Iterative High-Throughput Polymorphism Studies on Acetaminophen and an Experimentally Derived Structure for Form III

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.