Redesigning the physical structure of existing drugs to enhance their effectiveness without altering their fundamental pharmaceutical activity
In the constant battle to develop more effective medicines, scientists face a persistent challenge: many promising therapeutic compounds possess poor solubility, stability, or absorption within the human body. Rather than creating entirely new drugs from scratch—an enormously costly and time-consuming process—what if we could simply redesign the physical structure of existing drugs to make them work better? This is precisely the promise of multi-component crystals, an innovative approach where drug molecules are combined with other compounds to create new crystalline forms with enhanced properties without altering their fundamental pharmaceutical activity 1 .
Think of it like reorganizing a cluttered toolbox—the same tools are present, but arranged more efficiently, they become dramatically more accessible and useful. In the pharmaceutical world, this molecular reorganization can transform poorly soluble drugs into highly bioavailable medications, turning marginal therapeutic candidates into life-saving treatments.
From improving anti-cancer medications to enhancing antifungal agents, this cutting-edge technology represents a paradigm shift in drug development, offering new hope for patients while streamlining the path from laboratory to pharmacy shelves 3 6 .
of marketed drugs have poor solubility issues
of developmental drug candidates face solubility limitations
bioavailability without chemical modification
Multi-component crystals are sophisticated crystalline materials composed of two or more different molecular or ionic compounds that coexist within the same crystal lattice in a fixed stoichiometric ratio 1 . In pharmaceutical applications, one component is always the Active Pharmaceutical Ingredient (API)—the therapeutic compound itself—while the other components are carefully selected "coformers" that help reorganize the crystal structure 1 .
At the heart of crystal engineering lies the concept of the supramolecular synthon—the fundamental building block formed through specific non-covalent interactions between molecules 1 . These synthons act as architectural guides that dictate how molecules will arrange themselves in the solid state.
The strategic use of these molecular recognition patterns enables researchers to deliberately design crystal structures with desired properties. For instance, a drug molecule containing a carboxylic acid group might be paired with a coformer featuring a pyridine group, as these complementary functionalities reliably form stable heterosynthons through hydrogen bonding 1 .
The pharmaceutical industry faces a critical problem: approximately 40% of marketed drugs and nearly 90% of developmental drug candidates suffer from poor solubility, significantly limiting their therapeutic effectiveness 3 . Multi-component crystals address this challenge by creating crystal structures with improved dissolution profiles and enhanced bioavailability.
Unlike alternative approaches such as nanotechnology or solid dispersions, cocrystallization modifies pharmaceutical properties without chemically altering the drug molecule itself, preserving its intrinsic pharmacological activity 1 . This method demonstrates remarkable versatility, capable of enhancing not just solubility but also stability, compressibility for tablet production, and even reducing hygroscopicity (moisture absorption) 1 3 .
A compelling recent study demonstrates how multi-component crystal technology addressed significant limitations of osimertinib (AZD), a heavyweight medication used for non-small cell lung cancer treatment 3 . Despite its therapeutic importance, osimertinib suffers from poor water solubility (only 0.513 μg/ml) and stability issues in its commercial form 3 .
Twenty-four potential coformers were virtually screened based on safety, pharmacological activity, and molecular compatibility
Computational approaches identified promising candidates
Eight different multi-component crystals were successfully prepared
Crystals were analyzed to confirm structures and properties
The multi-component crystal strategy produced dramatic improvements in osimertinib's pharmaceutical properties:
| Crystal Form | Solubility Improvement | Key Interactions |
|---|---|---|
| AZD-SAC | Significant increase | N-H···O bonds |
| AZD-25DHB | Significant increase | N···H-O bonds |
| AZD-34DHB | Significant increase | N-H···O bonds |
| AZD-FSM | Significant increase | N···H-O bonds |
Table 1: Solubility Enhancement of Osimertinib Multi-Component Crystals
Perhaps most notably, researchers successfully created drug-drug multi-component crystals that combine osimertinib with other active compounds like 5-fluorouracil, furosemide, and sulfadiazine 3 . These innovative structures enable the simultaneous delivery of multiple therapeutic agents to target cells, potentially overcoming drug resistance—a major challenge in cancer treatment 3 .
