Xanthan-Gum/Pluronic-F-127-Based-Drug-Loaded Polymeric Hydrogels Synthesized by Free Radical Polymerization Technique for Management of Attention-Deficit/Hyperactivity Disorder

Smart and intelligent xanthan gum/pluronic F-127 hydrogels were fabricated for the controlled delivery of atomoxetine HCl. Different parameters such as DSC, TGA, FTIR, XRD, SEM, drug loading, porosity, swelling index, drug release, and kinetics modeling were appraised for the prepared matrices of hydrogels. FTIR confirmed the successful synthesis of the hydrogel, while TGA and DSC analysis indicated that the thermal stability of the reagents was improved after the polymerization technique. SEM revealed the hard surface of the hydrogel, while XRD indicated a reduction in crystallinity of the reagents. High gel fraction was achieved with high incorporated contents of the polymers and the monomer. An increase in porosity, drug loading, swelling, and drug release was observed with the increase in the concentrations of xanthan gum and acrylic acid, whereas Pluronic F-127 showed the opposite effect. A negligible swelling index was shown at pH 1.2 and 4.6 while greater swelling was observed at pH 7.4, indicating a pH-responsive nature of the designed hydrogels. Furthermore, a higher drug release was found at pH 7.4 compared to pH 1.2 and 4.6, respectively. The first kinetics order was followed by the prepared hydrogel formulations. Thus, it is signified from the discussion that smart xanthan gum/pluronic F-127 hydrogels have the potential to control the release of the atomoxetine HCl in the colon for an extended period of time.


Introduction
Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in childhood and adolescence. This disorder affects between 2.2% and 17.8% of all school-aged children and adolescents. Different developmental deficits such as learning limitation, control of executive functions, as well as global impairments of social skills are associated with ADHD in children [1]. As early as 1902, "deficiencies in "volitional inhibition" and an excessive inability to pay attention for long periods of time" were seen with a group of restless children. In 1937, it was discovered that the levels of hyperactivity and behavioral issues could be reduced by amphetamine. In the 1950s, the term "minor brain damage" (MBD) was often used to describe these symptoms in children; however, in most cases, no evidence of neurological damage was identified. Until 1960, the disorder was known and labeled as ADHD and attention deficit disorder performed for the fabricated networks of hydrogel. Gelation mechanism of prepared hydrogels is shown below in Scheme 1. Scheme 1. Gelation mechanism of XG/PF-127 hydrogel.

FTIR Analysis
The nature of new bond formations and changes in the chemical structure of developed hydrogels were elucidated by FTIR analysis. The FTIR spectra of all components are indicated in Figure 1. XG indicated FTIR spectra by bands at 3280 and 1608 cm −1 , demonstrating hydrogen-bonded OH groups and COO-groups, whereas the bending of O-H and C-H was seen by peaks at 1018 and 1420 cm −1 [12,13], respectively. The FTIR spectra of PF-127 represent a C-O-C stretching vibration within the 1202-1002 cm −1 range. Likewise, the stretching vibration of COC and COC-CH2 was seen by peaks at 1098 and 1059 cm −1 , whereas the CC-COC bond was confirmed by a peak at 1148 cm −1 . Two characteristic bands were observed at 1342 and 1468 cm −1 , indicating a CH2 group. An absorption peak at 2918 cm −1 was assigned to the methyl group [14,15]. Similarly, the FTIR spectrum of Aa indicated a stretching vibration of -CH2 by a broad band at 3014 cm −1 . Furthermore, the stretching vibration of C=O of the carboxylic acid was presented by a peak at 1702 cm −1 [16]. The FTIR spectra of the XG/PF127 hydrogel indicated prominent peaks of XG, PF127, and Aa. Certain new peaks were formed while some were modified, indicating the successful crosslinking among hydrogel components. The prominent bands of XG and PF127 were changed from 3280, 1608 cm −1 , and 2918, 1468 cm −1 to 2910, 1490, 2950, and 1505 cm −1 , respectively. Similarly, the position of certain peaks of Aa were also modified, like bands at 3014 and 1702 cm −1 which were moved to 3042 and 1685 cm −1 . This all demonstrates the synthesis of hydrogels. The FTIR spectrum of ATMH indicated the stretching vibration of the amino group (N-H) by a peak at 3270 cm −1 , while the stretching vibrations of CH2 and COOH groups were observed at 2940 and 3322 cm −1 , respectively. The C=C ring stretching and the C-H bending of CH2 groups were detected at 1598 and 1438 cm −1 [17]. After loading, a slight change was observed in the peaks of ATMH as 1438 and 2918 cm −1 were Scheme 1. Gelation mechanism of XG/PF-127 hydrogel.

