A New Publication
Dr. Jian Wang, of Center for Pharma Crystallization (CfPC) at J-Star Research, has served as a speaker of PCS 2020 and 2021, session host in 2020 and 2022, as well as the director of PCS from 2020 to 2022.
Their new publication has just become available: “Novel Computational Approach to Guide Impurities Rejection by Crystallization: A Case Study of MRTX849 Impurities”, Yuriy A. Abramov, Amanuel Zelellow, Cheng-yi Chen, Jian Wang, and Sivakumar Sekharan, Cryst. Growth Des. 2022, https://pubs.acs.org/doi/full/10.1021/acs.cgd.2c00957.
Computational methodologies are playing more and more important roles in supporting fast paced new drug development, including crystallization process development. In this publication, a novel model was proposed on impurity rejection by crystallization. The model considers solvent, lattice substitution, and doping level contributions and provides a comparison of rejection efficiencies of multiple impurities and solid forms. It overcomes the current models’ shortage of one mechanism and one impurity at one time. Application of this model provides intuitive guidance for the experimental design and testing, allows significant reduction of material needs and experimentation time.
2022 Q1 Publications
Prof. Calvin (Changquan) Sun of University of Minnesota is a keynote speaker of 2021 Pharma Crystallization Summit (PCS) in the session of Particle Engineering & DS-DP Co-Processing. He presented “Challenges and Opportunities in Optimizing Mechanical Properties of Drugs by Incorporating Excipients”. In 1st quarter of 2022, six new articles have been published by Prof. Sun and his team on pre-formulation, formulation, and material science & engineering.
“Nanomechanical testing in drug delivery: Theory, applications, and emerging trends”, Sushmita Majumder, Changquan Calvin Sun, Nathan A. Mara, Advanced Drug Delivery Reviews 183 (2022) 114167,
The teams of Prof. Sun and Prof. Mara reviewed the applications of nanomechanical testing methods in pharmaceutical industry of recent years. The article clearly highlighted the important role of nanomechanical testing in mechanical properties characterization of drug crystals and developing better knowledge for solid form selection, milling, formulation design and manufacturing.
Publications 2 and 3
“Simultaneous improvement of physical stability, dissolution, bioavailability, and antithrombus efficacy of Aspirin and Ligustrazine through cocrystallization”, Kairu Wang et al, International Journal of Pharmaceutics 616 (2022) 121541
“Complexation with aromatic carboxylic acids expands the solid-state landscape of berberine”, Ziyao Gao, Shuyu Liu, Changquan Calvin Sun, International Journal of Pharmaceutics 617 (2022) 121587
Both papers focus on the solid form studies, new cocrystals were synthesized and showed improved physicochemical properties than the existing forms.
“Air entrapment during tablet compression – Diagnosis, impact on tableting performance, and mitigation strategies”, Gerrit Vreeman , Changquan Calvin Sun, International Journal of Pharmaceutics 615 (2022) 121514
The authors investigated on how air entrapment affects the tablet properties using a compaction simulator and importance of precompression turned out for formulation design.
“Mechanisms of Crystal Plasticization by Lattice Water”, Chenguang Wang, Changquan Calvin Sun, Pharmaceutical Research (2022),
Three mechanisms on the effect of lattice water on crystal plasticization were studied at molecular level. All hydrates are featured with more facile, slip planes, lower packing efficiency, and lower density in 5 different systems than the anhydrates.
“Profound effects of gastric secretion rate variations on the precipitation of erlotinib in duodenum – An in vitro investigation”, Yiwang Guo , Changquan Calvin Sun, International Journal of Pharmaceutics 619 (2022) 121722
The authors investigated the relationship between pH and precipitation behaviors of erlotinib in duodenum, and further impact on bioavailability.
“What Are the Important Factors That Influence API Crystallization in Miscible Amorphous API−Excipient Mixtures during Long-Term Storage in the Glassy State?”, Ann Newman and George Zograf, Mol. Pharmaceutics 2022, 19, 378−391
In this paper, important factors besides min Tg – T value were determined for storage of drug product as amorphous API (or ASDs) and coamorphous systems for long-term, including the ability of the additive to act on thermodynamic and dynamic processes at the local level of bulk and surface phases, particularly to reduce local non-diffusional molecular mobility in addition to bulk diffusional molecular mobility.
“Emerging Landscape of Computational Modeling in Pharmaceutical Development”, Yuriy A. Abramov, Guangxu Sun, and Qun Zeng, J. Chem. Inf. Model. 2022, 62, 5, 1160–1171
In this publication, Dr. Abramov shared an overview on computational chemistry supporting in each step of small molecule drug development process. It states that solid form designs including polymorph, cocrystal, salt and solvate screening got supported from crystal structure prediction (CSP) to guide the crystallization development efficiently, even though there are lots of challenges need to be overcome especially for salt and solvate(hydrate) screening.
Prof. Junbo Gong of Tianjin University is a speaker in 2021 Pharma Crystallization Summit (PCS) in the session of Particle Engineering & DS-DP Co-Processing. He presented “Crystal Habit Modifications and Spherical Crystallization Design in Solution” (see abstract at …). Nine new articles have been published by Prof. Gong and his team in 1st quarter of 2022 on crystal form studies, nanocrystals and experimental-simulation relationship studies.
