Handbook of Solvents - George Wypych - ChemTech - Ventech!

1118 Christine Barthélémy, Michel Bauer
Scanning electron microscopy (SEM) carried out on these crystals reveals different
behaviors according to the drying conditions tested. The crystals obtained from dioxane are
similar to blocks of sintered particles since they consist of microcrystallites bound to each
other, as if partially welded. 5 In fact, the measurement of mercury porosity indicated a very
high porosity. This sintered aspect concords with the non-transmission of light through the
whole crystal.
In fact, paracetamol forms a solvate with dioxane. 5 Its departure does not modify the
crystal habit but the surface can be seen as perforated.
When the drying is very moderate, the crystal surface is perforated by numerous holes
through which solvent escapes; these anfractuosities give the impression of a porous
sintered-like texture (Figure 15.2.3.2). With progressive drying, the number of holes decreases
(Figure 15.2.3.3). On the contrary, when the drying is drastic, the surface is relatively
smooth (Figure 15.2.3.4). This can be explained by the too drastic drying conditions
involving the formation of a crust at the surface of the crystal preventing the escape of the
solvent from the crystal.
Residual solvent determination
Gas Phase Chromatography (for dioxane and ethanol) was performed on a Varian 1440
Chromatograph with a Flame Ionization Detector; packed column Porapack Super Q
(Alltech, France), mesh range 80/100, length 1.8 m; internal diameter 2.16 mm; carrier gas
was nitrogen (40 ml/min); injector: 210°C; detector: 250°C.
For dioxane: column temperature: isotherm at 170°C. Injection: 10µl. Retention
Times (RT): methanol 1.5 min; dioxane 16 min.
For ethanol: column temperature: isotherm at 210°C. Injection: 5µl. RT: ethanol 1.5
min; 1-butanol 4 min.
Determination of residual water on paracetamol crystallized in water: according to the
titrimetric direct method of Karl Fischer.
The residual solvent concentrations of the crystals obtained are reported in Table
15.2.3.4.
Table 15.2.3.4. Residual solvent content of crystals obtained from different solvents
and submitted to different drying conditions (Data from reference 2 )
Drastic Drastic under vacuum Progressive Moderate
Dioxane 126 ppm 183 ppm 25 ppm 53 ppm
Ethanol 2045 ppm 2501 ppm 1495 ppm 2072 ppm
Water 0.59 % 0.68 % 0.51 % 0.56 %
Whatever the drying conditions may be, the content of dioxane is always lower than
the 380 ppm ICH limit 1,6 (Table 15.2.3.5). Progressive drying always gives lower level residual
solvent. In fact, drastic drying, in a ventilated oven and under vacuum, leads to the
formation of a superficial “crust” which hinders the solvent escape; this can be clearly visualized
on the scanning electron photomicrograph (Figure 15.2.3.4); and can explain the relatively
high content of residual solvents.