Inventory of Several Technical Methods Used in Crystal Form Research

Polymorphs are widely studied and used in pharmaceutical preparations. The crystal form and crystal form of the drug are different, and their stability, solubility, dissolution rate, and bioavailability will vary. For the determination of the drug crystal form, the preliminary characterization is generally carried out by XRD, DSC/TG, ssNMR, RAMAN/FTIR, etc., and then single crystal or two-dimensional NMR; X-ray powder diffraction method is the most commonly used and effective method for studying drug polymorphs Some new drug R&D outsourcing agencies can conduct research on the polymorphic form of drugs.

1. XRD

XRD is called X-ray diffraction (X-Ray Diffraction). It is usually used to measure bulk materials such as powder, single crystal or polycrystal. The diffraction phenomenon of X-ray in the crystal is used to obtain the characteristics of the X-ray signal after diffraction, and the diffraction can be obtained after processing. Atlas. The use of spectral information can not only determine the phase of the conventional microscope, but also have a “perspective eye” to see whether there are defects (dislocations) and lattice defects inside the crystal. X-ray diffraction technology is an effective analysis and detection method for the composition and structure of solid drug samples. The study found that the X-ray diffraction method was used to determine the different crystal forms of atorvastatin calcium raw materials, and the X-ray diffraction method was used to identify the different crystal structure of atorvastatin calcium raw materials. It was found that the method was highly specific, accurate and reliable. It can be used to identify different crystal forms of atorvastatin calcium and can be combined with microscopy, infrared spectroscopy and other techniques to provide reliable crystal form information. Some researchers also use phthaloyl amlodipine and hydrazine hydrate as starting materials, through Gabriel reaction, salt formation reaction, and recrystallization process to obtain a new crystal form of the target compound. Results The structure of the target product was confirmed by mp, 1H-NMR, IR and XRD [1]. The results of the study found that the process produced a new crystal form of the target compound with better solubility and stability.

2. Thermal analysis method

Differential scanning calorimetry (DSC), thermogravimetric analysis (TG), and differential thermal analysis (DTA) are common thermal analysis methods. Thermal analysis is a quick and easy tool to determine the phase change of drugs under certain heating conditions , To conduct research by judging the difference in thermal effects between the stable crystal form and the metastable crystal form of the drug, and qualitative and quantitative research can be carried out through certain analytical methods. In the outsourcing of new drug development, thermal analysis method has become a common method in drug quality research, especially in the development and research of new drugs, which has attracted more and more attention. Thermal analysis is a common method in scientific research and characterization. Some researchers use a variety of physical/chemical methods to screen the polymorph of mifepristone; use powder X-ray diffraction analysis, differential scanning calorimetry, and thermogravimetric analysis. Characterization of polymorphic samples obtained by screening method and infrared spectroscopy; evaluation of the stability of polymorphic samples under high temperature, high humidity, and light conditions; drawing the dissolution curve of polymorphs in 6 different solvent media [2 ]. As a result, it was found that there is a polymorphism in mifepristone, and a new solvent-free crystal form was obtained through screening. The solubility of this crystal form is better than that of mifepristone. Through powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis, the newly discovered solvent-free crystal form of mifepristone can be distinguished from the raw material of mifepristone.

3. ssNMR

ssNMR (solid nuclear magnetic resonance) can be used for the qualitative and quantitative study of polymorphs, because the same atomic nucleus of different crystals or molecules of different configurations in the same crystal form is in different positions in the NMR spectrum due to different local chemical environments. In 2007, the US Food and Drug Administration listed solid-state nuclear magnetic technology as a recommended technology for the study and characterization of polymorphs in generic drugs. At the same time, the ICHQ6A guidelines also list solid-state nuclear magnetic technology as the recommended technology for analyzing the polymorphs of pharmaceutical raw materials or preparations. Medicilon provides new drug R&D outsourcing services. It has professional scientific research talents and advanced equipment in drug crystal form research, and has rich experience in crystal form research and kilogram-level process development.

4. RAMAN/FTIR

RAMAN (Raman spectroscopy) can be applied to the quantitative monitoring of crystal transformation during the synthesis of raw materials, polymorph identification, online evaluation of co-crystallization, etc. Raman spectroscopy has obvious advantages in the detection of low-frequency vibrations, and can even detect the lattice vibration of molecules. The relationship between the band intensity and the concentration of the analyte complies with Beer’s law and can be used for quantitative analysis of compounds; and simple sample preparation, It can be directly detected, avoiding the influence of the sample preparation process on the crystal form. Some researchers have used Fourier transform infrared (FT-IR) and Raman spectroscopy to characterize the hydrated and crystal-free forms of at room temperature, and the molecular vibration modes of the two crystal forms Attribution. The results show that the two crystal forms are significantly different in molecular vibration mode [3]. In addition, the Raman spectroscopy technique is used to study the dynamic characteristics of the crystal form transition of the hydrated crystal form due to water loss during the heating process, and the characteristic peaks at 785 and 798 cm-1 in the Raman spectrum whose peak area changes with heating time are selected. Establish a single exponential data fitting model. It can be seen from the results that during the heating and transformation of the hydrated crystal form, the disappearance of the characteristic peaks of the hydrated crystal form is consistent with the appearance of the characteristic peaks of the non-crystalline form. This result provides a theoretical basis for the quality control of polymorphic drugs and the establishment of drug crystal form transformation models. Mastering the research methods of polymorphs and understanding the properties of polymorphs play an extremely important role in formula development, pre-determination of drug formulations, optimization of production processes, drug quality control, storage conditions and clinical efficacy. In addition, polymorphs The role of research in the drug development process is not only to optimize performance, but also to ensure new intellectual property (IP) status and ensure effective intellectual property protection.

[1] Preparation of new crystal form of amlodipine aspartate [J].

[2] A new solvent-free crystal form of mifepristone [J].