Handbook of Solvents - George Wypych - ChemTech - Ventech!

14.21.1 Use of solvents in manufacture of drugs 987
• Displacement by water vapor in an oven, keeping in mind that this method may
introduce some degradation leading to processability problems. 11,24
• Extraction by supercritical CO 2 25,26 but the extraction power of CO2 is basically
limited to slightly polar solvents.
14.21.1.3.1.4.2.2 Solvent inside the crystal
The solvent remains inside the crystalline structure. Three situations can arise.
14.21.1.3.1.4.2.2.1 Occluded solvents
During rapid crystallization, some degree of disorder (amorphous phases, crystalline
defects) can arise, creating pockets where residual solvent can be occluded. Through a process
of dissolution/recrystallization this “hole” moves towards the external faces of the
crystal releasing the solvent at the end. This phenomenon is more frequent for large crystals
(500 µm/600 µm) but rare for smaller crystals (1 - 100 µm). The solvent odor which is detected
when opening a drum or a bag containing a substance which was dried in the normal
way can be explained by this mechanism.
14.21.1.3.1.4.2.2.2 Solvates
At the end of the crystallization process, the substance can be isolated as a solvate (hydrate),
i.e., as a pseudopolymorph. The solvates generally have quite different
physicochemical properties from the anhydrous form. Their stability can be questionable
and in any case deserves to be investigated. In some cases it is possible to remove the solvent
from the crystal without changing the structure of the lattice leading to an isomorphic
desolvate which displays a similar X-ray diffraction pattern to that of the parent compound.
2,27 The lattice of the desolvated solvate is in a high energy state relative to the original
solvate structure. A better dissolution rate and compressability can be expected, 28 but the
drawbacks are hygroscopicity and physico-chemical instability. The lattice could undergo a
relaxation process over time which increases the packing efficiency of the substance by reducing
the unit cell volume.
When developing a new chemical entity all these aspects have to be considered to
avoid unpleasant surprises during development or once the drug is on the market. Due to the
need for process scale-up and of making the manufacturing process more industrial,
changes are introduced especially in the crystallization and the drying processes, (e.g.,
change from static drying to dynamic drying). Because the drying is a particularly disturbing
process for the integrity of the lattice, defects and/or amorphous phases may be created
favoring subsequent polymorphic or pseudopolymorphic transformations of the crystalline
form developed so far, if it is not the most stable one.
14.21.1.3.1.4.2.2.3 Clathrates
In contrast to solvates, clathrates do not show any stoichiometric relationship between
the number of molecules of the substance and the number of molecules of solvent.
Clathrates actually correspond to a physical capture of solvent molecules inside the crystal
lattice without any strong bonds including hydrogen bonds. Molecules of one or several solvents
can be trapped within the crystalline structure as long as the crystallization has been
performed with a pure solvent or a mixture. The case of the sodium salt of warfarin giving
“mixed” clathrates with water and isopropyl alcohol is well known and the existence of
8/4/0 or 8/2/2 proportions has been shown. 11
It is fairly obvious that some powder properties like wettability can be modified by the
formation of clathrates. Because their formation is not easy to control, some batch to batch
inconsistency may be expected in this situation.