Three crystal forms of acetaminophen were prepared and characterized using a newly developed high-throughput crystallization platform, CrystalMax. The platform consists of design software, robotic sample dispensing and handling, and high-throughput microanalytics and is capable of running thousands of crystallizations in parallel using several different methods to drive supersaturation and subsequent crystallization. Additionally, structural models of the elusive third form of acetaminophen will be discussed on the basis of powder X-ray diffraction data. One structure suggested has a bilayer motif, held together by O-H...O(H) hydrogen bonds, and helps explain the difficulty associated with preparing this form from solution.
Surveys of crystal form diversity of two test compounds, 1 (an experimental angiotensin II antagonist) and 2 (sertraline HCl, the active drug in Zoloft), have been performed with high-throughput (HT) crystallization. Compound 1 was found to have at least 18 crystal forms based on a HT recrystallization experiment using diverse solvents, compared with nine forms originally reported from a traditional screening effort. The efficiency of screening in HT mode is estimated to be about 2 orders of magnitude greater than traditional bench-scale approaches. The multiple patented forms of 2 have been summarized and evaluated based on published information, which is found to include several transient species and at least one mixture of known phases. A comparison between results of HT experiments and data on the disclosed forms shows that the HT effort generates the viable crystal forms; highly unstable hydrates and one metastable polymorph IV were not observed. In attempting to recover form IV, a novel acetic acid solvate was discovered and characterized by single crystal X-ray diffraction. Additionally, a previously undisclosed ethyl acetate hemisolvate of 2 was identified as an intermediate en route to form T1. The study demonstrates that highly polymorphic pharmaceutical compounds can be surveyed by HT form experimentation, and that an HT strategy coupled with critical analysis of reported form diversity can be used to rank the utility of crystal forms.
Magnetic resonance imaging (MRI) allows important visualization of the brain and central nervous system anatomy and organization. However, unlike electroencephalography (EEG) or functional near infrared spectroscopy, which can be brought to a patient or study participant, MRI remains a hospital or center-based modality. Low magnetic field strength MRI systems, however, offer the potential to extend beyond these traditional hospital and imaging center boundaries. Here we describe the development of a modified cargo van that incorporates a removable low-field permanent magnet MRI system and demonstrate its proof-of-concept. Using phantom scans and in vivo T2-weighted neuroimaging data, we show no significant differences with respect to geometric distortion, signal-to-noise ratio, or tissue segmentation outcomes in data acquired in the mobile system compared to a similar static system in a laboratory setting. These encouraging results show, for the first time, MRI that can be performed at a participant’s home, community center, school, etc. Breaking traditional barriers of access, this mobile approach may enable imaging of patients and participants who have mobility challenges, live long distances from imaging centers, or are otherwise unable to travel to an imaging center or hospital.
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