*3.4. Stability and Interrelation Pathways among the Solvates and Anhydrous Forms*

The stability of SCHCl3-H2O in front of temperature was studied when heating it in a DSC experiment, and it was observed that from 50 ◦C this solvate was no longer stable and began to transform into form III (Figure 5).

The stability of SCHCl3-H2O in front of relative humidity has been studied at r.t. by placing this sample inside desiccators containing different saturated salt solutions which create different RH conditions. From 0% to 43% RH, SCHCl3-H2O was stable at least during one month. At 57–75% RH, this form began to transform into form III after one month.

In addition, the stabilities of forms I, III and SCHCl3-H2O were studied under different chloroform atmospheres. While the relative thermodynamic stability of polymorphs depends only on the temperature at constant pressure, the stability relationship between a solvate and a non-solvated form, or two solvates, depends not only on the temperature but also on the activity of the solvent at constant pressure. To obtain different relative solvent vapor pressures, chloroform solutions in DMF were prepared according to the Raoult's law [28]:

$$\mathbf{x} = \frac{p}{p\_0} = \frac{n}{n\_0 + n} \tag{2}$$

where *x* is the solvent mole fraction in solution; *p*<sup>0</sup> is the vapor pressure of pure solvent; *p* is the partial solvent vapor pressure over the solution; *n* represents the amount of used solvent in the solution; *n*<sup>0</sup> is the moles of DMF in the solution. The samples were placed in desiccators with the prepared solutions of different partial pressures of chloroform. At 0–40% CHCl3, forms I and III remain invariable while SCHCl3-H2O transformed into II + traces of I at 0% and into I at 20–40% CHCl3. While increasing chloroform proportion to 60–80%, form I did not change; form III transformed into a mixture of III+I, and SCHCl3-H2O remained invariable. Under 100% chloroform atmosphere, both anhydrous forms transformed into SCHCl3-H2O.

Curiously, at r.t. under 0% RH, SCHCl3-H2O does not desolvate, while under 100% DMF atmosphere, mixture of II+traces of I is obtained.

The information obtained during the solid form screening and the study of the temperature- and moisture-dependent stability and interrelation pathways among the solid forms of BL has been summarized in Figure 8.

**Figure 8.** Pathways for phase transformations of BL solid forms as a result of heating or exposure to different solvents.

Form I is the most stable anhydrous form at r.t. which can be obtained by slurry in ethanol from the other anhydrous forms. Form II can be obtained from I and from III by increasing temperature, as it is enantiotropically related with both forms. A slurry in CHCl3 at r.t. produces the heterosolvate S3CHCl3-H2O which is transformed into SCHCl3-H2O when taken out of the solution. Heating SCHCl3-H2O produces its desolvation and transformation into form III. On the other hand, the slurry of SCHCl3-H2O in DMF leads to form I while maintaining SCHCl3-H2O under DMF atmosphere allows the isolation of form II in short time (form I appears later). Finally, the use of anhydrous chloroform leads to chloroform solvate SCHCl3 which transforms also to SCHCl3-H2O when taken out of solution.
