Graft Copolymers of Carboxymethyl Cellulose and Poly(N-vinylimidazole) as Promising Carriers for Metronidazole

Abstract

Carboxymethyl cellulose sodium salt is a common water-soluble derivative of cellulose. It serves as a bioinert mucoadhesive material extensively used in biomedicine, particularly for crafting targeted drug delivery systems. In our study, we demonstrate that graft copolymers of sodium carboxymethyl-cellulose with poly(N-vinylimidazole) can function as carriers for the antibacterial drug metronidazole. Non-covalent associations form between the components, excluding the involvement of the nitro groups of the drug in the interaction. These loaded copolymers exhibit the capability to release the drug under conditions mimicking the stomach environment for up to 48 h. This renders the obtained associations promising candidates for the development of a metronidazole-targeted delivery system.

1. Introduction

Carboxymethyl cellulose sodium salt (Na-CMC) is a commonly used polyanionic derivative of cellulose, and is composed of anhydroglucose repeating links bounded by β-1,4-glycosidic bonds. It retains valuable properties such as biocompatibility, non-immunogenicity, bioresorption, affordability, and abundance. Na-CMC is easier to process for further modification, forming strong gels or solutions, and it finds diverse applications compared to native cellulose due to the presence of anionic carboxymethyl groups in its structure that replace hydrogen atoms on hydroxyl groups of the original cellulose [1]. Its solubility depends on the degree of substitution and the pH of the medium [2,3]. Leveraging these properties, Na-CMC is extensively utilized in the food industry and biomedical field.

As a component of biomedical systems, such as drug delivery systems or wound dressings, it is crucial for Na-CMC to interact effectively with various components, like drugs, vitamins, etc. Therefore, further modification of Na-CMC should enhance its interactions with bioactive substances. A promising approach to incorporating new functionalities into Na-CMC macromolecules is grafting side polymeric chains with high complexing ability, such as poly(N-vinylimidazole) (PVI). PVI is a synthetic, biocompatible [4], water-soluble, and thermally stable [5] polymer with a pK_a around 6.0. It is a pH-sensitive functional polymer that can be deprotonated in basic conditions and protonated in acidic media [6]. Poly(N-vinylimidazole) and its copolymers have been utilized in heavy metal chelation and removal [7,8], as catalysts [9,10,11], for CO₂ separation [12], for nanofiltration [13], and to inhibit gene expression as drug and protein delivery vehicles [14,15,16]. Building on this, incorporating Na-CMC and PVI into one macromolecule enables the production of biocompatible, water-soluble products that serve as promising carriers for drug delivery.

We previously demonstrated that graft copolymers of Na-CMC and poly(N-vinylimidazole), Na-CMC-g-PVI, form complexes with the anti-tumor drug Paclitaxel which are capable of releasing it in the pH range of 5.5–7.4 for 144 h. Furthermore, the loading efficiency of the Na-CMC-g-PVI copolymers is up to 70% higher compared to the original Na-CMC [17], emphasizing the efficacy of grafting modification. In other studies [18,19], the Na-CMC-g-PVI copolymer has shown promise as an enzyme support for cysteine proteases, namely, bromelain, ficin, and papain. Complexation with the copolymer enhances enzyme performance by increasing their proteolytic activity by up to 2.5 times and storage stability by up to 12 times. These findings affirm the interaction efficiency of the Na-CMC-g-PVI copolymer with various biologically active substances with complex structures, highlighting its potential as a drug carrier.

