2.1.4. X-ray Diffraction (XRD)

The diffractograms obtained for pure drugs (CUR and MTX), polymers (PCL and PEG 6000), and nanocapsules NCUR-1, NCUR-2, NMTX-1, NMTX-2, NCUR/MTX-0, NCUR/MTX-1, and NCUR/MTX-2 are shown in Figure 2. CUR presented typical peaks at 2θ values of 8.85◦, 14.25◦, 17.04◦, and 23.10◦ as previously reported [34,35], which confirmed its crystalline nature. MTX showed main crystalline peaks at 9.16◦, 12.8◦, 19.42◦, and 26.74◦ as previously described [36]. Also, PCL revealed two crystalline peaks at 21.59◦ and 23.72◦. XRD data for PEG 6000 showed 2θ values at 19.17◦ and 23.41◦.

**Figure 2.** Diffractograms of CUR, MTX, PCL, PEG 6000, and CUR and/or MTX-loaded and non-loaded NCs obtained by XRD analysis.

CUR and/or MTX-loaded and non-loaded NCs exhibited similar non-crystalline pattern with a remarkable decrease of crystalline peaks from the drug(s) and polymers. In that sense, drug amorphization was demonstrated for all CUR and/or MTX-loaded formulations. This behavior is related to the molecular dispersion of such drugs when NCs were obtained using the interfacial deposition of preformed polymer method. Solid-state substances may have crystalline and/or amorphous characteristics. In general, the amorphous solids are more soluble than those in the crystalline state due to the free energies present in the dissolution process. In the amorphous state, molecules are randomly arranged and, therefore, lower energy is required to separate them, resulting in a faster dissolution when compared to the crystalline form [37]. Therefore, the amorphous pattern of CUR and/or MTX into NCs is considered to be advantageous because it allows the drug(s) dissolution and leads to drug(s) diffusion through the polymer wall, resulting in a sustained release of the encapsulated drug(s) [34,38].

2.1.5. Fourier-Transform Infrared Spectroscopy (FTIR)

The FTIR spectra recorded for CUR, MTX, PCL, PEG 6000, physical mixture, and CUR and/or MTX-loaded and non-loaded NCs are depicted in Figure 3.

**Figure 3.** FTIR spectra of CUR, MTX, PCL, PEG 6000, physical mixture, and CUR and/or MTX-loaded and non-loaded NCs.

The FTIR spectrum of pure CUR presented the typical bands previously reported [35,39,40]. A sharp band at 3508 cm−<sup>1</sup> and a broad band at 3387 cm−<sup>1</sup> were assigned to the stretching of –OH group. Stretching vibrations of the carbonyl group and C–C bond of benzene ring were observed at 1627 cm−<sup>1</sup> and 1510 cm−1, respectively. CUR showed a bending vibration at 1427 cm−<sup>1</sup> assigned to –CH group connected to the benzene rings. A band at 1276 cm−<sup>1</sup> was recorded for C–O stretching vibration. Two bands at 1155 cm−<sup>1</sup> and 1028 cm−<sup>1</sup> were assigned to stretching vibrations of C–O from ether group and C–O–C group, respectively. Bands at 960, 813, and 713 cm−<sup>1</sup> were related to bending vibrations of the C–H bond of alkene groups.

MTX presented bands at 3412 and 3387 cm−<sup>1</sup> assigned to the stretching vibration of amine groups. A band at 2927 cm−<sup>1</sup> was related to stretching of the O–H group from a carboxylic acid. The stretching of the C=O bond was observed at 1645 cm−<sup>1</sup> while the stretching of N-H bong from amide was recorded at 1600 cm<sup>−</sup>1. Stretching bands at 1500, 1543, and 1448 cm−<sup>1</sup> were assigned to the aromatic ring. A band at 1207 cm−<sup>1</sup> was related to the stretching of the C–O bond from carboxylic acid [41].

PCL presented an intense band at 1730 cm<sup>−</sup>1, corresponding to the stretching of the C=O group from aliphatic esters. Two bands at 2943 and 2864 cm−<sup>1</sup> were attributed to the asymmetric and symmetric stretching vibrations of –CH2 group, respectively. Stretching bands at 1174 and 1043 cm−<sup>1</sup> were assigned to C–O bond.

The FTIR spectrum of PEG exhibited its typical broad band at 3520 cm−1, corresponding to the stretching of –OH group. In addition, two bands at 2883 cm−<sup>1</sup> and 1110 cm−<sup>1</sup> were assigned to –CH group from an aliphatic chain and asymmetric stretching of C–O–C from dialkyl ethers, respectively.

Bands at the same wavenumber range of FTIR spectrum to those recorded for the physical mixture was observed for CUR and/or MTX-loaded NCs. Considering the mild nanoencapsulation conditions used, no covalent functionalization occurred among polymers and drugs when formulations were obtained.
