3.5.1. Release Kinetics of NPX

The release dynamic of NPX from NPX/pHEMA and NPX/pHPMA drug carrier systems with different compositions are shown in Figures 14 and 15, respectively. As it can be seen from the curve profiles obtained for both systems, the maximum percentage of NPX released is reached with the drug carrier systems containing 2 wt% of NPX content. The comparison between the NPX release capacities for these two different systems during 72 h of the release process reveals that the NPX/pHEMA shows the best performance. Indeed, for the NPX/pHEMA2, a maximum of 42 wt% of NPX was released in neutral pH medium during this period and about 31 wt% in acidic media (pH 1 and 3), while for the NPX/pHPMA2, only 10.5% wt% of NPX was released in neutral pH medium and 7.4% in acidic media (pH 1 and 3) during the same period. This represents a reduction in NPX release dynamics of about a quarter. The decrease in NPX release dynamics observed by replacing pHEMA by pHPMA appears to be due to a dramatic decrease in the hydrophilicity of the carrier polymer caused by the additional methyl group in the substituent. The decrease in hydrophilicity when passing from the pHEMA to pHPMA carrier reduces the degree of swelling as revealed in Table 2. This limits the water amount absorbed by the polymer carrier necessary for the dissolution of a significant part of NPX incorporated in this material. It was also observed from these same curves, for both systems, the behavior of NPX release versus time is characterized by two pseudo stable zones of the release dynamic. The first zone, which is rapid and short, is observed during about the first 4–7 h of the release process, depending on the nature of the drug-carrier used and the pH of the medium. The second zone, which is long and slow, is observed during the 65 h of the release process. The first step is mainly attributed to the leaching of a fraction of NPX particles deposited on the surface or slightly embedded in the sample film. The second step characterizes the steady state in which the release of NPX in the media is governed mainly by a material transfer mechanism.

**Figure 14.** Release kinetics of NPX from (**A**) NPX/pHEMA2, (**B**) NPX/pHEMA5 (**C**) NPX/pHEMA7, (**D**) NPX/pHEMA10 drug carrier system at different pHs.

**Figure 15.** Release kinetics of NPX from (**A**) NPX/pHPMA2, (**B**) NPX/pHPMA5 (**C**) NPX/pHPMA7, (**D**) NPX/pHPMA10 drug carrier system at different pHs.

#### 3.5.2. Enhancement of NPX Solubility

The improvement of the solubility of NPX in water is an integral part among the objectives targeted by this investigation. To reach this goal, a comparison between the solubility of NPX in its powder form and that incorporated in the NPX/pHEMA and NPX/pHPMA drug carrier systems was carried out at 37 ◦C. An excess amount of NPX powder was dissolved under continuous stirring in a known volume of water maintained at 37 ◦C until the appearance of a stable precipitate, indicating the supersaturation of the solution. The solution was then filtered through a Whatman filter number 1. The solubility of NPX was determined by means of UV-visible spectroscopic analysis. Two solutions of pH 1 and 7 were prepared, and the results obtained are gathered in Table 6. The maximum NPX amount dissolved in these media was deducted from the maximum release of this medication from the NPX/pHEMA and NPX/pHPMA drug carrier systems, and the results obtained are also grouped for comparison in this table. The comparison of the maximum solubility data obtained reveals that the pHEMA is much more efficient than the pHPMA used as supports. These data also reveal an enhancement of the solubility of NPX in pH media 1 and 7, in which the NPX/pHEMA system was able to dissolve 2.60-fold that of that of because the NPX amount dissolved from the NPX/pHEMA10 system is more than 1.34 times in pH medium 1 and 2.60 times in neutral pH from the NPX/pHPMA system. The comparison of the NPX solubility data obtained by direct dissolution of the powder with that deduced from the release process involving these two polymers reveals a marked improvement when this drug is incorporated in the molecular state in one of these two polymers. These results also show that the pHEMA used as a support is more efficient than the pHPMA in increasing the solubility of NPX in water. For example, in neutral pH medium, pHEMA was able to improve the solubility of this medication by 3.32 times that of its direct dissolution as powder and 2.33 times in pH medium 1, while pHPMA increased this solubility by only 1.28 and 1.74 times in pH media 7 and 1, respectively.

