RESULTS

Physicochemical Characterization
At first, physical-chemical properties of raw material were characterized to investigate changing in drug solid state after formulation. ATR-FTIR was used to assess main peaks related to PVA, PHEA, and ibuprofen sodium, respectively. Notably, this method allows identification of creation of hydrogen bonding that might indicate the formation of new bonds between drug and polymers (35). Figure 1 presents ATR-FTIR spectra for raw material and peak assignation was reported in Table II. Peak assignation was coherent with literature, and ibuprofen sodium spectra resulted in being consistent with pure drug spectra in the crystalline form (36–38).
Fig. 1 ATR-FTIR spectra of raw materials PVA, PHEA, and ibuprofen sodium
Table II Peak Assignation for Each Raw Material PVA, PHEA, and Ibuprofen Sodium. Data Are Coherent with Literature Findings (36–38)
Raw material Peaks Assignation
PVA 3290 cm−1 Stretching O–H group
2939 cm−1 Asymmetric stretching C–H group
1732 cm−1 Stretching C=O
1567 cm−1 Stretching C=C
1421 cm−1 Symmetric bending CH2 group
PHEA 3276 cm−1 Stretching O–H bond
2938 cm−1 Aliphatic stretching C–H group
1633 cm−1 Stretching C=O group
1525 cm−1 Vibrations N–H group
1427 cm−1 Aliphatic bending C–H group
1362 cm−1 Bending O–H group
1056 cm−1 Ester group
Ibuprofen sodium 2951 cm−1 Asymmetric stretching CH3 group
1698 cm−1 Stretching C=O group
1545 cm−1 Stretching vibrations C=C
1251 cm−1 C–O stretching
748 cm−1 Vibration CH2 group
PVA polyvinyl alcohol, PHEA poly-N-hydroxyethyl-aspartamide
Drug solid-state morphology is an essential parameter to evaluate to understand the dissolution profile. DSC analyzed thermal properties of drug and polymers, and thermograph of PVA showed an endothermic peak at 192°C recognized to be the melting point of polymer which is present in crystalline form. This finding relates to the literature (39), while PHEA was amorphous and no peak is visible at DSC. Ibuprofen sodium showed a sharp peak at 101°C (Δcp 10.89 J/g), confirmed by existing literature, which indicates that it is present in its crystalline form (31).
Once patches were formulated, they were evaluated for the presence of a hydrogen bond between polymers and drug to assess the formation of interactions that might occur during the formulation process. Spectra are shown in Fig. 2. ATR-FTIR spectra of pure PVA and films containing only PVA and water (F1 and F2) were consistent with pure PVA spectra, and no water was detected. In formulations F3 and F4, there were observed peaks at 3284 cm−1 for F3 and 2939 cm−1 for F4, respectively assigned to O–H group and C–H group in PVA. It was also noticed that the presence of peaks at 1633 cm−1 and 1056 cm−1 both related to PHEA chemical structure. But no new peak was observed demonstrating no hydrogen bond formation. In ATR-FTIR spectra of F5 and F6, there were characteristic peaks of ibuprofen sodium which were seen. For instance, a peak was observed at 2950 cm−1 in F5 film due to the asymmetric stretching of the CH3 group. Also, a peak was observed at 1647 cm−1, which was assigned to stretching of C=O group. Fingerprint region of F5 and F6 films showed similar activity to raw ibuprofen sodium with peaks at 1252 cm−1 for F6 film which is apportioned to C–O stretching. Also, a peak was highlighted at 749 cm−1 of F5 film which is assigned to vibration of CH2 group. No peaks referring to the formation of new bonding were identified.
