Crystal Structure Prediction

Traditionally, solid-state studies for small molecule drug candidates rely almost exclusively on experimental screening. However, under the constraints of time and material supply, it is often challenging and expensive to determine the best crystalline form for drug production. Crystal structure prediction (CSP) can quickly and reliably identify the most stable crystal forms in 2-3 weeks and provide their thermodynamic stability rankings across a range of temperatures (0K-400K). In combining CSP with experimental screening, researchers can judge with greater confidence whether the current experimental screening is sufficient, verify the purity of the selected crystal powder, and understand the stability risks of crystal forms obtained in the laboratory. This integrated approach effectively accelerates the solid-state research and decision-making process and greatly reduces the overall risk in late-stage development.

A CSP solution designed for pharmaceutical research must be fast, highly accurate, and reliable even when handling complex molecular systems. XtalPi combines quantum physics, computational chemistry, artificial intelligence, and cloud computing technology to build a state-of-the-art high-performance CSP platform that can screen billions of crystal structures and determine their stabilities with exceptional accuracy and efficiency. With the XtalPi platform, the CSP for a common-case small molecule drug candidate can be completed within just 2-3 weeks. For more complex molecular systems, including highly flexible molecules with more than 15 rotatable bonds, complex isomerization of multiple flexible rings, salts, co-crystals, hydrates, and solvates, the CSP process takes 5-6 weeks. XtalPi’s proprietary CSP platform can deploy millions of cores of cloud computing resources within minutes, run hundreds of CSP tasks simultaneously, and has proven itself as a valuable tool in expediting solid form screening and selection and de-risking drug R&D projects for innovative pharmaceutical companies worldwide.

Added Value of XtalPi’s CSP service

  • Accomplish crystal form study in just a few weeks and improve R&D efficiency
  • Significantly reduce the number of experimental trials and the time needed, reducing R&D costs
  • Help ensure the quality and efficacy of drugs and avoid the risk of recall
  • Ensure the completeness of polymorph screenings, effectively protect the intellectual property rights of drugs, and fend off competition’s challenge during patent exclusivity.

Scope of XtalPi’s CSP service

  • Provide all of the screened experimental structures, as well as potential thermodynamically stable and metastable structures
  • Provide stability ranking of different structures across a range of temperatures (0K-400K)
  • Provide stability assessment between anhydrate and hydrate forms
  • Provide three-dimensional crystal structure information corresponding to XRPD
  • Study the disorder of terminal groups at different temperatures

Case Studies

Case 1

Accelerating the R & D Process

Crystal structure prediction can accelerate the selection process of the optimal medicinal solid form, reduce the risks associated with form selection, and increase the success rate of the solid form development.

---case study with a Chinese innovative pharmaceutical company

Background: An innovative drug company in China wanted to determine the medicinal crystal form of a drug candidate in its pipeline and control the risk associated with form selection within 2 months. The project schedule was tight, requirements were high, and traditional experiments could not meet the customer’s demand. In this case, XtalPi was invited to conduct crystal structure prediction on the molecule to help the client solve the problem within the limited timeframe.

In 37 days, with a combination of experiments and calculations, XtalPi conducted a complete solid form risk assessment to identify the most ideal form based on the client’s needs. Through the cross-validation of the experimental and computational screening results, XtalPi quickly predicted and physically identified freebase crystal forms I / III / V and determined form I to be the most stable form.

This combination of experiment and CSP can effectively improve the efficiency of solid-form screening and provide crucial insight to support drug development decision-making, ultimately shortening the project cycle.

Case 2

Patent Protection and Shelf Life Extension

The polymorph patent is the most important physical patent besides the composition of matter patent. CSP can provide complete coverage of crystal structures in the low energy region, helping pharmaceutical companies to evaluate whether there are additional potential high-quality crystal forms. As proven in many cases, XtalPi’s CSP service can provide information critical for decision-making within the scope of crystal patent protection and helps to reduce patent risk and protect the patent validity, safeguarding the drug throughout its exclusive sales period.

---XUS001, case study with a top multinational pharmaceutical company

Background: The drug candidate XUS001 was in the clinical development stage when a multinational pharmaceutical company bought the innovator company that developed the drug. During the acquisition, the acquiring company found through experimental research that the original company did not conduct a complete crystal form research on the compound that is up to its own filing standard. Therefore, there was a potential polymorph patent risk. The negotiation deadline was near, and the acquiring company did not have enough time to carry out sufficient crystal form screening with experiments. So it chose our CSP service to determine the polymorph risk and aid in negotiations during the acquisition process.

In the absence of any experimental information, XtalPi was able to help the acquiring company solve this problem by completing CSP within 17 days. From the CSP, we accurately predicted all three experimental crystal forms and their relative stability was determined. The CSP and stability ranking with temperature correction demonstrated that Form I, which was the form selected innitially for clinical trials, was the most stable crystal form. Based on these results, the acquiring company decided to complete the acquisition of the original company and started to market the drug XUS001 according to the original plan.

Case 1

Accelerating the R & D Process

Crystal structure prediction can accelerate the selection process of the optimal medicinal solid form, reduce the risks associated with form selection, and increase the success rate of the solid form development.

---case study with a Chinese innovative pharmaceutical company

Background: An innovative drug company in China wanted to determine the medicinal crystal form of a drug candidate in its pipeline and control the risk associated with form selection within 2 months. The project schedule was tight, requirements were high, and traditional experiments could not meet the customer’s demand. In this case, XtalPi was invited to conduct crystal structure prediction on the molecule to help the client solve the problem within the limited timeframe.

In 37 days, with a combination of experiments and calculations, XtalPi conducted a complete solid form risk assessment to identify the most ideal form based on the client’s needs. Through the cross-validation of the experimental and computational screening results, XtalPi quickly predicted and physically identified freebase crystal forms I / III / V and determined form I to be the most stable form.

This combination of experiment and CSP can effectively improve the efficiency of solid-form screening and provide crucial insight to support drug development decision-making, ultimately shortening the project cycle.

Case 2

Patent Protection and Shelf Life Extension

The polymorph patent is the most important physical patent besides the composition of matter patent. CSP can provide complete coverage of crystal structures in the low energy region, helping pharmaceutical companies to evaluate whether there are additional potential high-quality crystal forms. As proven in many cases, XtalPi’s CSP service can provide information critical for decision-making within the scope of crystal patent protection and helps to reduce patent risk and protect the patent validity, safeguarding the drug throughout its exclusive sales period.

---XUS001, case study with a top multinational pharmaceutical company

Background: The drug candidate XUS001 was in the clinical development stage when a multinational pharmaceutical company bought the innovator company that developed the drug. During the acquisition, the acquiring company found through experimental research that the original company did not conduct a complete crystal form research on the compound that is up to its own filing standard. Therefore, there was a potential polymorph patent risk. The negotiation deadline was near, and the acquiring company did not have enough time to carry out sufficient crystal form screening with experiments. So it chose our CSP service to determine the polymorph risk and aid in negotiations during the acquisition process.

In the absence of any experimental information, XtalPi was able to help the acquiring company solve this problem by completing CSP within 17 days. From the CSP, we accurately predicted all three experimental crystal forms and their relative stability was determined. The CSP and stability ranking with temperature correction demonstrated that Form I, which was the form selected innitially for clinical trials, was the most stable crystal form. Based on these results, the acquiring company decided to complete the acquisition of the original company and started to market the drug XUS001 according to the original plan.

Core Technology

Crystal Search Technology XForce Field Technology Lattice Energy Calculation Technology Stability Ranking HPC Computing Technology Crystal Structure Prediction Technology