**Table 6.** Maximum solubility of NPX dissolved in pH media 1 and 7 at 37 ◦C.


#### 3.5.3. Surface Morphology

Figure 16 groups the micrographs of NPX powder, virgin pHEMA, NPX/pHEMA2, and NPX/pHEMA10 film samples before and after the release process in media pH 1 and 7 chosen among the most significant images. The NPX image shows crystal particles aggregated into defined geometric shapes resembling piles of rubble from houses destroyed by an earthquake. These aggregates, which are sized between 3 μm × 3 μm × 2 μm and 50 μm × 25 μm × 6 μm, show smooth and homogeneous morphology surfaces, while the micrograph of the virgin pHEMA film presents roughness on the surface, which is probably due to the film preparation. NPX/pHEMA systems containing 2 wt% and 10 wt% NPX contents before the release process show comparable morphology surfaces, in which the observed obliquely aligned parallel grooves mark the surface of the mold where they were prepared. These same samples observed after the NPX release process in pH 1 and 7 media exhibit surface morphologies very marked by the very hollow relief and cavities, thus revealing the large amount of NPX released and also show a significant degree of swelling of the film notably in pH medium 1. Regarding the NPX/pHPMA drug carrier system, as shown in Figure 17, the images are practically comparable to those of the system involving pHEMA as carrier are observed. Indeed, the surfaces of the samples before the drug release process as for the blank carrier show the same type of grooves, except that with 10 wt% NPX, in which they are less marked. This reveals that the surfaces of the

two carriers involved in the drug carrier system behave substantially the same during the drug release and show no particular mark distinguishing one or the other polymer.

**Figure 16.** SEM images of NPX powder and surface morphology of virgin pHEMA, NPX/pHEMA2, and NPX/pHEMA10 film samples before and after the NPX release process in media pH 1 and 7.

**Figure 17.** SEM images of NPX powder and surface morphology of virgin pHPMA, NPX/pHPMA2, and NPX/pHPMA10 films samples before and after the NPX release process in media pH 1 and 7.

3.5.4. Diffusion Behavior of NPX

The diffusion behavior of NPX from NPX/pHEMA and NPX/pHPMA drug carrier systems was investigated. According to Lin et al. [52], for a percentage less than 60 wt% of a substance released from the initial amount incorporated into a material, the diffusion of this substance in its liquid state through this material follows a Fickian model, as long as, in this investigation, the limit of the percentage of NPX released is far from being reached

whatever the drug carrier system and the composition. Fick model is therefore applicable to describe the diffusion behavior of NPX from the polymer matrix [53]. The equation resulting from the Fickian model is given by Equation (12) [54–56]

$$\frac{m\_{\rm f}}{m\_{\rm o}} = k\sqrt{t},\tag{12}$$

where *mt*/*mo* is the fraction of drug released, *t* is the release time, and *k* is a constant characteristic of each sample.

If the drug released from the drug carrier system obeyed the Fick diffusion model, the graph showing the change in the fraction of drug released *mt*/*mo* versus the square root of time would give a straight line with a slope *k*. Under these conditions, the value of the diffusion coefficient (*D*) will then be deduced from Equation (13) [57]:

$$k = \sqrt[\prime]{\frac{D}{\pi \times l^2}}\tag{13}$$

where *l* is thickness of film, from which the drug is released. The *k* and *D* values were calculated from the data of Figures 18 and 19 using Equations. (11) and (12) and the results obtained are gathered in Table 7.



As it can be seen from these data, all the *R<sup>2</sup>* values are close to unity. This indicates that the data correspond well to the linear regression of these curve profiles. These results also indicate that the NPX release behavior from both NPX/pHEMA and NPX/pHPMA systems follows a Fickian model with an order of 0.5. The higher the value of k, the higher the diffusion coefficient and, therefore, the faster the rate of the drug diffusion through the carrier. In general, the *k* and *D* values increased with the pH medium regardless of the drug carrier system used. This can be explained by the solubility of NPX, which becomes more soluble in media of higher pH. Knowing that the pKa of Naproxen is equal to 4.19 [58], the solubility of this drug increases with increasing pH of the medium due to the passage of the carboxylic acid group towards the carboxylate salt group that is more soluble in water, notably when the pH medium becomes equal to or greater than the pKa. In addition, it can also be seen in Figures 18 and 19, as the amount of NPX increases, the D value decreases. This can be explained by two main factors that can intervene simultaneously in the management of the drug release process: (i) the increase in the viscosity of the medium, which reduces the rate of diffusion and (ii) the presence of an NPX excess not

soluble in the polymer matrix, which hinders the passage of soluble molecules during the diffusion process.

