Handbook of Solvents - George Wypych - ChemTech - Ventech!

15.2.3 An innovative GC method 1123
Figure 15.2.3.10. DSC and thermogravimetry curves of
paracetamol agglomerates.
The residual solvent concentrations of
the polycrystalline particles are reported in
Table 15.2.3.8.
The wide-open texture of paracetamol
spherolites hinders the crusting phenomenon;
it is therefore normal that there should
be no difference between the effectiveness of
the two types of drying: progressive and
drastic (at 100°C for two hours). However, a
surprisingly good result is observed when the
drying temperature is 156°C whereas a prolonged
time at 100°C does not improve the
solvent escape in spite of the low boiling
points of solvents, all much lower than
100°C (dichloromethane: 39.5°C;
tetrahydrofuran: 66°C; hexane: 69°C). Using
a DSC method, it can be observed that a
slight non constant exotherm at 85°C fol-
lowed by a small constant endotherm at nearly 156°C occurs before the melting endotherm
at 169°C (Figure 15.2.3.10). In fact, the paracetamol obtained by the crystallization process
described is mainly the usual monoclinic form. However, as has been demonstrated by
Ettabia 10 the formation of a certain amount of the amorphous form, causes the slight
exotherm. The amorphous form recrystallized at 85°C into the orthorhombic metastable
form, which transits into monoclinic form at 156°C, causing the small endotherm observed
at nearly 156°C.
The thermogravimetric analysis shows that no solvation occurs during crystallization.
Furthermore, the sudden solvent escape is not specific to one definite solvent, whereas all
the contained solvent amounts dramatically decrease at 156°C. The loss of mass is high
(about 0.7%) when the substance is about to melt (Figure 15.2.3.10).
Table 15.2.3.8. Residual solvent concentration of paracetamol agglomerates
submitted to different drying conditions (Data from reference 3 )
"Flash drying" 156°C
for 10 min
for 30 min
PD*
PD*+ “flash” (10 min at 156°C)
DD **
DD**+"flash" (10 min at 156°C)
Dichloromethane Tetrahydrofuran Hexane
< 200 ppm
< 200 ppm
315±3 ppm
< 200 ppm
309±3 ppm
< 200 ppm
1095±5 ppm
630±24 ppm
2066±1 ppm
883±10 ppm
2014±30 ppm
873±2 ppm
167±1 ppm
88±4 ppm
305±3 ppm
145±5 ppm
313±4 ppm
140±1 ppm
* PD: Progressive drying (30 min at 60°C + 30 min at 80°C +1hat100°C), ** DD: Drastic drying (2 h at 100°C)
Paracetamol, containing three different solvents, exhibits low dichloromethane content
(200 to 320 ppm). The referencing limits remain higher than the experimental results
when these particles are submitted to different drying conditions (Table 15.2.3.5). The same
observation is valid for tetrahydrofuran for which the allowed upper limit is 5000 ppm. But
the residue in hexane is sometimes above the regulatory threshold. The only way to be definitely
below this limit is to heat paracetamol to 156°C; this confirms the advantage of flash
drying this substance. As previously described, this temperature is critical for paracetamol
recrystallization in the solvents used.