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The research contents of drug crystalline forms mainly include: screening research on the state of polymorphic substances of drugs and lead compounds, characterization of crystalline substances by different analytical techniques, research on the safety and stability evaluation of crystalline substances, and biological activity evaluation of crystalline substances Research, evaluation of crystal forms of superior drugs, research on effective detection and analysis methods of crystal drug bulk drugs and solid preparations, and research on crystal drug standards.
Biological evaluation of crystal drugs
It is necessary to adopt scientific methods of biological evaluation that conform to the laws of the state of crystalline substances. Evaluation methods such as in vitro cell evaluation methods in solution state and administration in suspended liquids that have undergone transformation cannot reflect the true biological characteristics of solid crystalline substances. Therefore, in vivo animal experiments and solid administration methods should be used to obtain true biological evaluation data of crystalline substances.
Evaluation of the solubility or dissolution of crystalline drugs
When the raw material crystalline material state is different, the dissolution or dissolution properties of the crystalline raw material or solid preparations may be quite different, so it is necessary to study the relationship between the crystalline material and the dissolution or dissolution properties. Take solubility or dissolution rate, dissolution rate or dissolution rate as evaluation index.
The drug substance adopts the dissolution curve method, and the solid preparation adopts the dissolution curve method. You can refer to the relevant content of the “Guidelines for the Dissolution Test Technology for Oral Solid Preparations” for comparison of dissolution curves or dissolution curves.
When the substance is crystallized, due to various factors, the intra-molecular or intermolecular bonding mode is changed, resulting in different arrangement of molecules or atoms in the lattice space, forming different crystal structures. The phenomenon that the same substance has two or more spatial arrangements and unit cell parameters, forming multiple crystal forms is called polymorphism. Although only one crystal form is thermodynamically stable under a certain temperature and pressure, the process of transforming from a metastable state to a stable state is usually very slow, so many crystalline drugs have polymorphism. Solid polymorphs include conformational polymorphs, configurational polymorphs, color polymorphs, and pseudo-polymorphs.
Different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., thus affecting the stability, bioavailability and efficacy of the drug. This phenomenon is manifested in oral solid preparations. It is especially obvious. Drug polymorphism is one of the important factors affecting the quality and clinical efficacy of drugs. Therefore, when developing and reviewing drugs with polymorphism, special attention should be paid to their crystal structure analysis.
X-ray diffraction (X-ray diffraction) X-ray diffraction is the main method to study the crystal form of drugs. This method can be used to distinguish between crystalline and amorphous states, identify crystal types, distinguish mixtures and compounds, determine the crystal structure of drugs, and determine unit cell parameters (such as interatomic Distance, ring plane distance, double-sided included angle, etc.) can also be used to compare different crystal types. X-ray diffraction is divided into powder diffraction and single crystal diffraction. The former is mainly used for the identification and purity inspection of crystalline materials, and the latter is mainly used for the determination of molecular weight and crystal structure.
Infrared absorption spectroscopy
Certain chemical bond lengths and bond angles in different crystalline drug molecules will be different, causing their vibration-rotation transition energy levels to be different, and some of the main characteristics of the corresponding infrared spectrum such as absorption band frequency, peak shape, and peak position There will also be differences in peak intensity, etc., so infrared spectroscopy can be used for drug polymorph research. At present, there are more than 20 drugs known to have different infrared spectra due to different crystal forms.
Melting point method and hot stage microscope method
As mentioned above, the melting point of different drug crystal forms may be different. In addition to the common capillary method and melting point tester method, hot stage microscope is also one of the common methods to study the existence of drug polymorphs by melting point. This method can directly observe Crystal phase transition, melting, decomposition, recrystallization and other thermodynamic dynamic processes, so using this tool to determine the melting point according to the Pharmacopoeia can preliminarily determine whether the drug is polycrystalline.
The difference in melting point between the polymorphs of some drugs is small, or even no difference, so the determination of the polymorphs by the difference in melting point is only one of the preliminary detection methods. Generally speaking, the higher the stability of the crystal form, the higher the melting point; the difference between the melting points of the two crystal forms can be relatively estimated. If the difference between the melting points of the two crystal forms is less than 1°C, the two crystal forms can be precipitated at the same time during the crystallization process, and the relative stability of the two is difficult to distinguish. The closer the melting point of the two is, the more difficult it is to obtain the unstable crystal form.
Thermal analysis method
Different crystal types have different heat absorption and heat release during heating or cooling. The thermal analysis method is to measure the relationship between the physical and chemical properties of the substance and the temperature under program temperature control, and to judge the similarities and differences of the drug crystal forms through the measured thermal analysis curve. Thermal analysis methods mainly include differential scanning calorimetry, differential thermal analysis and thermogravimetric analysis. The thermal analysis method requires a small amount of sample, the method is simple, the sensitivity is high, and the reproducibility is good. It is commonly used in the analysis of drug polymorphs.
Polarized light microscope method
In addition to the structure of a general optical microscope, the most important feature of the polarizing microscope is that it is equipped with two polarizing parts, namely a polarizer (also called a lower polarizer) installed under the stage and an analysis lens (also called a lower polarizer) installed in the lens barrel. Called upper polarizer). Both mirrors are composed of artificial synthetic polarizers, and the incident light source can be converted into orthogonal polarized light by adjusting the angle. Because of this, this method is mainly suitable for transparent solid drugs.
The observation of transparent solid drugs is generally performed under cross-polarized light. Due to the different crystal structure and the birefringence effect when polarized light is incident, under the orthogonal action of the upper and lower polarizers of the polarizing microscope, when the crystal sample is placed on the stage and rotated 360º, the crystal appears short-lived and shiny , When the crystal is lost, the angle of intersection between the crystal and the direction of the polarizer’s vibration is called the extinction angle. The different extinction angles can determine the crystal type of the crystal].
Polarized light microscopy can also study the phase transition between crystal forms, and can accurately determine the crystal melting point; it has a special identification function for the structure of anisotropic animal and plant materials (such as fibrin, starch granules).
Nuclear magnetic resonance method
There are subtle differences in the chemical environment of the atoms in molecules in different crystal structures. Similar nuclei produce different responses to the applied external magnetic field, causing similar nuclei to resonate at different chemical shifts. Therefore, their 13C-NMR spectra are different. The comparison of different crystalline forms can determine whether the drug has polymorphism. By comparing with the 13C-NMR of known crystalline forms, the specific crystalline form of the test sample can also be obtained. In particular, the application of new technologies such as solid-state 13C-NMR, high-efficiency proton decoupling, cross-polarization (CP), and magic angle spin (CAS) that have emerged in recent years has enabled us to obtain high-resolution 13C-NMR spectra. This kind of spectrum can give detailed atomic level information about dynamics and local chemical environment. Therefore, this high-resolution 13C-NMR spectrum can be used for polymorphic mixed crystal analysis and certain characteristic crystal forms. Determination.
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