“Insoluble Salt of Memantine with a Unique Fluorescence Phenomenon”, Wenjie Kuang et al, Mol. Pharmaceutics 2022, 19, 5, 1389–1399
Memantine for Alzheimer’s disease treatment was studied and four crystal forms of insoluble salt Mem−Pam (memantine – pamoic acid) were prepared and characterized. Fluorescence emissions were found different for different crystal forms and might be applied to the slow release of drugs and the real-time monitoring of drug delivery.
“Novel Drug−Drug Multicomponent Crystals of Epalrestat− Metformin: Improved Solubility and Photostability of Epalrestat and Reduced Hygroscopicity of Metformin”, Jingjing Sun et al, Cryst. Growth Des. 2022, 22, 1005−1016
Drug-drug cocrystal of epalrestat (EP) and metformin (MET) (both used for diabetes treatment) showed improved physicochemical properties, in terms of hygroscopicity solubility, dissolution rate, and photostability, compare with individual usage of parent drugs.
“Structural Insights into the Highly Solvating System of Axitinib via Binary and Ternary Solvates”, Haibin Qu et al, Cryst. Growth Des. 2022, 22, 1083−1093
Seven more solvates out of more than 70 were found for Axitinib. The publication states hydrogen bonds, molecular shape, size, and weak interaction forces are important factors to form solvates, and stability of solvates is more related to the interaction energy of the solvent molecules in the crystal structures.
“Bendable and Twistable Crystals of Flufenamic Acid Form III with Bending Mechanofluorochromism Behavior”, Yu Liu et al, Cryst. Growth Des. 2022, 22, 1312−1318
A plastic organic crystal form of flufenamic acid showed unique bending mechanofluorochromism behavior with single face bending. It may provide a new possibility for design of future flexible optical devices and tunable fluorescent materials.
“Theoretical and Structural Understanding of the Different Factors Influencing the Formation of Multicomponent Crystals of 2,4- Dichlorophenoxyacetic Acid with Nheterocyclic Compounds”, -Lan Fang et al, Cryst. Growth Des. 2022, 22, 1707−1719
Multicomponent crystals were prepared by solution crystallization method and studied by computational tools. The main factors of formatting multicomponent crystals include hydrogen bonds, water molecule, conformation and molecular flexibility, etc..
“Ultrasound assisted crystallization of cephalexin monohydrate: Nucleation mechanism and crystal habit control”, Zeren Shang et al, Chinese Journal of Chemical Engineering 41 (2022) 430–440
Ultrasound affects metastable zone width & induction time for cephalexin monohydrate preparation. Parameters, such as ultrasonic power, ultrasonic time, ultrasonic mode, seeding, supersaturation control and removal of fine crystals are important for preparing high-quality monohydrate product.
“Progress and Principle of Drug Nanocrystals for Tumor Targeted Delivery”, Meng Bai et al, AAPS PharmSciTech (2022) 23: 41
The article overviewed drug nanocrystals from four aspects including advantages of nanocrystals, applications of nanocrystals in drugs, targeting mechanisms of nanocrystals in tumors and surface modified of drug nanocrystals.
Papers 8 and 9
“The solid-liquid equilibrium behavior of 2,7-dihydroxynaphthalene in eleven organic solvents: Thermodynamic analysis and molecular simulation understanding”, Lan Fang Li et al, The Journal of Chemical Thermodynamics 170 (2022) 106781
“Thermodynamic analysis and molecular dynamic simulation of the solubility of 2,2-Bis(hydroxymethyl)propionic acid in 12 monosolvents”, Zhixu Li et al, J. Chem. Thermodynamics 164 (2022) 106625
In above two articles, solubility of target molecules in multiple solvents were analyzed both experimentally and computationally. Different models/equations were used for simulation.
“Absolute configuration determination of pharmaceutical crystalline powders by microcrystal electron diffraction (MicroED) via chiral salt formation”, Bo Wang et al, Chem. Commun., 2022, 58, 4711-4714
Dr. Bruhn and team of Biogen demonstrated a new method by Microcrystal electron diffraction (MicroED) to determine configuration of chiral APIs via chiral salt formation. This approach may provide a new tool for determining the absolute configuration of a new API in early drug development. The article was published as front cover paper in ChemComm.
“The interplay of intra- and intermolecular errors in modeling conformational polymorphs”, Gregory J. O. Beran et al, J. Chem. Phys. 156, 104112 (2022)
This study provided how delocalization error impacts the performance of quantum chemistry methods in describing intra- and inter-molecular interactions in conformational polymorphs. The CP1b and CP2b benchmark datasets were generated, which is important for validating quantum chemistry models in challenging real-world systems with complex interplay between intra- and inter-molecular interactions caused by delocalization error.
“A Digital Mechanistic Workflow for Predicting Solvent-Mediated Crystal Morphology: The α and β Forms of L‑Glutamic Acid”, Thomas D. Turner et al, Cryst. Growth Des. 2022, 22, 3042−3059
A digital mechanistic workflow of solvent-mediated morphological prediction model has been developed for routine modeling involved in crystallization process R&D. The study showed the importance of lattice energy and the specific intermolecular interactions on stability of polymorphs.
“Influence of a polymeric additive on the crystallisability and nucleation mechanism for the model fuel system of eicosane crystallising from supersaturated toluene solutions”, Peter L.Kaskiewicz et al, Journal of Crystal Growth 581 (2022) 126470
The impact of improver additive (IA) on crystallisability and nucleation mechanism were studied by two turbidity analysis routes. The effect of IA on solubility, relationship between crystallization temperatures & IA treat rate as well as relationship between IA rate & rate of nucleation were investigated.