Metronidazole (MTZ), also known as 2-methyl-5-nitroimidazolyl-1-ethanol, is an imidazole nitro-derivative used as an antibiotic and antiprotozoal drug. It is commonly prescribed for the treatment of gastrointestinal tract infections, reproductive system infections, skin conditions, etc. [20]. The effectiveness of metronidazole relies on high concentrations, attributed to its hydrophilic structure and limited ability to penetrate hydrophobic cell membranes [21]. However, the administration of high MTZ concentrations can lead to toxic effects on the body and significant side effects, reducing patients’ quality of life. One approach to mitigating these issues is forming complex structures of the drug, enabling prolonged release and maintenance of therapeutic concentrations. Various vehicles have been proposed for transporting metronidazole, including: a polycaprolactone (PCL)-based therapeutic deep eutectic system for intravaginal MTZ administration [22]; PCL and polylactide nanofibers [23,24]; silver nanoparticles [25] for treating periodontal disease; guar gum-based tablets [26]; microcapsules based on mesoporous functionalized calcium carbonate coated with ethyl cellulose or chitosan [27] for colonic MTZ release; sodium alginate/Carbopol 934P microcapsules for release at the gastric mucosa [28]; innovative ZIF-90 nanoparticles for improved pediatric sepsis management [29]; and chitosan/graphene oxide bionanocomposite capsules [30] capable of releasing MTZ over a broad pH range. However, due to the diverse methods of metronidazole administration and the varying characteristics of administration media, particularly the wide range of pH values, developing new vehicles that offer stable and prolonged MTZ release remains promising. In Russia, metronidazole is primarily used for treating gastritis. Therefore, this research focuses on developing carriers capable of releasing MTZ under stomach conditions.

Given the structure and application areas of metronidazole, mucoadhesive compounds containing azole rings, which can be molded into various pharmaceutical forms, appear to be promising candidates for its carrier. Therefore, the aim of this study is to investigate the interaction features of Na-CMC-g-PVI copolymers with metronidazole and the release of MTZ from the loaded copolymers.

2. Materials and Methods

2.1. Materials

Carboxymethyl cellulose sodium salt with a molecular weight of 90 kDa and DS of 0.7, provided by Sigma, Saint Louis, MO, USA, was used in the copolymer synthesis. Na-CMC was dried to a constant weight at 60 °C before modification. N-vinylimidazole (VI; ≥99%), with a boiling point of 78–79 °C/11 mmHg and n²⁰_D = 1.5338, was purchased by Sigma, Saint Louis, MO, USA, and purified by vacuum distillation immediately before synthesis. Potassium persulfate and sodium metabisulfite (both Vekton, Saint-Petersburg, Russia) served as the initiator mixture and were recrystallized from distilled water. Metronidazole, an analytical standard provided by Sigma, Saint Louis, MO, USA, was used without any purification.

2.2. Synthesis and Characterization of the Na-CMC-g-PVI Copolymers

For copolymer synthesis, the following molar Na-CMC/VI ratios were chosen: 1/3, 1/5, and 1/10. The synthesis of Na-CMC-g-PVI copolymers was conducted in an aqueous solution with material initiation, following procedures described elsewhere [18,19].

Copolymer composition evaluation and characterization of the grafted PVI chains were carried out through copolymer oxidation destruction in a 0.1 M NaNO₂/HCl water solution for 24 h at 25 ± 2 °C. Following incubation, the resulting solution was poured into acetone and centrifuged, and the precipitate was dried to a constant weight in a vacuum oven.

The PVI weight content in the copolymer, denoted as PVI, %, was calculated as follows:

$$PVI, \%=\frac{m_1}{m_2}\times 100$$

(1)

where m₁ and m₂ are the masses of isolated PVI chains and the copolymer used in destruction, g, respectively.

The molecular weights of grafted PVI chains were evaluated by GPC with the use of an Agilent 1200 Series instrument (Agilent Technologies, Santa Clara, CA, USA) equipped with an isocratic pump, a refractometric detector, and a PLmixC column (Agilent Technologies, Santa Clara, CA, USA), as described in [19]. Based on the values of copolymer content and molecular weight of the grafted PVI chains, the frequency of grafting, FG, was calculated by the following equation [31]:

$$FG=\frac{PVI, \%}{M_{PVI}}\times \frac{M_{AGU}}{Na-CMC, \%},$$

(2)

where PVI, % is the percentage of grafted PVI in Na-CMC-g-PVI; M_PVI is the molecular weight of PVI; M_AGU is the average weight of anhydrous glucose unit of Na-CMC; and Na-CMC, % is the percent of Na-CMC in Na-CMC-g-PVI. Characteristics of the Na-CMC-g-PVI copolymers are shown in

Table 1. Characteristics of the Na-CMC-g-PVI copolymers *.