FTIR Analysis
The nature of new bond formations and changes in the chemical structure of developed hydrogels were elucidated by FTIR analysis. The FTIR spectra of all components are indicated in Figure 1. XG indicated FTIR spectra by bands at 3280 and 1608 cm −1 , demonstrating hydrogen-bonded OH groups and COO-groups, whereas the bending of O-H and C-H was seen by peaks at 1018 and 1420 cm −1 [12,13], respectively. The FTIR spectra of PF-127 represent a C-O-C stretching vibration within the 1202-1002 cm −1 range. Likewise, the stretching vibration of COC and COC-CH 2 was seen by peaks at 1098 and 1059 cm −1 , whereas the CC-COC bond was confirmed by a peak at 1148 cm −1 . Two characteristic bands were observed at 1342 and 1468 cm −1 , indicating a CH 2 group. An absorption peak at 2918 cm −1 was assigned to the methyl group [14,15]. Similarly, the FTIR spectrum of Aa indicated a stretching vibration of -CH 2 by a broad band at 3014 cm −1 . Furthermore, the stretching vibration of C=O of the carboxylic acid was presented by a peak at 1702 cm −1 [16]. The FTIR spectra of the XG/PF127 hydrogel indicated prominent peaks of XG, PF127, and Aa. Certain new peaks were formed while some were modified, indicating the successful crosslinking among hydrogel components. The prominent bands of XG and PF127 were changed from 3280, 1608 cm −1 , and 2918, 1468 cm −1 to 2910, 1490, 2950, and 1505 cm −1 , respectively. Similarly, the position of certain peaks of Aa were also modified, like bands at 3014 and 1702 cm −1 which were moved to 3042 and 1685 cm −1 . This all demonstrates the synthesis of hydrogels. The FTIR spectrum of ATMH indicated the stretching vibration of the amino group (N-H) by a peak at 3270 cm −1 , while the stretching vibrations of CH 2 and COOH groups were observed at 2940 and 3322 cm −1 , respectively. The C=C ring stretching and the C-H bending of CH 2 groups were detected at 1598 and 1438 cm −1 [17]. After loading, a slight change was observed in the peaks of ATMH as 1438 and 2918 cm −1 were slightly shifted to 1412 and 2950 cm −1 , representing the successful loading of ATMH by the XG/PF-127 hydrogel [18]. slightly shifted to 1412 and 2950 cm −1 , representing the successful loading of ATMH by the XG/PF-127 hydrogel [18].

TGA
TGA was performed for XG, PF-127, and prepared hydrogels as illustrated in Figure  2. The TGA curve of XG indicated a weight loss of 8 and 42% at 218 and 400 °C, respectively. The initial loss of weight was correlated with the release of volatile matter and absorbed water. On the other hand, stability can be seen by the TGA of PF-127 till 378 °C. Further rise in temperature resulted in the decomposition of PF127. A 95% weight loss was observed as temperature reached 423 °C. Increasing temperature led to a further decomposition of PF127, which still continued to entire degradation. The loss in the weight of PF-127 was due to the elimination of functional groups with the increase in temperature [19,20]. A degradation of 37% in weight was observed by TGA of XG/PF-127 as temperature approached 310 °C. This might be due to the removal of absorbed and bonded moisture and loss of hydroxyl groups. Similarly, a weight loss of 48% was seen at 487 °C. Further decomposition of developed hydrogel was seen with the increase in temperature. Comparing the thermal stability of XG and PF127 with the formulated hydrogel, we can demonstrate that the prepared hydrogel exhibited higher thermal stability than pure polymers, which basically indicated enhancement in the thermal stability of excipients after crosslinking among them [21].

