Crystal habits of acetaminophen were classified into four typical shapes of prismatic, rhombohedral, hexagonal, and needle
with sizes ranging from 50 μm in the cosolvent system of THF and acetone (see Figure 2a) to 4.5 mm in the cosolvent system
of MEK and 1,4-dioxane (see Figure 2b) and aspect ratios, defined as length divided by breadth, ranging from 1.07 in the cosolvent
system of nitrobenzene and N-butyl alcohol (see Figure 2c) to 7.33 in the cosolvent system of THF and acetonitrile (see Figure
2d) (20). The composition of solvents is known to influence nucleation and growth rates (21). Because THF, acetone, nitrobenzene,
1,4-dioxane, and MEK are hydrogen-bond accepting solvents, they might have preferentially adsorbed at specific faces, thus
inhibiting the growth of acetaminophen crystals, or have similar structures to acetaminophen, thus hindering the regular deposition
of oncoming molecular layers (22).
Figure 2: Optical micrographs of crystal habit of acetaminophen Form I crystals grown by cooling in (a) tetrahydrofuran and
acetone, (b) methyl ethyl ketone and 1,4-dioxane, (c) nitrobenzene + N-butyl alcohol, and (d) tetrahydrofuran and acetonitrile
(scale bar = 500 μm).
All acetaminophen crystals harvested from the 88 cosolvent systems exhibited the same typical DSC melting endotherm of about
171 °C for Form I acetaminophen as shown in Figure 3. No other polymorph was observed, even though a change in the morphology
to a needle shape could be a strong indication of the presence of acetaminophen Form II crystals (14). This important case
serves as a reminder that a definitive identification of polymorphism must be based on spectroscopy, X-ray diffraction, or
thermal analysis, and not on microscopy alone (7).
Figure 3: A typical differential scanning calorimetry scan of acetaminophen Form I crystals grown in nitrobenzene and N,N-dimethylformamide
The percent of crystallinity of acetaminophen crystals was quantified by dividing the area of a sample melting endotherm by
the largest area of melting endotherm of all samples, which turned out to be the acetaminophen crystals grown in the cosolvent
system of nitrobenzene and DMF with the enthalpy of melting, ΔH
m, of 195.24 J/g (see Table II). The authors suggest two possible reasons that this particular sample had the highest crystallinity.
First, the slope of the solubility curve was not steep, so that cooling recrystallization took place gradually. Second, the
molecular structures of nitrobenzene and DMF were similar to that of acetaminophen, which might have slowed down the nucleation
and growth rate of acetaminophen crystals to yield high-quality crystals (22).