Polymer	n(Na-CMC)/n(VI), mol/mol	Mn of PVI	PVI, %	FG × 102	LE, %	EE, μg × mg−1
Na-CMC	-	-	-	-	31 ± 2	310 ± 9
Na-CMC-g-PVI-1	1/10	15,690	86	6.05	57 ± 3	570 ± 13
Na-CMC-g-PVI-2	1/5	7690	64	4.12	69 ± 3	690 ± 14
Na-CMC-g-PVI-3	1/3	6190	41	2.08	42 ± 2	490 ± 11

*M_n is the number-average molecular weight; n(Na-CMC)/n(VI) is the component molar ratio used in synthesis of the copolymers; PVI, % is the PVI content in copolymer; FG is the frequency of grafting; LE is the loading efficiency; EE is the encapsulation efficiency.

.

2.3. FTIR-ATR Spectroscopy

FTIR spectroscopy was utilized to confirm the formation of the copolymer. Dry powder samples were placed on the surface of the attenuated total reflectance (ATR) attachment Platinum 1000 (Bruker Corporation, Billerica, MA, USA), which features a single reflection diamond working element, and maintained at 25 °C. The FTIR spectra of the samples were recorded using a Bruker Vertex 70 spectrometer (Bruker Corporation, Billerica, MA, USA) with a resolution of 4.0 cm⁻¹ within the frequency range of 800–4000 cm⁻¹.

2.4. TGA/DSC

The TGA/DSC research was performed using the simultaneous thermal analyzer STA 449F3 Jupiter (Netzsch, Selb, Bayern, Germany). The samples were placed in aluminum crucibles and studied in a nitrogen atmosphere in the temperature range of 28–600 °C with a heating rate of 10 °C/min. Indium was used as the calibration standard.

2.5. XRD

XRD patterns were obtained with an Empyrean B.V. diffractometer (Malvern Panalytical B.V. Ltd., Malvern, UK), equipped with a Cu-Kα radiation source (λ = 1.54 nm, 45 kV, and 35 mA), in the scattering angle range of 2θ from 5° to 50°, with a resolution of 0.1° and a scanning speed of 0.2°/min.

2.6. Metronidazole Loading and Encapsulation Efficiency

For a typical loading experiment, 100 mg of the powder Na-CMC-g-PVI copolymer sifted through a sieve with a mesh size of 50 μm was dissolved in 10 mL of distilled water (pH = 5.5 ± 0.1), mixed with 10 mL of MTZ solution with a concentration of 10 mg/mL, and stirred for 3 h at 25 ± 2 °C. Subsequently, the solution was poured into a prewashed dialysis tube (cut off 3 kDa) and dialyzed overnight against distilled water to remove unbound MTZ. Following dialysis, the loaded Na-CMC-g-PVI copolymer was isolated via lyophilization for further experiments.

The metronidazole concentration was assessed spectrophotometrically by recording the absorption at λ_max = 319 nm (UV-Vis spectrophotometer SF-2000, LOMO-Microsystems, Saint-Petersburg, Russia), and concentration determination was performed using a calibration plot within the wide concentration range of 1–9 × 10⁻⁵ mol/L to confirm linearity (Figure 1). The amount of unbound MTZ in the wastewater was also calculated for further analysis.

The loading efficiencies (LE, %) and encapsulation efficiencies (EE, μg of drug per mg of Na-CMC-g-PVI) of metronidazole were calculated using the following equations [32]:

$$LE=\frac{c_0-c_1}{c_0}\times 100,$$

(3)

$$EE=\frac{c_1}{100\times c_{Na-CMC-g-PVI}},$$

(4)

where c₀ and c₁ are the MTZ concentrations before and after loading, mg/mL, respectively; and c_Na-CMC-g-PVI is the copolymer concentration, mg/mL.

Each experiment was performed in triplicate, and the results are presented as the average ± SD.

2.7. Release Experiments

Metronidazole-loaded Na-CMC-g-PVI copolymers, milled and sifted through a 50 μm sieve, were immersed in 0.05 M citrate buffer with pH = 2.0 ± 0.1 at T = 38 ± 2 °C to investigate drug release kinetics.