**Figure 18.** Diffusion behavior of NPX through (A) NPX/pHEMA2, (B) NPX/pHEMA5 (C) NPX/ pHEMA7, (D) NPX/pHEMA10drug carrier system with different NPX contents in different pH media.

**Figure 19.** Diffusion behavior of NPX through (A) NPX/pHPMA2, (B) NPX/pHPMA5 (C) NPX/ pHPMA7, (D) NPX/pHPMA10drug carrier system with different NPX contents in different pH media.

#### 3.5.5. Effect of the Initial NPX Amount

The influence of the initial NPX amount loaded in pHEMA and pHPMA carriers on the dynamic release of this medication from the corresponding drug-carrier systems was studied at a selected period of 72 h of the release process. The results obtained for NPX/pHEMA and NPX/pHPMA systems are plotted for comparison in Figure 20. As can be observed from these curve profiles, the two drug carrier systems have practically the same trends, in which the release dynamic decreased, passing through a reflection point at 6.0 wt% of NPX common for all samples and then stabilizes or tends to stabilize when the percentage of NPX is greater than 7.0 wt%.

**Figure 20.** Cumulative NPX released from (A) NPX/pHEMA and (B) NPX/pHPMA drug carri-er systems at 72 h of the release process.

A more rapid decrease in the release dynamic is also observed on these profiles in neutral pH medium when the initial NPX loaded in the drug carrier systems was less than 5 wt%. The decrease in the NPX released observed in all pH media, when the drug content in the polymer matrix increased, is mainly due to the limited solubility of this drug inside the drug carrier system and to the increase of the viscosity of the solution inside the polymer matrix. Indeed, dissolving loads greater than 5 wt% seems to be difficult, especially in acidic pH media.

#### 3.5.6. Effect of pH Medium

The impact of the pH of the medium on the release dynamic of NPX from NPX/pHEMA and NPX/pHPMA systems was carried out at 72 h of the release process, and the results obtained are plotted in Figure 21. These curve profiles reveal comparable dynamics of the NPX released by the two drug-carrier systems regardless of the time period. Pseudostability of the release dynamics is observed for all samples in very acidic media (pH 1 and 3), then a slight increase or decrease depending on the initial NPX amount incorporated in the polymer matrix is observed at higher pH (5 and 7), except that containing the lowest NPX load (2 wt%), in which the release dynamic rapidly increased. The pseudoreproducibility of the behavior of the drug release dynamics at different periods for these two systems shows that the transfer of NPX from the polymer material is mainly handled by a stable, purely mechanical process. The increase in the release dynamic with the pH of the medium is mainly due to the increase of the solubility of Naproxen in neutral pH media inside the polymer matrix. Indeed, as previously revealed from the results of Table 6, the solubility of NPX increased dramatically when the media pH increased. These results were also observed by Kumar et al. [59] and attribute the low solubility of Naproxen in lower pH media to its unionization. These same authors add that the unionization of the drug can facilitate its permeability through the polymer material, but drug solubility is the limiting factor.

**Figure 21.** Variation of the NPX released from NPX/pHEMA and NPX/pHPMA drug carrier systems versus the pH of medium taken at 72 h of the release process.

### 3.5.7. Performance of XPN/pHEMA and NPX/pHPMA Drug Carrier Systems

As it was noted in Section 3.5.1, for both the drug carrier systems, it was revealed that the release behavior of NPX versus time followed two main stages regardless of the composition and the pH of the medium. Each stage is characterized by a zone, in which the release dynamic of NPX passes by pseudo stability. The rate of NPX released during the corresponding period was taken from the slope of the pseudo linear curve, and the data obtained are illustrated for NPX/pHEMA and NPX/pHPMA systems in Tables 8 and 9, respectively, noting that the cumulative percentage of the drug released during each period was calculated by multiplying the rate by time. Knowing that, for a system to be effective in the field of drug delivery, it must be able to uniformly deliver an appropriate amount of this drug in the intestines (neutral pH) and in the stomach (pH = 1–3). On this basis, the performance of these two systems on the NPX release was founded, and the results obtained are summarized for NPX/pHEMA in Table 8 and for NPX/pHPMA in Table 9. These data reveal that the two systems containing 2% by weight NPX appear to be the most effective of all the others because NPX/pHEMA2 drug-carriers were able to release 28.68 wt% of NPX uniformly during 65 h of the release process into a neutral medium with a release rate of 0.441 wt%·h−1. In contrast, only 21.32 wt% was released uniformly (0.328 wt%·h−1) during this same period into the acidic medium (pH = 1). On the other hand, during the same period, the drug carrier system involving the pHPMA2 was able to release uniformly 6.83 wt% of NPX in neutral pH with a rate of 0.102 wt%·h−1; at the same time, only 4.62 wt% was released in medium with pH = 1 with a constant rate of 0.069 wt·h<sup>−</sup>1. In general, the comparison of the performances of these two systems reveals that involving the pHEMA appears to be the most efficient.


