Structure elucidation of olanzapine molecular salts by combining mechanochemistry and MicroED

Abstract

Olanzapine (OLN), an anti-psychotic drug, is one of the most widely studied pharmaceutical materials. Although OLN and most of their multicomponent solids are highly crystalline, some of their molecular salts are difficult to crystallize and optimization takes long time. After several batches of failed crystallization, we applied mechanochemistry and microcrystal electron diffraction (MicroED) for structure elucidation. This combined approach was successful not only in structure determination of the drug molecule but also in characterizing traces of impurity present in a bulk solid. This study demonstrates that the combined approach is fast and efficient for structure elucidation of pharmaceutical materials when generation of suitable single crystals is challenging.

MicroED as a Powerful Tool for Structure Determination of Macrocyclic Drug Compounds Directly from Their Powder Formulations

“…Microcrystal electron diffraction (MicroED) − is a cryogenic electron microscopy (cryo-EM) method capable of determining atomic structures from submicrometer sized crystals, as small as a billionth the size as those required for single crystal X-ray diffraction (XRD). − Due to the many unique advantages of MicroED as compared to other structural methods, including the small amounts of material required, the fact that structures can be obtained rapidly directly from powder formulations, and the possibility of determining structures from compound mixtures, MicroED has been recognized as a new method for contemporary drug discovery. − In some recent examples MicroED was used to determine the composition of small molecule drug mixtures, the structure of antihistamine levocetirizine, which has resisted determination for over 25 years, the novel structure of mirabegron, and new molecular salts of the antipsychotic drug olanzapine . Although impressive examples, these molecules all fall well within the rule of 5 space with restricted size, flexibility, and complexity.…”

“… 14 − 16 In some recent examples MicroED was used to determine the composition of small molecule drug mixtures, 17 the structure of antihistamine levocetirizine, which has resisted determination for over 25 years, 18 the novel structure of mirabegron, 19 and new molecular salts of the antipsychotic drug olanzapine. 20 Although impressive examples, these molecules all fall well within the rule of 5 space with restricted size, flexibility, and complexity.…”

Distinct Conformations of Mirabegron Determined by MicroED

“…For example, MicroED was utilized to solve elusive crystal structures of drugs like Bismuth subgallate, 13 Methylene blue derivative (MBBF4), 14 Orthocetamol, 15 Lomaiviticins, 16 Levocetirizine dihydrochloride. 17 Another application is the screening of different polymorphs, salts, co-crystals, and solvates of drug molecules, such as the polymorphs of Remdesivir, 18 Indomethacin, 19 Vemurafenib; 20 co-crystal structure of 2-Aminopyrimidine succinic acid (2:1); 21 Olanzapine salts; 22 and Methyl piperazine-1-carboxylate as a solvated crystal. 23 Here we use MicroED to determine the atomic structure of Mirabegron that has remained elusive for decades despite its wide use and FDA approval.…”