For each experiment, 125 mg of the loaded copolymer was dissolved in 10 mL of citrate buffer, stirred until fully dissolved, and transferred into a test tube divided into two sections by a cellulose membrane for measuring. The upper section contained the copolymer solution, while 50 mL of blank buffer was added to the lower section. To analyze release kinetics, 1 mL of buffer was withdrawn from the lower section for spectrophotometric determination of the MTZ concentration over 48 h. Following this, 1 mL of fresh buffer was replenished into the lower section to maintain a constant volume. The experimental results are presented as the cumulative release versus time.

Each experiment was performed in triplicate, and the results are presented as the average ± SD.

2.8. Release Modeling

To comprehend the reasons and mechanisms behind MTZ release, the experimental data were analyzed using kinetic mathematical models.

The zero-order model is described by the following equation [33]:

$$q_t=q_0+k_{0}t,$$

(5)

The first-order model is expressed as [34]:

$$\ln q_t=\ln q_0-k_{0}t,$$

(6)

The Korsmeyer–Peppas model is [35]:

$$\frac{q_t}{q_{\infty }}=k_{KP}\times t^n,$$

(7)

or in a logarithmic view:

$$\ln \frac{q_t}{q_{\infty }}=\ln k_{KP}+n\ln t,$$

(8)

where q₀, q_t, and q_∞ are the amount of the drug released at times 0 (q₀ = 0), t, and at the moment of reaching equilibrium, respectively; k₀, k₁, and k_KP are the release rate constants of the zero-order, first-order, and Korsmeyer–Peppas models, respectively; and n is a power exponent determining the type of diffusion and the drug transport mechanism. If n ≤ 0.45, the transport of the released drug occurs via Fickian diffusion. For values where 0.45 < n < 0.89, the transport of the released drug is attributed to non-Fickian diffusion. When n = 0.89, Case II transport is observed, wherein the process is governed by swelling and relaxation of the polymer matrix and remains independent of time. For values where n > 0.89, super Case II transport is observed, characterized by the transport of the released drug induced by changes in conformational states in hydrophilic glassy polymers that swell in aqueous media [26].

3. Results and Discussion

3.1. Na-CMC-g-PVI Copolymer Loading and Interactions with Metronidazole

Metronidazole is an antibacterial and antiprotozoal drug commonly used to treat diseases of organs covered with mucous membranes, such as gastritis. However, achieving therapeutic effectiveness often requires high drug dosages, leading to a plethora of side effects. Hence, this study aims to investigate the interaction between the drug and mucoadhesive Na-CMC-g-PVI copolymers, as well as its release under conditions mimicking the stomach environment.

The possibility of interaction between a drug and carrier is a crucial parameter influencing its suitability as a component for targeted drug delivery systems. Therefore, the first stage of this research involves examining the interaction features of MTZ with the Na-CMC-g-PVI copolymer using FTIR spectroscopy.

Figure 2 displays the FTIR spectra of metronidazole, Na-CMC-g-PVI copolymer, and their complex obtained in distilled water (pH = 5.5 ± 0.1). The FTIR spectrum of MTZ exhibits characteristic absorption bands at the following wavenumbers (cm⁻¹): 3209 for stretching of OH groups; 3099 for stretching of C-H of the imidazole rings; 1533 for stretching of C=N bonds; 1472 and 1367 for asymmetric stretching of N=O; 1427 for stretching of C-C bonds; and 1157–1072 for stretching of C-O ether bonds [36,37].

The FTIR spectrum of the Na-CMC-g-PVI copolymer exhibits characteristic absorption bands at the following wavenumbers (cm⁻¹): 1591, 1414, and 1321 for the stretching of dissociated carboxymethyl groups; 1053–1105 for vibrations of the pyranose rings and C-O bonds, including C-OH; 3111 and 914 for vibrations of the imidazole rings; 2924 for vibrations of C-H bonds; and 3226 for stretching of OH groups [18,19,38].

