L.F. Diniz et al.
International Journal of Pharmaceutics 605 (2021) 120790
molecules. All these observations are in agreement with the crystallo-
graphic analysis, which had previously shown not only the proton
transfer but also real H-atoms positions on both DIL tertiary amine
moiety and coformer carboxylic group.
hence, on its pharmacological response (Williams et al., 2013). Apart
from that, crystal engineering is a well-consolidated approach to opti-
mize this property, especially for ionizable APIs. For DIL, which presents
short elimination half-life due to high solubility, the synthesis of less
soluble crystal forms is a central requirement for future extended-release
formulations. The equilibrium solubility of DIL-HCl and its new solid
forms in buffered media that mimic physiological conditions is pre-
sented in Fig. 8. Overall, even though the DIL-OXA-H2O and DIL-SUC-
H2O salts have high solubility values, being even close to the ones found
for the DIL-HCl, the DIL-FUM-H2FUM salt-cocrystal, in turn, showed a
substantial decrease in its solubility, corroborating our expectations. It is
worth mentioning that all compounds submitted to the solubility and
intrinsic dissolution tests were found to be stable at the end of the ex-
periments. The final pH values, measured after the solubility studies, did
not show any significant variation (Table S17). Besides that, the FT-IR
data showed that the crystal structure of the solid residues and the un-
dissolved disks obtained after the solubility and dissolution experiments,
respectively, remain the same that the original ones (data not shown),
excluding even the formation of hydrates.
3.3.3. Thermal analysis
The thermal profile of the DIL crystal forms was assessed by a
combination of DSC, TG, and HSM analyses, as depicted in Fig. 7. DSC
and TG plots of DIL-HCl were included for comparative purposes. The
DIL-HCl salt is thermally stable up to 220 ◦C and its DSC curve exhibits a
single endothermic melting peak at 213.9 ◦C (Tonset = 211.5 ◦C, ΔH =
91.54 J gꢀ 1). The DIL-OXA-H2O DSC curve, in turn, is characterized by
two endothermic peaks at 59.8 ◦C (Tonset = 43.27 ◦C, ΔH = -72.53 J gꢀ 1
)
and 112.1 ◦C (Tonset = 105.98 ◦C, ΔH = -43.03 J gꢀ 1) that correspond to
the dehydration and melting processes of the sample, respectively. These
events are followed by a mass loss of ~ 7.2% in the wide temperature
range of 40–110 ◦C in the TG curve, being consistent with the release of
two structural water molecules and in agreement with the theoretical
value (7.0%). Since water molecules on this dihydrate salt are trapped
and interacting weakly via H-bonding in channels, dehydration, in this
case, could occur without crystal structure rupture, which suggests the
formation of its dehydrated form.
First, the DIL-HCl solubility in all dissolution media is in accordance
with the values found in the literature (Sood and Panchagnula, 1998). As
already mentioned, the hydrochloride form proved to be very soluble,
When we assessed the DSC curve of DIL-SUC-H2O, we noticed the
with values ranging from 545.01 ± 28.48 to 565.13 ± 9.96 mg mLꢀ 1
.
presence of only one endothermic peak centered at 70.6 ◦C (Tonset
=
Similarly, both oxalate and succinate hydrated salts also showed high
solubility values in all dissolution media. For these salts, for instance, the
solubility in purified water was 382.71 ± 3.85 mg mLꢀ 1 (DIL-OXA-H2O)
and 348.07 ± 31.60 mg mLꢀ 1 (DIL-SUC-H2O), being slightly lower (from
1.6 to 1.5-folds) than the DIL-HCl commercial form. In contrast, the
solubility of DIL-FUM-H2FUM salt-cocrystal, for being the compound
with a more dense and cohesive crystal packing, is considerably lower in
the four dissolution media (Fig. 8) compared to the other three DIL salts.
Significant solubility decreases ranged from 12.5 to 21.4-fold were
observed. From a structural point of view, these results can be attrib-
uted, in part, to the supramolecular architectures of the compounds. In
the DIL salts, their crystal packings are dominated by hydrophilic re-
gions, i.e., molecular channel subsets, where the anions/water mole-
cules, as well as the polar functional groups, are arranged. Apparently,
these crystal packing assemblies play a crucial role in the prompt API
solubilization.
