Easymax 102

A batch suspension
crystallization experiment was conducted for comparison using a 100
mL vessel in an EasyMax 102 (Mettler Toledo, U.K.) with overhead stirring
at 350 rpm. A steel pitched blade impeller with 45° inclined
blades and 38 mm diameter was used. An initial concentration of 1.0
g ibuprofen/g solvent and a solvent ratio of 3.99:1 ethanol/deionized
water was used. The solution was preheated to 50 °C to dissolve
the ibuprofen. A lower concentration was used in this batch experiment
than during the layer crystallization to enable agitation throughout
the experiment. The feed solution (100 mL, 92.01 g) was used, which
had an initial ibuprofen purity of 95.52% by relative peak area (impurity
4.48% by relative peak area). A cooling crystallization was conducted
as follows: cooling down from 50 to 35 °C at 1 °C/min, constant
temperature at 35 °C for 30 min, cooling down to 20 °C at
1 °C/min, constant temperature at 20 °C for 30 min, cooling
down to 8 °C at 1 °C/min, and constant temperature at 8
°C for 60 min. Total time for the experiment was 162 min. The
final temperature was the same as in the tube side in the falling
film crystallizer (FFC). At the end of the experiment, the crystals
produced were vacuum-filtered and weighed. A washing step was then
conducted using 40 mL of ethanol at 8 °C, vacuum-filtered, and
dried to calculate the yield.

First, 1.2 g of (RS)-KET and 0.69 g of dl-LYS (1:1 ratio) were suspended in 20 mL of methanol and left under stirring at 40 °C for 1 h. The suspension was then filtered (0.45 μm filter) directly in a Mettler Toledo Easymax 102 reactor. The solution was left under stirring for 5 min in the reactor; then, 100 mL of ethyl acetate was added, and the solution was cooled to −5 °C without solid formation. Ethyl acetate (20 mL) was added through a pipette in two aliquots (10 mL and 10 mL) to trigger nucleation. The system was left under stirring until the suspension became “milky”. An additional 30 min of stirring was applied. The precipitate was then filtered, and the collected sample was stored in a sealed vial at room temperature. The final KET–LYS P2 was obtained as a white powder (1.3 g, yield of 69%).

Dissolution and solubility were evaluated for both glasdegib monomaleate and glasdegib dimaleate. Dissolution was tested at different pH values using the following buffer solutions: pH 1.2 (United States Pharmacopeia 29), pH 4.0 (European Pharmacopoeia 7.0, ref. 4013800), pH 5.5 (European Pharmacopoeia 7.0, ref. 4002000) and pH 7.0 (European Pharmacopoeia 7.0, ref. 4008200) at 37 °C and 300 rpm using an EasyMax 102 reactor system (Mettler Toledo, Greifensee, Switzerland) using 50 mL reactor and a magnetic stirrer. Experiments were performed by adding excess glasdegib salts into the desired buffer solution already set at 37 °C. Samples were taken after stopping the stirring for 5–10 min (decantation) to avoid the contamination of samples with insoluble particles. Samples were then analyzed via UHPLC to measure glasdegib concentration.