In the FTIR spectrum of the associate, the aforementioned bands are present, along with changes in the shapes and positions of some absorption maxima. Notably, vibrations of pyranose rings and C-OH bonds, as well as the maxima of bands associated with imidazole rings, dissociated carboxyl, and hydroxyl groups, are shifted or altered in shape. This suggests that the association of MTZ with the Na-CMC-g-PVI copolymer predominantly involves these groups, likely facilitated by the formation of hydrogen bonds through interlayers of water molecules. Additionally, we cannot disregard the possibility of π–π stacking between the imidazole rings of MTZ and the graft copolymer [39].

FTIR-ATR data have demonstrated that non-covalent interactions between MTZ and Na-CMC-g-PVI copolymer, leading to the formation of their associate, involve hydroxyl and carboxyl groups, as well as imidazole rings. It is noteworthy that FTIR analysis did not reveal changes in the shape or position of bands corresponding to NO₂ groups of MTZ, indicating their non-involvement in interactions with the copolymer. This observation is significant as the antibacterial effect of metronidazole is attributed to these functional groups.

Thermal studies, such as TGA and DSC, can also confirm interactions between MTZ and Na-CMC-g-PVI copolymers. Figure 3 shows the TGA and DSC profiles of metronidazole, the Na-CMC-g-PVI-2 copolymer, and their associates. As can be seen, MTZ is characterized by two weight-loss stages. The first stage occurs in the temperature range of ~230–270 °C, with the residual mass after this stage being about 25%. The next stage is characterized by smooth weight loss, with the final residual weight being 15.5%. The TGA curves of the Na-CMC-g-PVI copolymer and its associate with MTZ have similar shapes; however, the associate curve is sharper and indicates faster weight loss. The initial weight loss up to 100 °C is due to water evaporation, with the residual mass of the copolymer after water removal being 91%, while that of the associates is 83%. This indicates that the associate contains more water compared to the blank Na-CMC-g-PVI copolymer. The next weight loss stage, up to ~300 °C, is due to the decomposition of Na-CMC and MTZ [40,41]. At this stage, the residual weights are 67% and 52% for the Na-CMC-g-PVI copolymer and its associate with MTZ, respectively. Finally, at T > 300 °C, PVI decomposition occurs, and the residual weights are 37% and 33% for the Na-CMC-g-PVI copolymer and its associate with MTZ, respectively.

The DSC profile of metronidazole shows an endothermic peak at 164.2 °C, corresponding to its melting point, and an exothermic peak at 270.1 °C due to its decomposition. These results are in good agreement with data published earlier [42]. In the DSC profile of the associate, these peaks shift to lower temperatures, indicating the partial destruction of the MTZ crystalline structure. Additionally, the glass transition temperature (T_g) value of PVI chains is 144 °C for the Na-CMC-g-PVI copolymer, which is close to the previously published result [43]. For the Na-CMC-g-PVI and MTZ associates, this value shifts to 125.1 °C. This shift is due to the higher water content of the associate compared to the blank copolymer. Water acts as a plasticizer for hydrophilic PVI chains and can decrease the T_g values.

The results of the XRD research also confirm association. According to the data obtained (Figure 4b), the Na-CMC-g-PVI copolymer and its associate have low degrees of crystallinity, as the patterns contain a halo region and some reflexes. Figure 4a shows the metronidazole XRD pattern, demonstrating signals at 12.5, 13.9, 24.8, 25.5, 27.4, and 28.0°, which correlate with previously published data [30]. These peaks are observed in the XRD pattern of the associate with the Na-CMC-g-PVI copolymer, confirming interaction with the copolymer. Additionally, the intensity of the MTZ signals in the associate’s XRD pattern is lower compared to that of the original drug. This is due to the lower amount of the drug in the associate with respect to the pure MTZ.

To quantitatively assess the resulting complexes, we evaluated the loading efficiency (LE) and encapsulation efficiency (EE). The results of these parameter determinations are presented in Table 1.

The presented data indicate that the loading and encapsulation efficiency of all resulting polymers surpass those of the original Na-CMC, underscoring the substantial contribution of the graft PVI chains to the formation of the complexes. Among the graft copolymers, the highest values of the studied parameters are attained for the Na-CMC-g-PVI-2 copolymer. However, there is no direct correlation between the azole content in the copolymers and the loading efficiency. The molecular weights of the grafted PVI chains and their distribution along the main polyglycoside chain also significantly influence the interaction process. The most effectively interacting polymer appears to be the Na-CMC-g-PVI-2 copolymer, characterized by a relatively high distribution of grafted chains (4 chains per 100 glycosidic rings) and a low molecular weight. This suggests the formation of a brush-like structure, facilitating steric accessibility of the copolymer’s active centers for interaction with metronidazole molecules.

