Handbook of Solvents - George Wypych - ChemTech - Ventech!

15.2.3 An innovative GC method 1121
Ibuprofen crystals observed under SEM are in total disorder (Figure 15.2.3.8). This
disordered arrangement of microcrystallites inside the polycrystalline particles gives them a
high isotropy of particles arrangement that should improve their compression capacity.
Residual solvent determination
For organic solvents, gas phase chromatography was performed on a Shimadzu
GC-14B chromatograph fitted with a Flame Ionization Detector and a CR-6A Shimadzu integrator.
The packed column was Porapack super Q (Alltech, France), mesh range 80/100,
length 1.80 m, internal diameter 2.16 mm. Carrier gas: anhydrous nitrogen. Injector temperature:
200°C. Detector temperature: 220°C. The chromatographic conditions were:
• For chloroform in meprobamate crystals: isotherm at 150°C, injection: 5 μl,
RT: methanol 0.8 min, chloroform 6.7 min.
• For ethanol in ibuprofen crystals: isotherm at 170°C, injection: 5 μl, RT:
ethanol 1.1 min, 1-butanol 5.3 min.
Determination of residual water was carried out using Karl Fischer’s titrimetric direct
method after calibration with natrium tartrate and dissolution of ibuprofen or meprobamate
crystals in methanol.
The residual solvent concentrations of the polycrystalline particles are reported in Tables
15.2.3.6 and 15.2.3.7.
Table 15.2.3.6. Residual solvent concentration of meprobamate spherical crystals
submitted to different drying conditions (Data from reference 3 )
Chloroform Water
Progressive drying* 345±22 ppm 0.71%±0.07%
Drastic drying** 321±8 ppm 0.21%±0.01%
*30 min at 60°C + 30 min at 75°C + 1 hour at 90°C; **2 hours at 90°C
Table 15.2.3.7. Residual solvent concentration of ibuprofen agglomerates submitted
to different drying conditions (Data from reference 3 )
Ethanol Water
2 hours at 40°C 42±3 ppm 0.76%±0.12%
2 hours at 60°C 21±4 ppm 0.44%±0.06%
As far as meprobamate spherical crystals are concerned, no significant differences are
to be observed between drastic and progressive drying. No crusting phenomenon appears
on meprobamate spherical crystals due to the loose tangling up of crystals, and so the solvent
may escape easily between them.
The residual ethanol content of ibuprofen agglomerates is very low because of the
open texture of agglomerates. Moreover, the crystallization phenomenon was relatively
slow, enabling the solvent to escape from crystals in formation. The higher the temperature,
the lower the residual ethanol content.
Both these crystals have a very porous texture. It seems that progressive drying is not
essential as far as the polycrystalline particles are concerned.
If we consider the official limits 1,6 reported on Table 15.2.3.5 for residual solvent contents,
we can note that the concentration of chloroform in meprobamate spherical crystals is
much higher than the limit allowed in any drying conditions. Due to its inherent toxicity,
this solvent should be avoided in the recrystallization process of meprobamate. The solvent