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Single crystal structure analysis is an important tool to determine the composition and crystal structure of drug molecules, which can obtain information about crystal cell parameters, molecular symmetry (crystal system, space group), molecular bonding mode (hydrogen bond, salt bond, coordination bond), molecular conformation, absolute conformation, etc. The structure of the APIs and possible impurities and intermediates designed in a pharmaceutical product needs to be confirmed when the drug is registered and declared. Therefore, it is extremely important for drug production to obtain a comprehensive and complete structural confirmation report.
ReadCrystal can provide comprehensive and rigorous services for the structural confirmation of drug molecules by cultivating single crystals of drug molecules in various ways. We can provide customized structural analysis solutions in combination with single crystal X-ray diffraction technology and MicroED technology.
Objective: To confirm the absolute conformation of drug molecules by single crystal culture and analysis
Single Crystal Culture
Conventional single crystal culture methods
Unconventional single crystal culture methods
Volatilization: The solution of the dissolved compound is made to evaporate continuously until the solution reaches a saturated, supersaturated state from an unsaturated one. Eventually the crystals precipitate out.
Vapor diffusion method: Using two organic solvents that are completely miscible and have a large difference in boiling point. The solid is readily soluble in the high boiling point solvent and intolerant or insoluble in the low boiling point solvent. In a closed container, the low boiling point solvent evaporates into the high boiling point solvent, reducing the solubility of the solid, which precipitates nuclei and grows into single crystals.
Sublimation method: Used only for solids. Usually a purification furnace (also known as tube furnace) is used and the furnace cavity is vacuumed, the solid is heated to sublimate it and cooled in temperature bands to obtain deposition, which can form single crystals within the walls.
Solubilization: A solute is dissolved in water or other organic solvent and then a solvent is added to the crystals to reduce the solubility of the solute in the original solvent so that it crystallizes rapidly. The added solvent is called solubilizers or precipitating agent. Solubilizers can be either gas or liquid.
Cooling method: The compound is dissolved in some kind of solvent and the process is controlled by slowly cooling it down to allow the compound to crystallize out.
Solvothermal method: The solutes are mixed in a specific solvent and placed in a closed, high-temperature metal container. The reactants react under the self-generated pressure of the system by heating. High temperature and long periods of time are benefit for crystallization. Better crystals can be expected to obtain by controlling conditions such as reaction temperatures.
Crystalline sponge method:
A method of visualizing structures without the need for single crystal incubation. It is suitable for small molecules and molecules that difficult to crystallize. Using the reticulated crystal sponge, the guest molecules to be analyzed are ordered in the pores of the main body of the crystal sponge through host-guest interactions and the molecular structure is then determined by X-ray diffraction, requiring samples which weigh down to micrograms or even nanograms.
• Samples which are difficult to crystallize
• Trace samples
• Oil-like molecules
Modification of drug molecules or addition of ligands:
Chemical structure modification of a drug is only changing some functional groups based on retaining the original basic chemical structure of the drug.
The main way to add ligands to a drug molecule is to make the drug molecule form a salt type, eutectic or solvate. Salt type means that the drug ionizes combines with counter ions to form crystals; eutectic is the product of combining API molecules and CCF molecules in the same lattice; when the solvent molecule that forms crystals together with the main drug molecule is an organic solvent, the crystal becomes a solvate.
X-ray single crystal diffraction
X-ray single crystal diffraction: An experimental method to determine the crystal structure by using the diffraction effect of single crystals on X-rays. The diffraction pattern is generated by the first Fourier transform, and then the structure resolution is completed by the second Fourier transform to obtain the stereo structure image of organic molecules.
The advantage of X-ray diffraction over the other four spectra (IR, UV, MS and NMR) in determining the structure of molecules is that only a suitable single crystal is needed to give the three-dimensional molecular structure of a substance independently of other information.
MicroED is our superior technology, it is a structure resolution technique developed based on cryo-electron microscopy. Electron diffraction data is collected and analyzed by diffracting electrons from tiny crystals. The technique requires extremely small crystal sizes, micro- and nano-sized crystals can produce diffraction signals with sufficiently high signal-to-noise ratios. High resolution diffraction data can be provided quickly and efficiently, significantly reducing the requirements for sample shape, purity and size.
If your cultured single crystals consistently fail to meet the size requirements for X-ray diffraction detection, try to use MicroED. It can save single crystal culture time and accelerate your project.