The most promising candidate for the development of prolonged oral-administered metronidazole formulations is Na-CMC-g-PVI-2, which demonstrates an effective drug encapsulation of 690 ± 14 μg of MTZ per 1 mg of carrier.

Thus, it is demonstrated that Na-CMC-g-PVI copolymers interact with metronidazole more effectively than the original Na-CMC. The metronidazole loading efficiency of Na-CMC-g-PVI copolymers depends not only on the content of PVI links, but also on their molecular weight, accessibility, and distribution along the polyglycosidic chain. The resulting graft copolymers are capable of accommodating the daily dose of metronidazole required for gastritis treatment (~1.5 g).

3.2. Investigating Metronidazole Release

The primary advantage of targeted drug delivery systems is the controlled, prolonged release of the drug over time. Consequently, the toxicity of the drug is minimized by avoiding a burst release, which could temporarily elevate concentrations to toxic levels. This aspect is particularly relevant for metronidazole, given its high effectiveness but significant side effects that impact patients’ quality of life during therapy.

The in vitro release experiments were conducted in a 0.05 M citrate buffer with pH = 2.0 ± 0.1 at T = 38 ± 2 °C to investigate the kinetics of metronidazole release. The selection of experimental conditions aimed to simulate the environment within the stomach.

In Figure 5, the release profiles of metronidazole from complexes with Na-CMC-g-PVI copolymers or Na-CMC are presented. As is evident from the data, all copolymers release almost the entire metronidazole content within 48 h, which is the average duration of changes in the gastric mucosa. This confirms the suitability of Na-CMC-g-PVI copolymers as polymer carriers for MTZ-based drug systems for the treatment of gastritis.

In all the studied copolymer complexes, two distinct stages of release could be observed in the kinetic curves. The first stage involved a rapid or burst release occurring within the initial 10–12 h, followed by a slower release rate after 12 h of incubation. The most pronounced release process was observed when the Na-CMC-g-PVI-1 copolymer was utilized, while the Na-CMC-g-PVI-3 copolymer exhibited the slowest release rate.

It is noteworthy that attempts to conduct a similar experiment with a complex of metronidazole and original Na-CMC were unsuccessful, as the complex is insoluble at pH = 2.0 ± 0.1. Instead, a process of complete explosive release of the entire loaded drug was observed within 2 h. This outcome renders the use of Na-CMC inappropriate.

To gain a deeper understanding of the reasons and mechanisms underlying the release of metronidazole from the loaded copolymers, the experimental data were analyzed using kinetic mathematical models. A review of the literature data revealed that the most appropriate models for describing the behavior of similar systems are the zero-order, first-order, and Korsmeyer–Peppas models [35,44]. Figure 6 presents the results obtained by processing the experimental data using these models.

Table 2. Kinetic models’ parameters of metronidazole release.

No	Copolymer	Zero-Order Model		First-Order Model		Korsmeyer–Peppas Model
		R2	k0, Hour−1	R2	k1, Hour−1	R2	kKP, Hour−1	n
Total release
1	Na-CMC-g-PVI-1	0.43	1.4 ± 0.4	0.31	3.8 ± 0.2	0.76	0.2 ± 0.02	0.5 ± 0.1
2	Na-CMC-g-PVI-2	0.56	1.8 ± 0.4	0.38	3.4 ± 0.2	0.83	0.1 ± 0.01	0.7 ± 0.1
3	Na-CMC-g-PVI-3	0.65	1.8 ± 0.3	0.38	3.0 ± 0.3	0.83	0.06 ± 0.01	0.9 ± 0.1
Fast release
4	Na-CMC-g-PVI-1	0.95	8.0 ± 0.6	0.78	0.2 ± 0.03	0.98	0.1 ± 0.01	0.9 ± 0.1
5	Na-CMC-g-PVI-2	0.99	7.7 ± 0.1	0.83	0.2 ± 0.03	0.99	0.06 ± 0.003	1.1 ± 0.04
6	Na-CMC-g-PVI-3	0.97	6.9 ± 0.2	0.79	0.3 ± 0.04	0.98	0.03 ± 0.001	1.4 ± 0.07
Slow release
7	Na-CMC-g-PVI-1	0.72	0.1 ± 0.03	0.71	(9 ± 3) × 10−4	0.76	0.9 ± 0.004	0.03 ± 0.01
8	Na-CMC-g-PVI-2	0.78	0.1 ± 0.02	0.78	(6 ± 2) × 10−4	0.84	0.9 ± 0.003	0.03 ± 0.004
9	Na-CMC-g-PVI-3	0.95	0.4 ± 0.04	0.94	(5 ± 0.6) × 10−3	0.98	0.6 ± 0.002	0.1 ± 0.001