Fig. 2 FTIR spectra of a PVA with F1 and F2; b PVA and PHEA with F3 and F4; and c PVA, PHEA, and ibuprofen sodium with F5 and F6
Therefore, drug morphology within formulations was investigated as it is a well-known effect on solid state on dissolution profile (40). DSC thermographs for F1, F2, F3, and F4 film showed endothermic peaks at 191°C, 189°C, 191°C, and 189°C, respectively. These peaks correspond to the melting temperature of PVA, confirming the crystalline form of PVA in films. Figure 3 shows the thermographs of formulations F5 and F6. Mainly, F5 film showed an endothermic peak at 96°C (Δcp 0.73 J/g), and F6 film showed an endothermic peak at 95°C (0.68 J/g). These two peaks correspond to the melting point of ibuprofen sodium and highlight the crystalline form. PVA crystalline peak, which is reported in Fig. 3, was not identified in F5 and F6, suggesting PVA amorphization. Confirmation about drug crystallinity could be sought to be identified, in the previous paragraph, of the main peak of ibuprofen sodium as a crystalline molecule. Moreover, it was observed that heat capacity (Δcp) of each formulation, F5 and F6, is respectively 7.5% and 6.98% of Δcp of ibuprofen alone, and this value is coherent with drug loading found for both formulations and described below.
Fig. 3 DSC graphs of ibuprofen sodium and pure PVA compared with F5 and F6 that present respectively peaks at 96°C and 95°C (endotherm down)
Later, the effect of different concentrations of PVA on particle size was investigated. SEM images indicate that formulation containing 7.5% (w/v) of PVA presents particle diameter of 30.05 ± 3.43 μm, a 1.38-fold increase (p < 0.0001) with respect to particles obtained with 5.0% % (w/v) of PVA with an average diameter of 21.68 ± 4.09 μm. Even if PVA usually reduces drug particle size when used as a single polymer, it is well known that it causes drug particle growth when combined with other polymers (41,42). In this study, PVA and PHEA combination lead to obtaining an overall particle diameter that was smaller than 200 μm, reported to be typical of PVA formulation (43). Particularly, increased particle size could be due to salting out of sodium increasing interaction between ibuprofen molecules. This event is recognized as happening when two soluble polymers are dissolved at higher concentration (44). Figure 4 shows SEM images of F5 and F6 of samples with two different magnifications. For each formulation, PDI was calculated and found to be respectively 1.08 and 1.12. This result shows that the drug was not monodispersed due to formation of aggregate that is noticeable in Fig. 4 (45).
Fig. 4 SEM images of F5 with a magnification of a × 350 and b × 700 and F6 with a magnification of c × 1K and d × 900

Drug Loading Evaluation and Dissolution Study
Ibuprofen sodium drug loading was evaluated for each formulation. Results showed that ibuprofen sodium loading in film F5 was 6.82% w/v ± 0.01 and 7.01% w/v ± 0.01 in film F6. Drug loading was expected to be 10% w/v, and F5 and F6 saw ~ 69% drug loading efficacy. The lower than anticipated drug content is expected when no stabilizing agents are added to a formulation (46). The in vitro dissolution profile of ibuprofen sodium was analyzed in PBS pH 6.8 to mimic buccal conditions and compared with the release profile of the drug from the film formulation. The dissolution rate percentage was calculated according to assessed drug loading and related to film weight. Data showed a slower dissolution rate with ibuprofen sodium alone compared to dissolution rate when incorporated within the film. In each profile, it was observed that drug in its crystalline state achieved a condition of supersaturation due to the solubilizing effect of polymer combination (47,48). The dissolution profile of ibuprofen sodium showed a drug release of 59% at 15 min, while F5 had a drug release of 74%, a 1.25-fold increase (p = 0.002), and F6 of 72%, a 1.22-fold increase (p < 0.0001), resulting in an immediate-like release. This data indicates that the dissolution rate was faster when the drug was incorporated into films compared to medication alone. The calculation of data also confirmed area under curve (AUC) which was increment from 7093 ± 179 μg/h/mL for ibuprofen sodium to 7922 ± 443.8 μg/h/mL (F5) and 8296 ± 185.1 μg/h/mL (F6). Moreover, data showed that lower concentration of PVA increases release profile as confirmed from previous literature findings (44). As the difference between two PVA concentrations is 1.02-fold difference, it is considered the possibility that an increase in drug dissolution profile is due to the addition of PHEA itself.