TGA
TGA was performed for XG, PF-127, and prepared hydrogels as illustrated in Figure 2. The TGA curve of XG indicated a weight loss of 8 and 42% at 218 and 400 • C, respectively. The initial loss of weight was correlated with the release of volatile matter and absorbed water. On the other hand, stability can be seen by the TGA of PF-127 till 378 • C. Further rise in temperature resulted in the decomposition of PF127. A 95% weight loss was observed as temperature reached 423 • C. Increasing temperature led to a further decomposition of PF127, which still continued to entire degradation. The loss in the weight of PF-127 was due to the elimination of functional groups with the increase in temperature [19,20]. A degradation of 37% in weight was observed by TGA of XG/PF-127 as temperature approached 310 • C. This might be due to the removal of absorbed and bonded moisture and loss of hydroxyl groups. Similarly, a weight loss of 48% was seen at 487 • C. Further decomposition of developed hydrogel was seen with the increase in temperature. Comparing the thermal stability of XG and PF127 with the formulated hydrogel, we can demonstrate that the prepared hydrogel exhibited higher thermal stability than pure polymers, which basically indicated enhancement in the thermal stability of excipients after crosslinking among them [21].

DSC
The DSC curve of individual excipients and prepared hydrogel is shown in Figure 3. An exothermic peak was demonstrated at 65 °C while a broad endothermic peak was detected at 280 °C by XG s DSC. The endothermic and exothermic peaks of XG indicated moisture loss and thermal decomposition. The DSC of PF-127 exhibited a strong endothermic peak at 70 °C, representing the devastation of crystalline network of the PF-127 chain. Similarly, an exothermic peak was seen at 113 °C. The developed hydrogel and individual components are quite compatible, as seen by the prepared formulation s peaks migrating towards a higher glass transition temperature than the parent components [22] because of the higher intermolecular hydrogen bonding [23]. Therefore, greater thermal stability was indicated by the formulated hydrogel [24].

XRD Analysis
The recorded XRD spectra of XG, PF127, and the formulated hydrogels are indicated in Figure 4. Prominent peaks were demonstrated by the XRD spectra of XG at 2θ = 20.19°, 32.10°, and 48.40°. XG is amorphous by nature and forms aggregates with the other side chains, hence restricting the proper packaging of polymer chains. Similarly, high sharp peaks of PF-127 were seen at 2θ = 19.20°, 21.83°, and 27.10°, respectively. The sharp high intense peaks of the PF-127 basically indicated its high stability and crystallinity. However, sharp and prominent peaks of XG and PF127 were replaced by dense peaks after crosslinking and polymerization reaction as indicated by the XRD analysis of the prepared hydrogel. All these factors indicate a decrease in pure reagent s crystallinity after polymerization. The reduction in crystallinity of the reagents as indicated by polymeric hydrogel may be the feature of the formation of the conjugate of Aa with XG and PF127 in the presence of MBA, hence indicating enhancement in the fraction of the amorphous phase [25,26].

DSC
The DSC curve of individual excipients and prepared hydrogel is shown in Figure 3. An exothermic peak was demonstrated at 65 • C while a broad endothermic peak was detected at 280 • C by XG's DSC. The endothermic and exothermic peaks of XG indicated moisture loss and thermal decomposition. The DSC of PF-127 exhibited a strong endothermic peak at 70 • C, representing the devastation of crystalline network of the PF-127 chain. Similarly, an exothermic peak was seen at 113 • C. The developed hydrogel and individual components are quite compatible, as seen by the prepared formulation's peaks migrating towards a higher glass transition temperature than the parent components [22] because of the higher intermolecular hydrogen bonding [23]. Therefore, greater thermal stability was indicated by the formulated hydrogel [24].

DSC
The DSC curve of individual excipients and prepared hydrogel is shown in Figure 3. An exothermic peak was demonstrated at 65 °C while a broad endothermic peak was detected at 280 °C by XG s DSC. The endothermic and exothermic peaks of XG indicated moisture loss and thermal decomposition. The DSC of PF-127 exhibited a strong endothermic peak at 70 °C, representing the devastation of crystalline network of the PF-127 chain. Similarly, an exothermic peak was seen at 113 °C. The developed hydrogel and individual components are quite compatible, as seen by the prepared formulation s peaks migrating towards a higher glass transition temperature than the parent components [22] because of the higher intermolecular hydrogen bonding [23]. Therefore, greater thermal stability was indicated by the formulated hydrogel [24].

