Introduction of Salt/Co-crystal
In the research of formulations, the choice of solid form of drugs is an important factor to consider. The solid forms of drugs mainly include polymorphs, salts, hydrates or solvates, and co-crystals. In the pre-research stage of drug prescription, the solid form of the drug needs to be selected according to the nature of the drug and the requirements of the target formulation. Salt/co-crystal is a crystalline substance in which API molecules and ligand molecules are embedded in the same crystal lattice. As a solid-state form of drugs that can be designed, salt and co-crystals with a wide variety of types and applications have received more and more attention in recent years. Salt/co-crystal enables to make the solid form of the drug more abundant, especially for the active pharmaceutical ingredients that are amorphous, non-dissociated or low in PKa, salt/co-crystal is an important approach to change the solid form of the drug. Therefore, salt/cocrystal screening as a tool for rational crystal engineering has an important role in drug research and clinical applications.
Figure 1. Classification of crystalline API forms. (Newman, A.; Wenslow, R. 2016)
Introduction of Salt/Co-crystal Screening
Salt/co-crystal screening is an experimental process to determine whether a candidate can crystallize with a known API. At Alfa Chemistry, the solubility characteristics, chemical structure, medicinal efficacy, and targeting of the compound are fully considered to perform an effective screening.
Advantages of Co-crystal
- Significantly improve the physical and chemical properties of API without destroying the covalent bond, such as melting point, solubility, permeability, stability, bioavailability, and mechanical properties.
- Mask the taste of drugs
- Improve the performance of drug compression
The fact that novel drug candidates are becoming increasingly insoluble is a major problem of current drug development. We apply various computational tools to solve this issue by screening for suitable solvents or by identifying potential novel salt/co-crystal formers that increase bioavailability. Alfa Chemistry provides easy-to-use models and computational tools for salt/co-crystal screening. Our rapid and high-quality services are as follow:
- Conductor-like screening model for real solvents (COSMO-RS )
We have established a fluid phase thermodynamics approach to investigate the drug solubility, solvate and cocrystal formation and many other thermodynamics properties in liquids. The excess enthalpy Hex between API and coformer mixture reflects the tendency of those two compounds to cocrystallize. And we use it to obtain a reasonable ranking of coformers for an API. Potential coformers are able to be identified for cocrystallization, and solvents with highest value of Hex with an API, are selected which had the least probability to form solid solvates.
1. We use the screening charge density as computed from first principles calculations in combination with fast statistical thermodynamics to calculate the chemical potential of a compound in solution.
2. Structures for database constituents have been obtained by AM1/COSMO geometry optimization followed by a single point DFT/COSMO calculation (BP-SVP level of theory) with TURBOMOLE.
3. Our scientists can extend the prediction of co-crystal formation into the predictive accuracy concerning coformer screening.
- Graph neural network (GNN)
At Alfa Chemistry, we have developed a novel GNN based deep learning framework to predict formation of the cocrystal.
1. We create a complementary strategy for the feature representation through combining the molecular graph and hand-selected molecular descriptors to collect and organize a large and reliable data set.
2. Our scientists also introduce a multi-head attention mechanism into the GNN method to further optimize the feature space through weighted summation of atom vectors.
- Synthon matching
Synthon matching is another important tool for the salt/co-crystal screening and our groups apply this powerful method to investigate the intermolecular interactions in the crystal structure.
1. We apply it to estimate the possibility of hydrogen bond formation between API and coformer.
2. Various methods are available to determine the intermolecular interactions in crystal structures qualitatively and quantitatively, such as the conformational similarity index for proteins, graphset analysis for hydrogen bonds, Voronoi-Dirichlet polyhedral for crystal packing, continuous symmetry measures, and the Hirshfeld surface.
3. Alfa Chemistry supports a diversity of computer programs such as ESCET, COMPACK, TOPOS, Xpac, Crystal Explorer, and dSNAP to perform synthon matching approaches.
- Fabian's method
We extract different sets of reliable salt/co-crystal forming structures from the CSD, and the molecular descriptors (single atom, bond and group counts, hydrogen bond donor and acceptor counts, size and shape, surface area and molecular electrostatic) are calculated for each molecule. On the basis of calculated molecular properties, the database described pairs of molecules that are able to form salt/co-crystals. The strongest descriptor correlation is related to the shape and polarity of salt/co-crystal formers.
Alfa Chemistry's Advantages
- ·We can achieve fast and accurate assessment of drug solubility and the identification of suitable solvents, solvate or co-crystal formers.
- ·Our well-designed approach is able to complete the salt/co-crystal screening avoiding costly quantum-chemical computations using a database of previously computed molecular fragments.
- ·Our model provides quick and accurate solution for the virtual salt/co-crystal screening by predicting the out-of-distribution of energetic salt/co-crystals with high accuracy.
- ·Furthermore, the dataset obtained from our salt/co-crystal screening also provides a data support for subsequent machine learning-based co-crystal study.
Our salt/co-crystal screening services remarkably reduce the cost, promote further experiments, and accelerate the process of drug design for customers worldwide. Our personalized and all-around services will satisfy your innovative study demands. If you are interested in our services, please don't hesitate to contact us. We are glad to cooperate with you and witness your success!
- Newman, A.; Wenslow, R. Solid form changes during drug development: good, bad, and ugly case studies. AAPS Open. 2016, 2(1): 2.