Handbook of Solvents - George Wypych - ChemTech - Ventech!

15.2.3 An innovative GC method 1115
Among all parameters influencing RS content, crystal texture is of utmost importance.
It is evident that a crystal exhibiting a porous texture will enable the easy escape of a solvent
while a compact and dense crystal will retain the solvent inside its structure whatever the
type of particles: monocrystalline (i.e., monoparticular) or “polycrystalline”. The term
“polycrystalline” particles will be employed to designate elementary particles that can be
composed of agglomerates, spherolites or “spherical crystals” according to Kawashima. 4
To illustrate the importance of the texture of particles on RS content, we can consider
some examples taken from our laboratory experiments. Several crystallization processes
were investigated on pharmaceutical products with different solvents leading either to compact
monocrystalline particles or “sintered-like” (i.e., microcrystallites fitted into each other
and partially welded involving a porous texture) or polycrystalline particles which were
more or less dense. 2,3 The physical study of these particles such as, optical microscopy, particle
size analysis, electron scanning microscopy and thermal analysis, have been used to
link the RS contents with the drying conditions of crystals and to demonstrate that the optimal
drying conditions differ greatly according to the texture of the particles.
As we shall see in a first example of monocrystalline particles of paracetamol
recrystallized in dioxane, a wide open texture is generally favorable to a low RS content after
a progressive drying at a moderate temperature to avoid the formation of a superficial
crust. In fact, in this case, the drying conditions of crystals highly influence their residual
solvent content. Optimal drying conditions seem to be the progressive and moderate ones.
In contrast, too drastic drying conditions may hinder the solvent escape by a “crust” effect.
This crust is due to a drying temperature which is too high, leading to a melt and a dissolution
of the surface of the crystals. Finally, when a desolvation occurs during the drying, it
can modify the texture of crystals and form a crust. The intensity of the phenomenon depends
on the solvent.
To remove the solvents efficiently, it is then necessary to exceed the desolvation temperature
of the solvates that may be produced during crystallization.
With this example we can clearly point out that the crystal texture is a determining factor
in the complete escape of the solvent: when the crystalline texture is sintered-like, after
the desolvation of solvate crystals, progressive drying is necessary to prevent the “crusting”
phenomenon.
The drying conditions should also be adapted to the area offered to the evaporation of
solvent, particularly in the case of polycrystalline particles presenting a high porosity and a
large surface to be dried. This important surface is due to the disordered rearrangement of
very small crystals inside the particles. To illustrate this, we shall see in a second example
the cases of spherical crystals of meprobamate and ibuprofen agglomerates. In both cases
the RS can escape easily from the large surface of polycrystalline particles.
Lastly, we shall see in a third example, that we must not forget that thermodynamic
phenomenon can occur under drying. This is a very particular example because the pharmaceutical
product used (paracetamol) presents a polymorphic transition that can occur during
the drying phase and lead to a new organization inside the crystal, allowing the escape of the
RS. This can be very interesting in the case of products with a low transition temperature.
The usual polymorphic form of commercialized paracetamol is the monoclinic form; but in
particular cases small amount of metastable orthorhombic form can be obtained. In the case
of paracetamol, at the transition temperature (156°C) we observe a brutal solvent escape
that could be due to the solid-solid transition undergone by the orthorhombic form into the
monoclinic one. The disorder produced and the increase of the specific volume occurring
during this first order transition allow the occluded solvents to escape more easily.