**Table 8.** Percentage of NPX released and instantaneous release rate of NPX from NPX/pHEMA system with different compositions.

SZ: stability zone; RNR: rate of the NPX release; CNR: cumulative NPX released; LR: linear regression.

As it can be seen from the results of Table 9, the NPX/pHPMA2 drug carrier system appeared to be the best performing system in terms of the percentage of NPX released into the medium at neutral pH over the longest period. Indeed, this system was capable to release uniformly the greatest percentage of NPX (28.67% by weight) in the medium at neutral pH (intestines) with a release rate of 0.44 wt%·h−<sup>1</sup> for 67 h of the release process. During this time, only 21.32 wt% of this drug was released into the medium at pH = 1 (similar to that of in the stomach), with a constant rate of 0.33 wt%·h−1. Concerning the system involving the pHPMA as a carrier, as in the case of that of the NPX/pHEMA system, the most efficient is that initially containing 2 wt% of NPX (NPX/pHPMA2). Indeed, 6.83 wt% NPX was released uniformly (0.102 wt%·h−1) from this system in the neutral pH medium and 4.62 wt% slowly (0.069 wt%·h−1) in acidic medium (pH1) during the same period. Thus, regardless of the polymer used as a carrier in this work, the most efficient system is the one that contains the least NPX load. Finally, the addition of a methylene group on the substituent of the hydroxyl ethyl methacryloyl unit of pHEMA had the effect of reducing by more than four times the percentage of NPX released, as well as its release rate in the various media invested. This can be attributed to the reduction in the hydrophilicity of the polymer upon switching from pHEMA to pHPMA.

**Table 9.** Percentage of NPX released and instantaneous release rate of NPX from NPX/pHPMA system with different compositions.


SZ: stability zone; RNR: rate of the NPX release; CNR: cumulative NPX released; LR: linear regression.

#### 3.5.8. Distribution of NPX Released on Target Organs

According to Belzer et al. [60], the mean total gastrointestinal transit time (GITT) is between 53 and 88 h divided into three main stages: (i) gastric transit (pH 1.5–3, 5), which lasts between one and 4 h; (ii) intestinal transit (pH 7–9), which varies between 4 and 12 h; (iii) transit in the colon (pH 5–7), which lasts between 48 and 72 h. Taking into account the pH of the medium and the GITT, it was possible to estimate approximately from the data in Tables 8 and 9 the distribution of the percentages of cumulative NPX released in different organs and the mean stomach/digestive organ ratio (SDOR) (Equation (14)), independently of the effects of enzymes and microorganisms.

$$SDOR\left(wt\%\right) = \frac{r\_{\rm s}}{r\_{\rm si} + r\_{\rm c}} \times 100\tag{14}$$

where *rs*, *rsi*, and *rc* are the percentages of NPX released in the stomach, small intestine, and colon, respectively, during a certain transit time.

The results obtained are gathered for comparison in Table 10. These data reveal that both the drug carrier systems containing 2 wt% of NPX are the most efficient because the NPX/pHEMA2 drug carrier systems are able to reduce the NPX amount released in the stomach to 3.18 wt% of the total amount released for the fast GITTs and 14.85 wt% for the slow GITTs, and 4.41 wt% and 14.83 wt% for the NPX/pHPMA2 system.


**Table 10.** Estimated distribution of the cumulative NPX released from NPX/pHEMA and NPX/ pHPMA drug carrier systems on the principal digestive organs timed, according to Belzer approach.

