Crystal Structure Determination

XRPD (X-Ray Powder Diffraction) is the most common method to identify the crystalline form because each XRPD pattern has its unique characteristic peaks with different positions and relative strengths. However, the XRPD signal is the superposition of the diffraction intensity of a large number of solid powder particles. An XPRD itself doesn’t provide enough information to answer important questions such as whether the solid powder is a single or pure crystal phase, is there a disorder of terminal groups, whether the impurities are contained. The FDA requires that three-dimensional (3D) structural information of all marketed drugs be provided to ensure the consistency of the solid form during manufacture. In recent years, CFDA has also become increasingly rigorous, making 3D structures a requirement for marketed drugs.

XtalPi has developed a crystal structure analysis technology based on the experimental data and theoretical methods, which can obtain the 3D structure information of drug solids that are traditionally hard to determine solely by experiments. With a small amount of solid powder or XRPD spectrum, the 3D structure information can be easily obtained. The 3D structure information of the solid powder obtained not only meet the legal requirements for quality-control but also provide a foundation for further calculations and analysis on important physicochemical properties, including stability, solubility, and moisture absorption. In cases where one has a limited amount of time and material available, this computational analysis could effectively assist in determining the ideal solid form of the drug candidate for early-stage drug development and discovery projects. This approach was widely used in some of XtalPi’s projects with top pharmaceutical clients and was shown to yield valuable results.

The Importance of Crystal Structure Research

Reporting Requirements

In the United States, Europe, China, Japan, and other major pharmaceutical markets, drug regulatory authorities (FDA/EMA/NMPA/PMDA) require that the single crystal structure of pharmaceutical solid form of API should be specified in the NDA application to prove that the applicant has thoroughly studied the crystal structure of API and has scientific and technical standards for production and quality control.

Patent Protection

For an API, patenting the crystal form is crucial to the compound form. The complete crystal patent and its comprehensive application prospects will have a significant impact on the life cycle of patented drugs and corporate profits. In recent years, crystal structure patents of some drugs have been invalidated because of inaccuracies in the descriptions of the characteristic XRPD peaks. The main reason is that there is no single crystal structure for the specific crystal pattern.

Quality Control

During the API production process, the manufacturer conducts sampling tests to determine the overall quality of the material. XRPD data of pure crystal powder, which depends on the confirmation of single crystal structure is needed. As long as the single crystal structure of specific crystal type is obtained, the standard of quality control can be clarified by simulating XRPD data, and further optimization of the production process and product quality can be achieved.

Property Analysis

For the research and development of innovative drugs, it is necessary to predict the physical properties of different solid forms to identify the ideal solid form for the drug product. The most common predictions include solubility prediction, polycrystalline diversity prediction, moisture absorption prediction, crystal habit prediction, and crystallizable condition prediction. The prediction results of the single crystal structure can help the experimentalists to narrow down the screening range and improve the efficiency of their research efforts.