XRD Analysis
The recorded XRD spectra of XG, PF127, and the formulated hydrogels are indicated in Figure 4. Prominent peaks were demonstrated by the XRD spectra of XG at 2θ = 20.19°, 32.10°, and 48.40°. XG is amorphous by nature and forms aggregates with the other side chains, hence restricting the proper packaging of polymer chains. Similarly, high sharp peaks of PF-127 were seen at 2θ = 19.20°, 21.83°, and 27.10°, respectively. The sharp high intense peaks of the PF-127 basically indicated its high stability and crystallinity. However, sharp and prominent peaks of XG and PF127 were replaced by dense peaks after crosslinking and polymerization reaction as indicated by the XRD analysis of the prepared hydrogel. All these factors indicate a decrease in pure reagent s crystallinity after polymerization. The reduction in crystallinity of the reagents as indicated by polymeric hydrogel may be the feature of the formation of the conjugate of Aa with XG and PF127 in the presence of MBA, hence indicating enhancement in the fraction of the amorphous phase [25,26].

XRD Analysis
The recorded XRD spectra of XG, PF127, and the formulated hydrogels are indicated in Figure 4. Prominent peaks were demonstrated by the XRD spectra of XG at 2θ = 20.19 • , 32.10 • , and 48.40 • . XG is amorphous by nature and forms aggregates with the other side chains, hence restricting the proper packaging of polymer chains. Similarly, high sharp peaks of PF-127 were seen at 2θ = 19.20 • , 21.83 • , and 27.10 • , respectively. The sharp high intense peaks of the PF-127 basically indicated its high stability and crystallinity. However, sharp and prominent peaks of XG and PF127 were replaced by dense peaks after crosslinking and polymerization reaction as indicated by the XRD analysis of the prepared hydrogel. All these factors indicate a decrease in pure reagent's crystallinity after polymerization. The reduction in crystallinity of the reagents as indicated by polymeric hydrogel may be the feature of the formation of the conjugate of Aa with XG and PF127 in the presence of MBA, hence indicating enhancement in the fraction of the amorphous phase [25,26].

SEM
The SEM of the XG/PF-127 hydrogel is illustrated in Figure 5. The prepared network displayed a hard surface with a few big pores, which may be connected to high crosslinking of the XG and PF-127 with the Aa content. The strong crosslinking among hydrogel reagents improved the mechanical strength and stability of the hydrogel; thus, it can be used as a controlled drug delivery carrier [27].

Sol-Gel Analysis
The cross-linked and uncross-linked fractions of the synthesized hydrogel were estimated by sol-gel analysis (Table 1). Gel is the cross-linked while sol is the uncross-linked fraction of the formulated hydrogel. Both sol and gel fractions were influenced highly by the incorporated reagents of hydrogel. With an increase in the XG and PF127 feed ratios, the gel fraction rose. During polymerization reaction, free radicals are produced, which leads to the crosslinking of XG and PF-127 with Aa by MBA. Thus, as the feed ratios of XG and PF127 increase, more free radicals are generated in the same way. Thus, greater

SEM
The SEM of the XG/PF-127 hydrogel is illustrated in Figure 5. The prepared network displayed a hard surface with a few big pores, which may be connected to high crosslinking of the XG and PF-127 with the Aa content. The strong crosslinking among hydrogel reagents improved the mechanical strength and stability of the hydrogel; thus, it can be used as a controlled drug delivery carrier [27].

SEM
The SEM of the XG/PF-127 hydrogel is illustrated in Figure 5. The prepared network displayed a hard surface with a few big pores, which may be connected to high crosslinking of the XG and PF-127 with the Aa content. The strong crosslinking among hydrogel reagents improved the mechanical strength and stability of the hydrogel; thus, it can be used as a controlled drug delivery carrier [27].

Sol-Gel Analysis
The cross-linked and uncross-linked fractions of the synthesized hydrogel were estimated by sol-gel analysis (Table 1). Gel is the cross-linked while sol is the uncross-linked fraction of the formulated hydrogel. Both sol and gel fractions were influenced highly by the incorporated reagents of hydrogel. With an increase in the XG and PF127 feed ratios, the gel fraction rose. During polymerization reaction, free radicals are produced, which leads to the crosslinking of XG and PF-127 with Aa by MBA. Thus, as the feed ratios of XG and PF127 increase, more free radicals are generated in the same way. Thus, greater

