Crystal Polymorph Search in the NPT Ensemble via a Deposition/Sublimation Alchemical Path

Aaron J Nessler; Okimasa Okada; Yuya Kinoshita; Koki Nishimura; Hiroomi Nagata; Kaori Fukuzawa; Etsuo Yonemochi; Michael J Schnieders

doi:10.1021/acs.cgd.3c01358

Crystal Polymorph Search in the NPT Ensemble via a Deposition/Sublimation Alchemical Path

Cryst Growth Des. 2024 Mar 9;24(8):3205-3217. doi: 10.1021/acs.cgd.3c01358. eCollection 2024 Apr 17.

Authors

Aaron J Nessler¹, Okimasa Okada², Yuya Kinoshita³, Koki Nishimura³, Hiroomi Nagata⁴, Kaori Fukuzawa⁵, Etsuo Yonemochi⁶, Michael J Schnieders^{1

7}

Affiliations

¹ Department of Biomedical Engineering, University of Iowa, 103 South Capitol Street, 5601 Seamans Center for the Engineering Arts and Sciences, Iowa City, Iowa 52242, United States.
² Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
³ Analytical Development, Pharmaceutical Sciences, Takeda Pharmaceutical Company Limited, 2-26-1, Muraoka-Higashi, Fujisawa 251-8555, Kanagawa, Japan.
⁴ CMC Modality Technology Laboratories, Production Technology and Supply Chain Management Division, Mitsubishi Tanabe Pharma Corporation, Osaka 541-8505, Japan.
⁵ Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
⁶ Department of Physical Chemistry, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
⁷ Department of Biochemistry, University of Iowa, 51 Newton Road, 4-403 Bowen Science Building, Iowa City, Iowa 52242, United States.

Abstract

The formulation of active pharmaceutical ingredients involves discovering stable crystal packing arrangements or polymorphs, each of which has distinct pharmaceutically relevant properties. Traditional experimental screening techniques utilizing various conditions are commonly supplemented with in silico crystal structure prediction (CSP) to inform the crystallization process and mitigate risk. Predictions are often based on advanced classical force fields or quantum mechanical calculations that model the crystal potential energy landscape but do not fully incorporate temperature, pressure, or solution conditions during the search procedure. This study proposes an innovative alchemical path that utilizes an advanced polarizable atomic multipole force field to predict crystal structures based on direct sampling of the NPT ensemble. The use of alchemical (i.e., nonphysical) intermediates, a novel Monte Carlo barostat, and an orthogonal space tempering bias combine to enhance the sampling efficiency of the deposition/sublimation phase transition. The proposed algorithm was applied to 2-((4-(2-(3,4-dichlorophenyl)ethyl)phenyl)amino)benzoic acid (Cambridge Crystallography Database Centre ID: XAFPAY) as a case study to showcase the algorithm. Each experimentally determined polymorph with one molecule in the asymmetric unit was successfully reproduced via approximately 1000 short 1 ns simulations per space group where each simulation was initiated from random rigid body coordinates and unit cell parameters. Utilizing two threads of a recent Intel CPU (a Xeon Gold 6330 CPU at 2.00 GHz), 1 ns of sampling using the polarizable AMOEBA force field can be acquired in 4 h (equating to more than 300 ns/day using all 112 threads/56 cores of a dual CPU node) within the Force Field X software (https://ffx.biochem.uiowa.edu). These results demonstrate a step forward in the rigorous use of the NPT ensemble during the CSP search process and open the door to future algorithms that incorporate solution conditions using continuum solvation methods.