There are various research methods for the solid-state characterization of drugs. With its inherent advantages, X-ray powder diffraction (XRPD) has been widely used in the qualitative and quantitative studies of drug solid states. Research and exploration of XRPD are present throughout all stages of drug solid-state research. XRPD provides indirect information on the structural parameters of compounds, which can vary greatly depending on the structure of the material. So, how should diffraction patterns be interpreted? How can we use XRPD patterns to understand the crystallinity of a sample and whether the crystal form is consistent across batches?
Cloud Lecture Hall invites Mr. Zhonghua Zhang, who has many years of experience in solid-state development, to share his expertise in interpreting spectra through practical cases. He will also address how to resolve the difficulties encountered in experiments.
Q: Is the error between the actual sample diffraction peak value and the CCDC simulated diffraction peak value also based on 0.2°? All other peak positions match, but there is one peak with a difference of 0.3°. What could be the possible reason for this?
Zhonghua Zhang: The diffraction patterns in powder testing are generally calculated with an error margin of 0.2°. However, it is important to note that when using CCDC, there might be some differences between the simulated XRPD patterns and the actual measurements. Because CCDC calculates patterns theoretically, actual samples can be influenced by factors such as stress, environment, temperature, etc., leading to certain differences in peak positions compared to the theoretically simulated results.
If, based on a case study, the measured sample differs from the theoretical simulation by only 0.3° for one peak, I believe it’s possible that they represent the same crystal form. This is because theoretical peaks often show larger discrepancies compared to measured peaks. Of course, if needed, we can get in touch to look at the graphs together and discuss further.
Solid Form Screening Service
Q: Is there a detection method for the content of amorphous components in samples?
Zhonghua Zhang: The answer is affirmative. Methods such as XRPD, DSC (Differential Scanning Calorimetry), or DVS (Dynamic Vapor Sorption) can be used to detect the content of amorphous components. However, method development and validation are necessary. The specific detection method chosen depends on the actual circumstances.
Q: Can a suspension directly detect the crystalline form of insoluble APIs? In the case of combination formulations, would the dissolved form of another API in the mixture become undetectable?
Zhonghua Zhang: If it’s a suspension, and if not the entire API has dissolved in it, you can obtain a solid sample by centrifugation or filtration for direct XRPD testing. This method allows for the determination of the API’s crystalline form. If another API in a combination formulation has completely dissolved, then at that point, it becomes undetectable via crystalline form analysis because the concept of crystallinity primarily applies to solid states. In solution state, the notion of crystalline form does not exist.
Q: How do you compare the crystalline forms of a generic product with that of the original drug (innovator's API)?
Zhonghua Zhang: First, you can check this variety. If the API in the formulated product is a single crystal form without any polymorphic phenomena, then at this time, the crystal form of the self-made product and the original sample product will definitely be consistent.
The second method is to review existing literature to see if it can confirm which crystal form of this API is stable. Because generally, innovative products are developed using thermodynamically stable crystal forms. That means if the public literature, patents, and other data can determine the crystal form, then it can also determine the crystal form of both the innovative and self-made products.
Thirdly, you can perform XRPD testing by purchasing the innovative product to compare it with our product. Of course, during testing, it’s necessary to separately test the blank excipients. My viewpoint is that it’s preferable to use blank excipients prepared by following the formulation process rather than testing them directly. This is because some excipients may undergo phase transitions during the formulation process. For rigor and accuracy, this approach is advantageous for subsequent crystal form determination.
Q: How can the peak response intensity of the sample be improved?
Zhonghua Zhang: You can improve the peak response intensity by using delayed scanning. For example, if the current scanning time per step for a sample is 0.2 seconds, you can try longer times such as 2 seconds/step, 10 seconds/step, or even higher. This can increase the response intensity. Another method is to replace the X-ray tube, although this might not be straightforward as X-ray tubes are typically replaced at the end of their lifespan.
Another way is to widen the divergence slit or the anti-scatter slit, which can also increase the intensity. However, widening these slits will improve sensitivity but may decrease resolution. It’s important to adjust them based on the actual situation and requirements.
Q: What is the general detection limit for polymorphs using XRPD?
Zhonghua Zhang: It depends on the specific substance. For some substances, polymorph detection limits can be as low as 0.5%, while for others, it may require concentrations of 10% or more. There is no fixed numerical value for this. It’s also important to consider the scanning parameters, especially the scanning rate, as the detection limit may be influenced by the intensity of the X-ray tube during scanning.
Q: If XRPD is established as a standard, how do we determine consistency?
Zhonghua Zhang: Based on my previous experience, the first step is to compare the two XRPD patterns. Check if the overall spectra are consistent, if all diffraction peaks align correctly in terms of their positions, and ensure that the intensity differences of the major peaks are not too significant. Of course, the most crucial aspect is the peak positions in XRPD. Typically, we define several major peaks, list their 2θ values, and compare them with the 2θ values from the XRPD pattern of the test sample. We then assess whether the overall patterns match to establish consistency.
Q: When determining the consistency between two crystal forms, is it necessary to consider whether the peak intensities are consistent?
Zhonghua Zhang: When determining the consistency of crystal forms, the critical factor is primarily the positions of the drug’s crystal diffraction peaks rather than their intensities or their relative strengths. Furthermore, peaks at lower angles are more critical than those at higher angles, and major peaks are more important than minor peaks.
Q: If the two powder peaks appear to be consistent across a wide range, but there are two more small peaks, is the crystal form consistent?
Zhonghua Zhang: The crystal forms may be considered consistent or inconsistent. It was mentioned during the livestream that similarity in XRPD patterns alone should not be used to conclude consistency of crystal forms. It’s important to consider whether the testing process for both samples accounted for the elimination of preferred orientation effects. Additionally, it’s important to ascertain whether the two minor peaks are due to impurities or other potential sources of mechanical contamination. It is more appropriate to draw conclusions only after these factors are eliminated. Certainly, combining techniques like DSC (Differential Scanning Calorimetry), TGA (Thermogravimetric Analysis), or other auxiliary methods can also assist in making an informed judgment.