Sol-Gel Analysis
The cross-linked and uncross-linked fractions of the synthesized hydrogel were estimated by sol-gel analysis (Table 1). Gel is the cross-linked while sol is the uncross-linked fraction of the formulated hydrogel. Both sol and gel fractions were influenced highly by the incorporated reagents of hydrogel. With an increase in the XG and PF127 feed ratios, the gel fraction rose. During polymerization reaction, free radicals are produced, which leads to the crosslinking of XG and PF-127 with Aa by MBA. Thus, as the feed ratios of XG and PF127 increase, more free radicals are generated in the same way. Thus, greater Gels 2023, 9, 640 7 of 14 reactive sites are available for the monomer to crosslink with the polymers. Similarly, high incorporated feed ratios of Aa also resulted in high levels of gel formation. Aa plays a key role in polymerization of hydrogel reagents. Crosslinking density of the hydrogel is improved with the high incorporated contents of Aa, thus high gel fraction is achieved. In other words, we can say that like XG and PF127, high feed rations of Aa also result in high gel fraction [27]. Khalid and coworkers reported high gel fraction with the high feed ratios of hydrogel reagents [28]. Unlikely, a reduction was observed in the sol fraction with the high incorporated hydrogel contents [29]. Nasir et al. (2019) reported low sol with high gel fractions for the developed gels with their high incorporated contents [30].

Porosity
The swelling and drug loading of the hydrogel and its sub-micro/nano particulate systems are dependent completely on their porosity. High porosity resulted in maximum swelling and loading of the drug. Porosity study was performed for the hydrogel formulations. Porosity was affected by different incorporated feed ratios of the hydrogel contents ( Figure 6). With XG's increased feed ratios, a rise in porosity was seen. Similarly, an increase was seen in porosity with the high feed ratios of Aa. This may be correlated with the formation of highly viscous mixture during the polymerization process, which restricted the evaporation of bubbles; as a result, interconnected channels were produced. Water molecules penetrated into the hydrogel networks through these channels, and thus high porosity was achieved. Unlike in the case with XG and Aa, PF127 also affected the porosity, but in a reverse way. An increase in PF127 contents resulted in a low porosity due to the formation of a highly cross-linked network, which increased the hardness and decreased the pore size of the prepared network. Hence, it can be demonstrated that an increase in feed rations of PF127 and a drop in porosity are observed while an increase in porosity is seen with the high incorporated feed ratios of XG and Aa [31,32].

Swelling Study
The swelling degree of hydrogels is shown in Figure 7A, indicating a low swelling index at pH 1.2 and 4.6; however, it augmented considerably with the increase in pH of the medium, i.e., to pH 7.4. This change in swollen hydrogels due to pH changes can occur due to the development of osmotic swelling forces. These forces are generated by the carboxyl groups (Aa) present in the hydrogel network. Carboxyl groups begin to ionize at pH 4 and completely ionize above pH 6. The existence of more ionic groups in the hydrogel network at high pH resulted in maximum swelling. The prepared XG/PF-127 hydrogel consist of both COO − and -COOH groups. These groups can change into one another under favorable conditions. At pH 1.2, -COO groups protonated into -COOH, but at basic pH 7.4, -COOH entirely deprotonated back into -COO groups. Moreover, XG contains O-acetyl, pyruvyl and unreacted hydroxyl groups, which also undergo deprotonation at pH > 6. Thus, high charge density was produced, and thus high electrostatic repulsion between negatively charged -COO − groups occurred, which led to high swelling of prepared hydrogel at higher pH values [33]. The hydrogen-bonding strength among hydrogel networks is most likely to be strengthened by the large ratio of protonated COOH groups, and thus low swelling was observed at pH 1.2 and 4.6 [30]. Similarly, hydrogel contents also have a significant impact on the hydrogel's swelling. A rise in swelling was seen with the high feed ratios of XG and Aa because of their high functional groups, while in case of PF-127, a drop was observed in swelling with the high levels of the incorporated PF-127 contents. The reason may be attributed to the formation of a hard and bulk network of hydrogel which did not allow the sufficient water molecules to enter into the hydrogel networks [34,35].