#### **4. Conclusions**

To conclude this work, we can say that the objectives of this work have been achieved. Indeed, the comparison between the physicochemical properties of pHPMA with those of pHEMA revealed properties slightly inferior to those of pHEMA necessary for the admission of pHPMA as a carrier in the drug delivery domain. The miscibility of NPX with pHEMA and pHPMA binary systems, in which the NPX is distributed uniformly in its molecule state, are proven in all compositions by the FTIR method through the presence of hydrogen bonds between their components. This miscibility was also confirmed by the DSC method through the shift toward the low temperatures of the *Tg* of the polymer, the disappearance of the melting temperature of NPX in the mixture, and by XRD through the disappearance of the signals characterizing the crystalline structure of NPX.

The cell adhesion essay and cytotoxicity test of pure polymers and drug carrier systems revealed that the NPX/PHPMA system, as well as the NPX/pHEMA system with compositions, generally exhibit good adhesion compared to the negative and positive controls used in this study. In addition, these two systems, as well as their pure polymers, induce low cytotoxicity compared to the negative and positive controls.

The swelling study of pHEMA and pHPMA carriers revealed that the presence of additional methylene group in the substituent of the HPMA unit of pHPMA caused the swelling capacity to drop to half that of pHEMA. The determination of the Flory–Huggins interaction parameters of the NPX/pHEMA and NPX/pHPMA binary systems reveals greater interactions between the components of NPX/pHEMA system at compositions equal to or less than 5 wt% NPX; on the other hand, they are greater for NPX/pHPMA at compositions greater than 5 wt% NPX.

The "in vitro" study of the release dynamic of Naproxen from NPX/pHEMA and NPX/pHPMA drug carrier systems revealed that the higher percentage of NPX released was obtained from each polymer carrier in neutral pH medium, and the diffusion of water and NPX solution trough these polymer matrices also obeys the Fickian model with a kinetics order close to 0.5, regardless of the pH of the medium. It was also found that the less the mass percent of NPX in the composites, the better its release will be. The comparison between the two drug carrier systems revealed that the pHEMA leads to the best performance in the release dynamic of NPX.

Regarding the Naproxen solubility in water, the results deducted from the "in vitro" study of NPX/pHEMA10 and NPX/pHPMA10 drug carrier systems reveal a very significant improvement in the solubility of NPX in media pH1 (2.33 times, 1.43 times) and 7 (3.32 times, 2.60 times), respectively, compared to those obtained by direct dissolution of Naproxen powder.

According to Belzer, the approximate estimation of the distribution of the percentages of cumulative NPX released in different organs and the mean stomach/digestive organ ratio, independently of the effects of enzymes and microorganisms, revealed that both drug carrier systems containing 2 wt% of NPX are the most efficient because the NPX/pHEMA2 drug carrier systems are able to reduce the NPX amount released in the stomach to 3.18 wt% of the total amount released for the fast GITTs, 14.85 wt% for the slow GITTs, and 4.41 wt% and 14.83 wt% for the NPX/pHPMA2 system. Although pHEMA seems to be the more performing carrier of the two polymers when administered orally (requiring a relatively large amount of drug absorbed at neutral pH), pHPMA combined with a small amount of medication (2 wt%) can also be used if the purpose is the application on the skin surface or as contact lenses to treat certain diseases of the surface of eyes caused by viruses, bacteria, parasites, and fungi because the eyes absorb only a tiny amount of the drug dissolved in a neutral medium. In this case, a regular release of small amounts of drug for as long as possible is desirable in order to limit the frequency of administration of the drug by this route, providing more comfort to the patient.

**Author Contributions:** Data curation, A.A., S.M.S.A. and A.S.; Formal analysis, A.A., T.S.A.-G., A.S. and T.A.; Funding acquisition, S.M.S.A. and W.S.S.; Investigation, T.A.; Methodology, A.A., S.M.S.A., T.S.A.-G. and T.A.; Project administration, S.M.S.A. and T.A.; Resources, S.M.S.A.; Software, A.A., S.M.S.A., T.S.A.-G. and W.S.S.; Supervision, S.M.S.A.; Visualization, T.S.A.-G., W.S.S. and A.S.; Writing—original draft, A.A., S.M.S.A. and T.A.; Writing—review & editing, T.A. All authors have read and agreed to the published version of the manuscript

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding author.

**Acknowledgments:** Authors extend their appreciation to Researchers Supporting Project (RSP2022R475) King Saud University, Riyadh, Saudi Arabia.

**Conflicts of Interest:** The authors declare no conflict of interest.
