,056 total experiments | 4 |
ENaCt enables 13,056 experiments with minimal material compared to traditional approaches
The applications of cocrystal technology in medicine are substantial and growing. By forming cocrystals, pharmaceutical scientists can significantly enhance several critical drug properties:
Cocrystals of poorly aqueous soluble APIs with highly soluble coformers can improve solubility by orders of magnitude, leading to better absorption and higher therapeutic concentrations in the bloodstream 4 .
The cocrystal lattice can protect sensitive active ingredients from degradation due to humidity, temperature, or light exposure, extending shelf life 5 .
By selecting appropriate coformers, scientists can design cocrystals that release their active ingredient over specific timeframes, enabling sustained-release formulations 2 .
Beyond their pharmaceutical advantages, cocrystals offer significant environmental benefits. The mechanochemical approaches often used in their synthesis typically require minimal solvent, qualify as green chemical processes due to their high yield and limited generation of by-products, and consume less energy than traditional chemical synthesis methods 5 .
| Tool/Reagent | Primary Function | Research Significance |
|---|---|---|
| Encapsulation Oils | Controls evaporation rate in ENaCt | Enables nanodroplet crystallization environment |
| Hydrogen Bond Donors/Acceptors | Molecular recognition and assembly | Facilitates predictable crystal structure formation |
| Liquid-Assisted Grinding (LAG) | Mechanochemical cocrystal formation | Green chemistry approach with minimal solvent |
| Single Crystal X-ray Diffraction (SCXRD) | Definitive crystal structure determination | Gold standard for characterizing new cocrystals |
| Cambridge Structural Database (CSD) | Predictive tool for crystal structures | Guides coformer selection through molecular complementarity analysis |
The quest for higher cocrystals represents more than just specialized crystal engineering—it embodies a fundamental shift in how we approach drug development and materials science. As research in this field advances, we're witnessing a transition from serendipitous discovery to rational design, where scientists can increasingly predict and create multicomponent crystals with precisely tailored properties.
The breakthroughs in high-throughput methods like ENaCt suggest a future where exploring complex multicomponent crystalline forms becomes routine, dramatically accelerating the development of better medicines. As we continue to unravel the intricacies of molecular self-assembly, each new higher-order cocrystal brings us closer to a new era of pharmaceutical design—one where the limitations of drug solubility and stability may become challenges of the past.
In the words of researchers pioneering this field, these advanced screening methods are providing "ready access" to increasingly complex molecular architectures , opening exciting possibilities for the next generation of therapeutics and functional materials. The molecular alliances we're learning to create today may well form the foundation of tomorrow's medical breakthroughs.