Swelling Study
The swelling degree of hydrogels is shown in Figure 7A, indicating a low swelling index at pH 1.2 and 4.6; however, it augmented considerably with the increase in pH of the medium, i.e., to pH 7.4. This change in swollen hydrogels due to pH changes can occur due to the development of osmotic swelling forces. These forces are generated by the carboxyl groups (Aa) present in the hydrogel network. Carboxyl groups begin to ionize at pH 4 and completely ionize above pH 6. The existence of more ionic groups in the hydrogel network at high pH resulted in maximum swelling. The prepared XG/PF-127 hydrogel consist of both COO − and -COOH groups. These groups can change into one another under favorable conditions. At pH 1.2, -COO groups protonated into -COOH, but at basic pH 7.4, -COOH entirely deprotonated back into -COO groups. Moreover, XG contains Oacetyl, pyruvyl and unreacted hydroxyl groups, which also undergo deprotonation at pH > 6. Thus, high charge density was produced, and thus high electrostatic repulsion between negatively charged -COO − groups occurred, which led to high swelling of prepared hydrogel at higher pH values [33]. The hydrogen-bonding strength among hydrogel networks is most likely to be strengthened by the large ratio of protonated COOH groups, and thus low swelling was observed at pH 1.2 and 4.6 [30]. Similarly, hydrogel contents also have a significant impact on the hydrogel s swelling. A rise in swelling was seen with the high feed ratios of XG and Aa because of their high functional groups, while in case of PF-127, a drop was observed in swelling with the high levels of the incorporated PF-127 contents. The reason may be attributed to the formation of a hard and bulk network of hydrogel which did not allow the sufficient water molecules to enter into the hydrogel networks [34,35].

Drug Loading and In Vitro Drug Release Studies
Drug loading was conducted for XG/PF-127 hydrogels as illustrated in Table 2. Like porosity and swelling, the contents of the hydrogel also affected the drug loading. Greater drug loading was detected with the high feed ratios of XG and Aa. The possible reason is the high porosity and swelling index of the hydrogel which occurred with the increase in XG and Aa contents [36,37]. Contrary to XG and Aa, a drop was seen in drug loading by the synthesized matrix as the feed ratios of PF-127 were enhanced [38].
Drug release tests were carried out at pH 1.2, 4.6, and 7.4 for the prepared hydrogels and commercial product Strattera ( Figure 7B,C). Maximum release of the drug was seen

Drug Loading and In Vitro Drug Release Studies
Drug loading was conducted for XG/PF-127 hydrogels as illustrated in Table 2. Like porosity and swelling, the contents of the hydrogel also affected the drug loading. Greater drug loading was detected with the high feed ratios of XG and Aa. The possible reason is the high porosity and swelling index of the hydrogel which occurred with the increase in Gels 2023, 9, 640 9 of 14 XG and Aa contents [36,37]. Contrary to XG and Aa, a drop was seen in drug loading by the synthesized matrix as the feed ratios of PF-127 were enhanced [38]. Drug release tests were carried out at pH 1.2, 4.6, and 7.4 for the prepared hydrogels and commercial product Strattera ( Figure 7B,C). Maximum release of the drug was seen at high pH values due to the deprotonation of XG and Aa functional groups, whereas minimum drug release was detected at pH 1.2 due to the protonation of such functional groups [39,40]. The release studies of the Strattera indicated a rapid release of drug at all three pH values. Almost a 90% concentration of the drug was released at pH 7.4 within the initial 2 h, while in the case of pH 4.6 and 1.2, a concentration of more than 80% of the drug was released within the initial 2 h. Comparing the drug release of Strattera and that of the prepared hydrogel, we can predict that the drug was sustained successfully for extended period of time by the developed hydrogels.
Similar to swelling, the hydrogel's contents also have an impact on drug release. High drug release was observed with the high incorporated XG and Aa contents [41], while a decline was perceived in drug release with the high PF-127 contents [42] and vice versa.

Release Mechanism
To establish the sequence and drug release from the prepared networks, multiple kinetic models were computed using the release data of the synthesized hydrogels. "r" values determine the most suitable kinetic order. Table 2 indicates that the "r" values for the first order were higher than the "r" values of all other kinetic models. As a result, we can state that all formulations of the prepared hydrogel follow the first order of kinetics. The diffusion type is determined by the "n" value. If 0.45 > n, Fickian diffusion occurs; otherwise, non-Fickian or anomalous transport similar to linked diffusion/polymer relaxation occurs. [43]. All formulations have "n" values between 0.5040 and 0.5790, indicating non-Fickian diffusion [44].

Conclusions
The free radical polymerization technique was adopted for the development of XG/PF-127 hydrogels. A stimuli-responsive effect was manifested by the graft copolymer. The controlled release of the ATMH was detected at pH 7.4 for 96 h. The compatibility among the various formulation components of the developed hydrogel was shown by FTIR. DSC and TGA showed an increase in the thermal stability of XG and PF-127 after the polymerization process. Similarly, SEM indicated a hard surface with few large pores through which water penetration occurred. After a polymerization process, XRD showed a reduction in the crystallinity of polymers. High swelling index was seen at pH 7.4, whereas at pH 1.2 and 4.6, low swelling was observed. Hence, it could be inferred from the results that the XG/PF-127 hydrogel can be employed as a potential agent for controlled drug delivery, which would be helpful not only in minimizing undesired GIT effects, but also in enhancing patient compliance and therapeutic output.

