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

Abstract

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.

Biowaiver monographs for immediate release solid oral dosage forms: Acetaminophen (paracetamol)

“…[4], [6] CHEMICAL PROPERTIES Polymorphism Three metastable forms of acetaminophen are known. [7][8][9][10][11][12] Orthorhombic acetaminophen is suitable for direct compression tableting and may also be slightly more soluble [13] but has been crystallized only in small quantities and the only commercially available form is monoclinic acetaminophen, the thermodynamically most stable modification. [14] Solubility One part of acetaminophen is soluble in 70 parts of water at room temperature [15], [16] and soluble 1 in 20 parts in boiling water.…”

Crystallization Behavior of Acetaminophen in Nanopores

“…A third polymorph of acetaminophen -called form III -is reported to be unstable and usually inaccessible in case of bulk samples. This form has been found only in special situations where acetaminophen was confined between glass plates or in thin glass capillaries [19,20]. Thus, there is limited information about this polymorph.…”

Polymorphism: an evaluation of the potential risk to the quality of drug products from the Farmácia Popular Rede Própria

“…In addition to being easily controllable, the more stable polymorphic form also complies with requirements described in the Q6A Guide of the International Commission on Harmonization (ICH) for solid form selection (Grant et al, 2004). Kristl et al, 1996;Sohn et al, 2008;Lutker et al, 2011;Tutughamiarso et al, 2012) Acetylsalicylic Acid Analgesic IV 2 I (TSRL inc, 2012; Klein et al, 1994;Vishweshwar et al, 2005;Bond et al, 2011) Ibuprofen Analgesic II 2 I (TSRL inc, 2012;Shankland et al, 1996;Erk et al, 2004;Stone et al, 2009;Derollez et al, 2010) Acetaminophen Analgesic IV 6 I (TSRL inc, 2012;Haisa et al, 1974;Naumov et al, 1998;McGregor et al, 2002;Parkin et al, 2002;Peterson et al, 2002;Fabbiani et al, 2004 (Otsuka et al, 1983;Stephenson et al, 1998;Kennedy et al, 2003;Kasim et al, 2004;Aguiar et al, 2011) Ciprofloxacin Antibiotic III 3 II (hydrate) (TSRL inc, 2012;Turel et al, 2003;Fabbiani et al, 2008;Fabbiani et al, 2009;Fabbiani et al, 2011) Doxycycline Antibiotic IV 2 ‡ (TSRL inc, 2012; Legendre et al, 2012) Erythromycin Antibiotic IV 4 Dihydrate (TSRL inc, 2012;Fukumori et al, 1983;Stephenson et al, 1997;Miroshnyk et al, 2006) Sulfamethoxazole Antibiotic IV 4 III (hemihydrate) (TSRL inc, 2012;…”