Materials and methods

Solvents. 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.

Solubility studies. 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).