Materials and methods
All materials and methods were the same as in the authors' previous experiments (7). Acetone [CH3COCH3, high-performance liquid chromatography (HPLC)–spectrometry grade, 99.9%, Lot: 601109], n-butyl alcohol [CH3 (CH2)3OH, ACS grade, 99.4%, Lot: 205027], n-heptane [CH3 (CH2)5CH3, HPLC–spectrometry grade, 99.4%, Lot: 111110], isopropyl alcohol (IPA) [(CH3)2CHOH, HPLC–spectrometry grade, 99.8%, Lot: 808907], methanol (CH3OH, HPLC–spectrometry grade, 99.9%, Lot: 703416), methyl tert-butyl ether (MTBE) [(CH3)3COCH3, certified grade, 99.9%, Lot: 712032], and methyl ethyl ketone (MEK) (C2H5COCH3, ACS grade, 99.6%, Lot: 201021) were purchased from Tedia (Fairfield, OH). Chloroform (CHCl3, ACS grade, 99.99%, Lot: E554180), N,N-dimethylformamide (DMF) [HCON(CH3)2, ACS grade, 99.8%, Lot: E705279], tetrahydrofuran (THF) (C4H8O, HPLC–spectrometry grade, 99%, Lot: E704198), and ethanol (CH3CH2OH, HPLC–spectrometry grade, 99.5%) were obtained from
Echo (Miaoli, Taiwan). Acetonitrile (CH3CN, analytical grade, 99.96%, Lot: 0043 X29B30), toluene (C6H5CH3, ACS grade, 100%, Lot: B46755), and xylenes [C6H4 (CH3)2, ACS grade, 98.8%, Lot: E03B34) were all received from Mallinckrodt Baker (Phillipsburg, NJ). Benzene (C6H6, ACS grade, 99%, Lot: 310008) and benzyl alcohol (C6H5CH2OH, gas chromatography grade, 99.9%, Lot: 70950) were purchased from Sigma-Aldrich Laborchemikalien (Seelze, Germany). Dimethyl
sulfoxide (DMSO) [(CH3)2SO, HPLC grade, 99.8%, Lot: SU0155] was obtained from Scharlau Chemie (Barcelona). N,N-dimethylaniline (DMA) [C6H5N(CH3)2, ACS grade, 99%, Lot: A0213203001], nitrobenzene (C6H5NO2, ACS grade, 99%, Lot: A0195683001), and p-xylene [C6H4 (CH3)2, ACS grade, 99%, Lot: 48754/2) were purchased from Acros Organics (Fair Lawn, NJ). 1,4-dioxane (C4H8O2, ACS grade, 98%, Lot: sp-3432R) was obtained from Showa Chemical (Tokyo). Ethyl acetate (CH3COOC2H5, ACS grade, 99.5%, Lot: G43342) was received from Grand Chemical (Daejeon, South Korea). Reversible osmosis (RO) water was
clarified by a water-purification system (Milli-RO Plus, Millipore, Billerica, MA). All solvents were colorless except for
the yellowish nitrobenzene. Stock solution of all 100 good cosolvent combinations represented as navy blue boxes in Figure
1 were premixed with a 1:1 volume ratio.
Approximately 50 mg of acetaminophen Form I crystals were weighed in a 20-mL scintillation vial. From 0.2 to 0.5 mL of cosolvent
was titrated carefully by micropipette into the vial with intermittent shaking for 2 min until all API solids were just dissolved.
The solubility of the API at a given temperature was calculated as the weight of the API in a vial divided by the total volume
of the cosolvent added to a vial (i.e., the gravimetric method) (7, 9). Solubility of the API in the same cosolvent at temperatures
of 15, 25, 40, and 60 °C was determined. All temperatures were maintained and controlled by a water bath. Although the gravimetric
method appeared to be imprecise, its advantages were its robustness, simplicity, lack of the need for calibration, and lack
of solvate formation. Polymorphism, crystallinity, and crystal habits of acetaminophen solids recrystallized by cooling from
60 to 25 °C were fully characterized by differential scanning calorimetry (DSC) and optical microscopy (OM).