Figure 3a: Polymorphic flow chart showing the preparation methods for the four anhydrous polymorphs of carbamazepine, the
thermal transition of Forms II–IV to Form I, and relationships (in blue) between carbamazepine Form I and Dihydrate I, and
Form III and Dihydrate III.
Initial solvent screening. Under the initial solvent screening, the 19 solvents for scale-up previously listed were chosen (28–30, 70). About 5 mg of
the API powders were weighed in a 20-mL scintillation vial the first time. Drops of a given solvent were titrated carefully
by a micropipette into the vial with 1–2-min intermittent shaking until all the API powders were just dissolved at 25 °C,
maintained by a water bath. The solubility of the API powders in that particular solvent was approximated as the weight of
the API powders in the vial divided by the total volume of the solvent added to the vial (i.e., the gravimetric method). A
good solvent was defined as a solvent that gave a solubility of ≥ 5 mg/mL at 25 °C and was designated by a yellow color. A bad solvent was designated by a red color later in the form space. The solubility of the API in the good solvent at 15, 40, and 60 °C
(or 50 °C if the boiling point of a solvent is close to 60 °C) was measured by the gravimetric method assuming the volumes
of solvents were the volumes of solution and the volumes of solvents did not change significantly with temperature. Although
the gravimetric method appeared to be imprecise, its advantages were its robustness, simplicity, the low amount of API required,
the lack of necessity for calibration, and the absence of solvate and hydrate formation.
Figure 3b: Polymorphic flow chart showing the preparation methods for the four anhydrous polymorphs of cimetidine; the mechanical,
thermal, and solution transition among Forms A–D; the preparation methods of the three monohydrates; and thermal transition
(in blue) of cimetidine Monohydrate I to Forms A–C.
Solvent-miscibility studies. Of the 19 solvents, about 1-mL portions of each solvent in a pair were intermittently shaken together for about 1–2 min in
a 20-mL scintillation vial (28–30). The solvent pair was considered to be miscible if no interfacial meniscus was observed
after the contents of the vial were allowed to settle. Otherwise, the pair was regarded as immiscible and designated by a
gray color later in the form space.
Figure 3c: Polymorphic flow chart showing preparation methods for the six anhydrous polymorphs of phenylbutazone; the thermal
transition and the solution transformation among Forms α, β, δ, ε, and ζ; the methods of preparation of six solvates; and
thermal transition (in blue) to Form δ.
Solids generation. Based on the predetermined solubility curves, solids generation of the API in each good solvent was achieved separately in
a 20-mL scintillation vial by cooling the saturated API solution at 60 °C and by moving the vial from a 60 °C water bath to
a 25 °C water bath with intermittent shaking (28–30). The crystal habits of all solids were characterized by optical microscopy
(OM) inside the vial under a slurry state. All solids were filtered, oven-dried under mild conditions at 40 °C overnight,
and characterized for their purity, polymorphism, solvates, and crystallinity by DSC, thermal gravimetric analysis (TGA),
and transmission FTIR.
OM. An optical microscope (SZII, Olympus, Tokyo) equipped with a charged-coupled device (CCD) camera (SSC-DC50A, Sony, Tokyo)
was used to take images of crystal habit.