Methods of Preparation
Xanthan gum (XG)-and pluronic (PF-127) [XG/PF-127]-based hydrogels were prepared by the free radical polymerization technique. A pre-weighed quantity of XG was dissolved in distilled water at 40 • C for 6 h. The PF-127 solution was mixed with the XG solution under constant stirring. Ammonium persulfate (APS) was poured into the mixture. After that, acrylic acid (Aa) was added in to the XG, PF127 and APS mixture. Finally, an MBA solution was mixed with the aforementioned mixture to crosslink the polymers and monomer on their specific sites. The entire mixture was kept on stirring until a transparent solution was formed, purged by nitrogen gas and then transferred into the glass molds, which were positioned in the water bath. The temperature of the water bath was maintained at 55 • C initially for 2 h, which was increased up to 65 • C later. The formulated gel was cut into 8 mm discs. A mixture of distilled water and ethanol was used for washing the prepared discs of gels. After that, hydrogel discs were placed for one week in a vacuum oven for dehydration. The dried discs were processed further for different studies. A set of formulations is shown in Table 3.

Characterization
FTIR, TGA, DSC, XRD, and SEM were performed according to our previous publication [45].

Sol-Gel Anaylsis
The sol and gel contents of the synthesized hydrogel were estimated by sol-gel analysis. The unreacted part of the hydrogel is known as the sol fraction, while the reactant part is known as the gel fraction. The weighed discs of the prepared hydrogel were placed for 12 h in distilled water. After that, the discs were removed and positioned in the oven for dryness. The dehydrated discs were weighed again [46]. Equations (1) and (2) were applied for the estimation of sol and gel fractions.
Gels 2023, 9, 640 11 of 14 Here, C 1 represents the initial weight of dried hydrogel before the extraction process, while C 2 is the final weight after the extraction process.

Porosity
The porosity study of the prepared hydrogels was performed in absolute ethanol. Hydrogel discs were taken, weighed (A 1 ) and immersed in ethanol for 3 days. After achieving equilibrium swelling, discs were removed and weighed (A 2 ) again [47]. Equation (3) was employed for the determination of porosity of the prepared hydrogels.
Here, ρ is the density of absolute ethanol while V is the swelling volume of hydrogel discs.

Swelling Study
Weighed hydrogel discs were soaked in buffer solutions of pH 1.2, 4.6 and 7.4. The discs were removed at a specific interval of time, blotted with filter paper, weighed, and placed again in the respective media [48]. Dynamic swelling (q) was determined by Equation (4).
where T 2 indicates the weight of the swollen hydrogel disc and T 1 represents the weight of the dried hydrogel disc at time t.

Drug Loading
A pH 7.4 phosphate buffer solution was used to prepare a 1% drug solution. For four days, precisely weighed hydrogel discs were submerged in the drug solution. Following that, discs were removed and cleaned with distilled water to remove any drugs that adhered to the hydrogel discs' surface. The cleaned discs were placed in a vacuum oven to dry [49].

In Vitro Drug Release Study
USP dissolution apparatus-II was employed for the drug release study. The release of the drug from the formulated hydrogel and commercial product Strattera (60 mg) (ELI LILLY and Co., Ltd.) was investigated at three different pH values, i.e., pH 1.2, 4.6 and pH 7.4. XG/PF127-loaded hydrogel discs and the commercial product were placed in 900 mL of each buffer solution with 50 rpm at 37 ± 0.5 • C. Samples of 5 mL were collected and fresh medium of the same quantity was added back to maintain constant sink conditions. The collected samples were analyzed by using a UV spectrophotometer (U-5100, 3 J2-0014, Tokyo, Japan) at the wavelength (λmax) of 226 nm [50].

Release Mechanism
The order and release mechanism of the drug from the prepared hydrogel was determined by using various kinetic models. The release data were fitted into zero-order, first-order, Higuchi, and Korsmeyer-Peppas models [51], respectively.

Statistical Analysis
SPSS Statistic software 22.0 (IBM Corp, Armonk, NY, USA) was performed for the statistical analysis of all experimental data. Differences between the tests were determined by Student's t-Test and considered significant statistically (p-value < 0.05).