Different crystal forms of the same drug often have different physicochemical properties, and may also have different solubility dissolution rate, bioavailability, chemical and physical stability, melting point color, filterability, density and fluidity. Some polymorphs are difficult to formulate due to their shape or hygroscopicity. For example, needle-like crystals are very "sticky" because they carry static electricity. The study of drug polymorphism and its quality control is of great significance to ensure the stability of drugs in the production and storage process and the safety and effectiveness in clinical use.
For example, aspirin has a crystal form and a crystal form, and the blood concentration measured after giving the same dose of the drug to healthy volunteers respectively shows that the blood concentration of aspirin exceeds that of aspirin by 70%.The anti-AIDS drug ritonavir (riton**ir) discovered by Abbott Pharmaceutical Company in 1992 existed in a type form and was launched in 1996, but in 1998, it was found that the marketed product ** appeared to be a more stable type, which seriously affected its effectiveness, resulting in ritonavir capsules (riton**ircap-sules) being withdrawn from the market and re-marketed after research and improvement. Therefore, the quality standard of BP2012 ritonavir indicates that this product has a polymorphic form.
In addition, in recent years, the number of patents for new drug forms has increased, and many manufacturers have conducted complementary research on new crystal forms of original products to maintain and extend the interests of products. At the same time, it is generally believed that most of the reasons for the differences in clinical efficacy between generic drugs and original drugs, the same drugs produced by different enterprises, and different production batch numbers of drugs by the same enterprise are due to the changes in the existence state of crystalline substances of solid chemical drugs. The same drug will not only have different physical properties due to different crystal forms, but also have obvious differences in its biological activity. The biological activity of some drugs with different crystal forms not only varies significantly, but also interferes with the clinical application of drugs. Therefore, it is of great practical significance to study the polymorph of drugs and formulate appropriate quality standards for controlling the polymorphs to improve the efficacy, safety and quality stability of drugs.
Infrared spectrophotometry
In the 70s of the 20th century, FTIR spectroscopy has developed into a new type of instrument that is widely used. It is the infrared light emitted by the light source modulated by the interferometer to obtain the interference light, after the interference light passes through the sample chamber, the detector to obtain the interference map containing the spectral information of the sample. The interferogram is a time-domain function, and the fast Fourier transform is performed by the computer to obtain the infrared spectral map with frequency variation. Dispersive infrared spectroscopy uses a monochromator to decompose polychromatic light into n resolving units, and determines its spectral pattern with frequency change one by one. Substances with different crystal forms have different lattice energies due to the different modes of intermolecular forces and intensities of their internal molecules, resulting in differences in infrared spectroscopy (IR), such as the movement of the position of the absorption peak, the change of the absorption intensity, and the increase or decrease of the number of absorption peaks. If the same drug obtains different infrared spectra, the presence of polymorphs must be considered, but it is difficult to distinguish when the infrared spectra between different crystal forms of the drug are small.
When using the IR method KBR tableting sample preparation to determine the drug crystal form, it should be noted that the grinding and tableting process may lead to the change of the drug crystal form, and the paraffin paste method or solution method can be tried to determine the drug crystalline. The mebendazole and palmithenicol included in the second part of the 2010 edition of the Chinese Pharmacopoeia are controlled by IR. In addition, the DRIFTS technique has been used to successfully separate the four crystal states of puerarin (i.e., crystal form, crystal form, crystal form and crystal form) and describe their characteristics separately.
Near-infrared spectrophotometry
At present, near-infrared spectrophotometry (NIRS) is widely used in the qualitative and quantitative study of drug crystal forms, and most of the common NIRS spectrometers on the market belong to the reflection type, especially the diffuse reflection type analyzer. The crystal form of chlorpiglirel sulfate raw materials produced by domestic manufacturers was analyzed by near-infrared spectroscopy, and it was found that there was an inconsistent crystal form of clopiglirel sulfate raw materials produced by domestic manufacturers. In the study of the polymorphism of zolpidem tartrate API by infrared spectroscopy, the results showed that there was a polymorphism problem in zolpidem tartrate API, and there were certain differences in the mixing ratio of samples produced by different enterprises. The characteristics of the effective A crystal form in cimetidine were analyzed by near-infrared method, and the results showed that the bioavailability of the A crystal form was the best. Several studies have shown that NIRS can effectively distinguish between drug polymorphic states;However, the spectral band of near-infrared spectroscopy is wide, the characteristics are not strong, and it is difficult to identify some organic functional groups, and the structural analysis cannot be carried out.
Because near-infrared spectroscopy and diffuse reflectance infrared spectroscopy do not require sample preparation, and have the advantages of fast, accurate, stable and simultaneous quantitative analysis of multiple components, the application of infrared spectroscopy in the study of pharmaceutical polymorphs has been expanded. Diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) is a newly developed infrared spectroscopy technique, which has high sensitivity and a wide range of sample concentrations, and can be used to measure samples without separation and extraction.
Summary. In recent years, infrared spectroscopy analysis technology has made great progress in polycrystalline analysis. The combination of diffuse reflectance infrared Fourier transform spectroscopy and near-infrared spectroscopy with thermal microscopy has made great contributions to the study of polycrystalline analysis. In particular, when combined with other analytical techniques, it is more conducive to the composition analysis, structure identification, and quantitative determination of drug polymorphs.
In summary, the use of infrared spectroscopy for the identification of pharmaceutical polymorphs is an aspect of infrared spectroscopy application in recent years. Infrared spectroscopy has the advantages of fast, non-destructive sample, and advanced detection, which is suitable for drug crystal form monitoring in the drug production process, and is a simple and exclusive identification method, which will surely become one of the drug polymorph identification methods. With the popularization of FTIR spectroscopy and the supporting use of computers, infrared spectroscopy will also play its unique role in the identification of drug polymorphs, especially the combination of infrared spectroscopy and other analytical methods will make its application in drug polymorph identification have broad prospects.