54.28 ◦C, ΔH = -182.57 J gꢀ 1) that was assigned, at first, as a typical
dehydration event. Nevertheless, the HSM photomicrographs (Fig. 7b)
revealed that this salt starts to melt simultaneously with its dehydration.
This unexpected behavior makes the DIL-SUC-H2O compound an ionic
liquid (IL), i.e., an organic salt with a melting point below 100 ◦C
(Stoimenovski et al., 2010). It is noteworthy that both events mentioned
are accompanied by an initial mass loss of about 3.0% in the range of
50–100 ◦C in the TG curve, agreeing with the theoretical value of 3.2%
that corresponds to the loss of one water molecule from the crystalline
lattice. On the other hand, the DIL-FUM-H2FUM thermal profile is
similar to that observed for DIL-HCl since the DSC plot of the salt-
cocrystal is also characterized by a single endothermic melting peak at
194.2 ◦C (Tonset = 191.76 ◦C, ΔH = -95.59 J gꢀ 1) and its TG thermogram
shows that this form is thermally stable up to ~202 ◦C. After this tem-
perature, a gradual mass loss can be observed in the TG curve.
According to the TG data, all thermal events in the DSC curves have
been assigned to dehydration or melting of the samples since they were
not accompanied by a significant weight loss step in the corresponding
TG thermograms. Based on the decomposition/melting temperatures of
each compound (see Table 3) and further considering that both melting,
and degradation processes require the rupture of the crystal structure,
the following thermal stability order can be established: DIL-HCl > DIL-
FUM-H2FUM > DIL-OXA-H2O > DIL-SUC-H2O. Finally, HSM experi-
ments successfully confirmed the DSC/TG result interpretations. In the
HSM photomicrographs (Fig. 7b), it is possible to note the beginning of
the crystals melting of the DIL-OXA-H2O (~112 ◦C), DIL-SUC-H2O
(~75 ◦C), and DIL-FUM-H2FUM (~194 ◦C). Also, for both oxalate and
succinate hydrated salts we observe the darkening of the DIL-OXA-H2O
and DIL-SUC-H2O crystals at approximately 60 ◦C due to their dehy-
dration processes.
3.4.2. Intrinsic dissolution and dissolution profile
Dissolution studies are complementary to those of solubility, being
crucial in understanding how the solid-state form dictates the drug
release rate (Siepmann and Siepmann, 2013). In order to investigate as
the new solid forms affected the dissolution behaviors, their intrinsic
dissolution rates (IDRs) and powder dissolution profiles have been
determined. All organic salts reported herein present lower IDRs values
compared to DIL-HCl (see Table 3). The DIL-OXA-H2O (9.65 ± 1.51 mg
cmꢀ 2 minꢀ 1) and DIL-SUC-H2O (8.41 ± 0.94 mg cmꢀ 2 minꢀ 1) exhibited
a 1.6 and 1.9-fold slower dissolution rate, respectively, compared to DIL-
HCl (15.68 ± 2.45 mg cmꢀ 2 minꢀ 1). Nevertheless, the dissolution rate of
the DIL-FUM-H2FUM is found to be about 13.7 (1.14 ± 0.34 mg cmꢀ 2
minꢀ 1) times lower than that of DIL-HCl, confirming that the cocrys-
tallization of DIL with fumaric acid has a remarkable influence on the
intrinsic dissolution rate of the API, as illustrated in Fig. 9a. This
behavior is expected from structures containing molecules efficiently
packaged that, when exposed to an aqueous medium, hinders the
rupture of the crystal structures by water molecules on the dissolution
process.
3.4. Pharmaceutical implications
As previously mentioned, the ready solubilization and dissolution of
the DIL are harmful to drug pharmacokinetics. Thus, after the in-deep
structural characterization of the new crystal solid forms, it is claimed
to verify their efficiency in optimizing the drug solubility and dissolu-
tion processes.
Meanwhile, it is noted that the dissolution profiles are quite similar
to each other (Fig. 9b). All compounds tested reached the concentration
referring to plateau, i.e., 100% of drug release, approximately within 7
min after inserting the capsules in the dissolution vessels. Even though
we succeeded in decreasing the solubility of the drug and its intrinsic
dissolution rate, the dissolution profile results suggest that the relatively
high solubility of the DIL crystal forms has made the capsule formulation
3.4.1. Equilibrium solubility
Solubility is regarded as the main biopharmaceutical attribute of an
API since it has an immense impact on the drug bioavailability and,
11