The success of this approach extended beyond theoretical interest. The AZD-5F multi-component crystal demonstrated significantly enhanced cytotoxicity against cancer cells compared to pure osimertinib, highlighting the very real therapeutic potential of this technology 3 .
The versatility of multi-component crystal strategy is further evidenced by its application to climbazole (CLB), a broad-spectrum imidazole antifungal drug hampered by low water solubility 6 . Researchers developed three novel multi-component crystals using different carboxylic acid coformers:
| Crystal Form | Type | Solubility vs. Pure CLB | Antifungal Activity |
|---|---|---|---|
| CLB-MA | Salt | 22 times higher | Enhanced |
| CLB-SA | Cocrystal | 12 times higher | Enhanced |
| CLB-AA | Cocrystal | 6 times higher | Enhanced |
Table 2: Climbazole Multi-Component Crystal Properties
These results demonstrate that multi-component crystals can significantly improve drug performance across multiple therapeutic classes. The dramatic solubility enhancements directly translated to improved antifungal efficacy, with all three forms showing lower minimum inhibitory concentrations than pure climbazole 6 .
Advanced crystal engineering relies on specialized techniques and materials for creating and characterizing multi-component crystals:
| Tool/Reagent | Function | Application Example |
|---|---|---|
| Single-Crystal X-ray Diffraction (SCXRD) | Determines precise molecular arrangement within crystal lattice | Considered "gold standard" for crystal structure determination 4 |
| Three-Dimensional Electron Diffraction (3DED) | Structure determination from nanocrystals too small for SCXRD | Solved structure from crystals 7 orders of magnitude smaller than SCXRD requirements 4 |
| Crystal Structure Prediction (CSP) | Computational prediction of possible crystal structures from molecular diagram alone | Polymorph risk assessment; structure solution from powder data 4 |
| Powder X-ray Diffraction (PXRD) | Analyzes crystalline phase and purity of powdered samples | Routine screening and quality control of crystal forms 4 |
| Thermal Analysis (TGA/DSC) | Measures thermal stability, phase transitions, and decomposition temperatures | Determining optimal processing conditions for pharmaceutical forms 6 |
| Carboxylic Acid Coformers | Common hydrogen bond donors in cocrystal formation | Malonic, succinic, and adipic acids in climbazole study 6 |
| Pharmaceutical Coformers | GRAS (Generally Recognized As Safe) compounds for pharmaceutical development | Saccharin, nicotinamide, carbamazepine in osimertinib study 3 |
Table 3: Essential Research Tools for Multi-Component Crystal Development
The sophisticated combination of computational prediction, experimental synthesis, and comprehensive characterization enables the rational design of multi-component crystals with tailored properties.
Computational methods identify potential coformers based on molecular compatibility and safety profiles.
Various methods including solvent evaporation and grinding are used to create multi-component crystals.
Advanced techniques like SCXRD and 3DED confirm the molecular arrangement within the crystal lattice.
Solubility, stability, and efficacy testing validate the improved pharmaceutical properties.
Multi-component crystals represent more than just a laboratory curiosity—they offer a powerful strategy for addressing some of the most persistent challenges in pharmaceutical development. By thoughtfully reorganizing drug molecules into more favorable crystalline arrangements, scientists can enhance solubility, stability, and bioavailability without altering the fundamental chemistry of the active ingredient.
This technology promises to breathe new life into shelved pharmaceutical candidates previously abandoned due to poor physicochemical properties.
The ability to create drug-drug multi-component crystals opens exciting possibilities for simplified combination therapies.
As research progresses, with advances in computational prediction methods 4 and synthesis techniques , we move closer to a future where crystal structures can be deliberately designed with precision, creating optimal versions of existing medications. In this emerging paradigm, the same drug molecules we've relied on for years may work better than ever before, all because scientists have learned to pack them more efficiently—proof that sometimes, it's not what you have, but how you arrange it that truly matters.