displays the values of the determination coefficient R², the rate constants, and the n parameter.

Based on the results of experimental data processing and the value of R², it is evident that the most appropriate model describing the total results is the Korsmeyer–Peppas model. The release mechanism may be attributed to a plasticization process on the surface of the copolymer particles, wherein the polymer chains must relax to facilitate molecular diffusion of the drug. The parameter n (lines 1–3 in Table 2) falls within the range of 0.45 < n < 0.89, indicating non-Fickian diffusion of the released MTZ. However, it should be noted that during the fast release stage, the zero-order model shows a good correlation (Figure S1), indicating a constant linear release of MTZ. In the slow release stage, the Korsmeyer–Peppas model is also found to be the most suitable.

For a more detailed understanding of the transport and release mechanism, the Korsmeyer–Peppas model was separately applied to the fast and slow release stages (Figure 6d, Table 2, lines 4–9). The data obtained indicate that this model reliably describes the fast stage (R² > 0.976), with the parameter n corresponding to the case n > 0.89. This suggests a special instance of non-Fickian diffusion transport, known as supercase II, attributed to conformational changes in macromolecular coils of hydrophilic polymers, including their plasticization upon contact with water [45]. Additionally, this suggestion is supported by DSC research showing that the T_g value for PVI chains decreases with an increase in the water content. For the slow stage, the determination coefficient values when processing experimental data using the Korsmeyer–Peppas model are somewhat lower (0.759 < R² < 0.982), and the values of the exponent n correspond to the case n ≤ 0.45. This indicates a transition to Fickian diffusion as the mechanism of transport for released metronidazole.

Thus, it has been demonstrated that all synthesized Na-CMC-g-PVI copolymers are suitable for use as carriers of metronidazole and are capable of releasing the drug within 48 h, which aligns with the maximum time frame for changes in gastric mucosa. The study of the release mechanism reveals a two-stage process, involving fast and slow stages. Release occurs due to conformational changes and the plasticization of polymer chains, with the transport mechanism of metronidazole differing between these two stages. The fast stage is characterized by non-Fickian diffusion, whereas the slow stage is characterized by Fickian diffusion.

4. Conclusions

The study of the interaction between metronidazole and Na-CMC-g-PVI copolymers using FTIR identified the functional groups involved in this process. The formation of the complex is attributed to the interaction between the hydroxyl and carboxyl groups of the copolymers, as well as the interaction between the azole rings of both the copolymers and metronidazole. Notably, the nitro groups of MTZ remain uninvolved in the process, preserving the drug’s antibacterial activity. The encapsulation and loading efficiency of the copolymers depend on the distribution of grafted PVI chains and their molecular weights. The highest parameters were achieved for copolymers with relatively high grafting frequency and low molecular weight. The loaded copolymers exhibited drug release under conditions similar to the stomach environment for 48 h, aligning with the duration of changes in gastric mucosa. It was observed that MTZ release was facilitated by the plasticization of the copolymers upon contact with water, occurring in two stages. The first stage involved fast release, with MTZ transport facilitated by non-Fickian diffusion, while the slow release stage was accompanied by Fickian diffusion. Furthermore, the resulting copolymers retained a sufficient amount of metronidazole, making them suitable for the formulation of tablet and suspension forms for oral administration.