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The identification and analysis of impurity structures are crucial steps in ensuring the safety and efficacy of pharmaceuticals. Inadequate impurity research may pose risks to the safety and effectiveness of medications. Therefore, researchers and biopharmaceutical companies must conduct a series of tests to ensure impurities are effectively controlled and managed.
Medicilon Cloud Lecture Hall invites Yilan Wu from the Process Analysis Department to discuss the latest advancements in impurity structure analysis and provide insights on optimizing experimental operations.
Q1. What is the difference between single-crystal diffraction and powder X-ray diffraction?
Yilan Wu: Both methods can be used to examine crystal structures. Single-crystal diffraction is a precise technique for crystal structure analysis, focusing on studying a single crystal of a pure substance. By growing a single crystal, we can observe the periodic arrangement of atoms within the crystal. When the single crystal is exposed to X-rays, diffraction occurs. Analyzing the diffraction pattern allows us to reveal the exact arrangement of atoms in the crystal, thus completing the structure analysis.
Powder X-ray diffraction, on the other hand, is a widely used technique for analyzing polycrystalline structures, especially in pharmaceutical polymorphism research. It helps distinguish different crystalline forms of a drug and can even identify amorphous substances. During drug screening, powder X-ray diffraction is used to verify whether the drug’s crystalline form meets quality requirements. By measuring the X-ray patterns and data, this information can be utilized for in-depth analysis in subsequent quality control and research.
Q2. When performing structure identification, when are TGA and DSC used?
Yilan Wu: The application of thermal analysis techniques in pharmaceutical quality control is relatively limited, but their importance cannot be overlooked. According to the 2015 edition of the Chinese Pharmacopoeia, the use of thermal analysis instruments is not explicitly required as a mandatory item for pharmaceutical quality control. However, in enterprise registrations approved by the drug administration, DSC (Differential Scanning Calorimetry) is primarily used to determine the melting point of pharmaceuticals. The 2022 edition of the Chinese Pharmacopoeia leans toward the application of thermal analysis in pharmaceutical polymorphism research. For example, TGA (Thermogravimetric Analysis) can reflect changes in drug quality with temperature, such as desolvation, melting, or decomposition, thereby providing relevant information on the drug’s thermal stability. DSC (Differential Scanning Calorimetry) reveals phenomena like crystallization, melting, and changes in melting points, offering key data for drug structure identification. If a drug contains crystal water, is a solvate, or exhibits polymorphism, thermal analysis becomes an indispensable analytical method.
Q3. When is it necessary to use high-resolution mass spectrometry for supplementary elemental analysis?
Yilan Wu: In the field of pharmaceutical analysis, when dealing with drugs containing elements such as fluorine and phosphorus, and when elemental analysis cannot quantify certain elements, high-resolution mass spectrometry can be used for supplementary research. High-resolution mass spectrometry, with its exceptional sensitivity and accuracy, allows for precise quantification of drug elements, thus providing important supplementary information for comprehensive component analysis of the drug.
Q4. What purity requirements should high-resolution mass spectrometry meet to replace elemental analysis?
Yilan Wu: In the technical guidance principles for structural confirmation of chemical drug raw materials, a reference standard is that the raw materials must achieve a purity of 99% and keep impurity content below 0.5%.
Q5. Why does the absence of a peak in ESI (Electrospray Ionization) indicate that a compound has low polarity?
Yilan Wu: From a detection principle perspective, ESI (Electrospray Ionization) uses an electric spray voltage to form small droplets from charged particles in a solution under the influence of an electric field. The solvent is then evaporated by gas flow, and the droplets undergo a phenomenon known as “Coulomb explosion,” leading to ionization of the compound. More polar compounds are more easily charged in the electric field, making them more likely to form ions in the ESI source.
On the other hand, APCI (Atmospheric Pressure Chemical Ionization) is an atmospheric pressure chemical ionization process. Under the influence of an electric field, solvent molecules are first ionized and charged. These charged solvent molecules then interact with the analyte, transferring the charge to the analyte and forming molecular ions. Therefore, less polar compounds are more likely to produce peaks in an APCI source, while their ionization in an ESI source is weaker.
Q6. How is heavy water exchange typically carried out? If there is interference between the water peak and the sample peak, how can it be resolved?
Yilan Wu: Heavy water exchange is an analytical technique used to identify active hydrogen. In cases where the sample is precious, the process involves recovering the NMR sample and adding 50-100 microliters of heavy water for treatment. The sample must then be thoroughly mixed before performing Nuclear Magnetic Resonance (NMR) analysis.
When the sample signal peak interferes with the residual water peak from heavy water, other deuterated reagents can be used for active hydrogen exchange, such as deuterated methanol or deuterated acetic acid. The choice of deuterated reagent for active hydrogen exchange depends on factors such as the actual peak appearance of the deuterated reagent and the stability of the compound’s solution. These alternative deuterated reagents help to eliminate interference.
