1. Introduction
Controlled-release drug delivery systems (CDDSs) have significantly transformed the pharmaceutical field. These systems are designed to administer medication in a regulated way over a prolonged period, effectively minimizing the need for frequent dosing [
1]. This can improve patient adherence to the medication and overall treatment outcomes [
2]. Various additional benefits can be obtained from developing CDDSs, as shown in
Figure 1. Various types of medication require the utilization of CDDSs: for instance, drugs with a short half-life, such as furosemide [
3], oxcarbazepine [
4], and metoprolol [
5], as well as medications with a narrow therapeutic window like theophylline monohydrate (THN) [
6,
7], lithium [
8], and phenytoin [
9]. However, the development of new CDDSs faces a range of challenges that must be addressed.
New controlled-release (CR) compounds require sufficient stability within the gastrointestinal tract (GIT) while releasing the drug molecules at predetermined intervals. Several medications have been recalled from the market for not meeting dissolution specifications, such as metformin CR tablets [
10], Adderall CR tablets [
11], indapamide CR tablets [
12], and metoprolol succinate CR tablets [
11,
13]. The frequent recalls of CR medications and the importance of CDDSs in the pharmaceutical industry highlight the ongoing potential for advancements in CDDS development [
4,
14,
15,
16]. Thus, the primary objective of this research was to develop new CDDSs suitable for Biopharmaceutical Classification System (BCS) Class I medications, utilizing a minimal number of excipients and a convenient preparation method.
The model drug for this study was THN. THN was selected due to the reported challenges in maintaining controlled drug release functionality in some THN CR formulations [
17,
18]. Additionally, delivering THN in a CR system is preferred due to its rapid absorption, narrow therapeutic window (10 to 20 mg/mL), and short half-life (7 to 9 h) [
6,
7]. THN is mainly used for chronic obstructive pulmonary disease (COPD) and asthma [
6,
19]. Additionally, recent research has shown some potential new pharmacological benefits of THN, for instance, in managing COVID-19 [
20] and post-tubercular lung illnesses [
21], and as an effective alternative to permanent pacemaker implantation [
22].
The matrix system stands out among the different developed CDDSs due to its simplicity in manufacturing, cost-effectiveness, and predictable drug release kinetics among other different features, as demonstrated in
Figure 1 [
3]. In a matrix system, the active pharmaceutical ingredient (API) is uniformly dispersed within a polymeric matrix, effectively controlling the drug release rate [
23]. There is a wide range of excipients used in the production of a matrix system. The selection of the matrix polymer depends on the desired release profile, method of preparation, and API characteristics, as well as on the various properties of the excipients [
24,
25,
26,
27].
In this study, three excipients were selected to develop a new controlled-release matrix system (CRMS). These chosen excipients were poloxamer-407 (P-407), hydroxypropyl methylcellulose (HPMC), and stearyl alcohol (STA). These excipients were chosen based on their physicochemical properties and their effectiveness in retarding drug release according to different research studies [
28,
29,
30,
31]. For instance, an in situ gel delivery system combining P-407 and methylcellulose prolonged drug release compared to administering the drug freely [
32]. Another study developed an intragastric floating tablet using HPMC and polylactic acid (PLA) that controlled drug release for 24 h [
2]. Similarly, STA and HPMC in a CRMS extended the release of sarpogrelate HCL for 24 h [
25].
P-407 is extensively utilized in the creation of drug delivery systems (DDSs) due to its various properties. It is known to be non-toxic [
33,
34], exhibits excellent compatibility [
28,
33], and has a high capacity to solubilize various medications [
33,
34]. The ability of P-407 to control drug release is attributed to the amphiphilic nature of poloxamers. This contributes to the formation of a gel around the formulation, which retards the rapid release of the drug molecules [
1,
31,
35,
36].
HPMC has a wide range of applications, for instance, as a thickener, emulsifier, and stabilizer [
37,
38], owing to its compatibility, excellent safety profile, and stability [
29]. Moreover, the utilization of HPMC to control drug release is attributed to its capacity to form a gel upon contact with water, establishing a dynamic barrier that controls the drug release rate, as has been reported in the literature [
31,
39].
STA has diverse applications that are attributed to its unique characteristics, including its emollient properties, viscosity enhancement, pH stability, and non-toxicity [
30,
40]. Additionally, STA in a CR formulation has the ability to form a hydrophobic domain that hinders drug diffusion and extends release duration [
40].
The current study aimed to develop and evaluate a novel matrix-based controlled-release system tailored for THN, a BCS Class 1 drug. Utilizing the fusion method, the system incorporates P-407, STA, and HPMC, and is encapsulated in a size 00 capsule.
In this study, several formulations with varying polymer ratios and types were prepared. These were assessed using an in vitro dissolution apparatus in media with different incubated pH levels (1.2, 4.5, and 7.5) to simulate varying gastrointestinal environments. Additionally, drug release kinetics were determined to elucidate the drug’s release mechanism from the matrix system. The selected formulation was comprehensively characterized through X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier transform infrared (FTIR) analysis, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). Stability studies were also conducted, involving the exposure of the formulations to various temperatures and humidity levels over a period of 72 h. Additionally, their stability under constant conditions was assessed over a storage period of three months.
3. Results
3.1. Calibration Curve and Drug Content
The calibration curve depicted in
Figure 2 exhibits a high level of precision, as evidenced by its correlation coefficient (r
2) of 0.9991. The high correlation coefficient (r
2) of 0.9991, as shown in
Figure 2, indicates the reliability of this calibration curve for the accurate determination of drug concentration in unknown samples. The drug content in CRMS-F15 was quantified as 300 ± 1.8 mg. This measurement aligns with the established criteria of the USP for drug content assays, confirming that the CRMS-F15 formulation adheres to these rigorous standards. This adherence to USP standards underscores the potential suitability of this formulation for further pharmaceutical applications [
59].
3.2. In Vitro Drug Release
This section presents the drug release profiles of the developed formulations and compares them to the THN drug without any added excipients. This comparison was designed to evaluate the effectiveness of the excipients in modulating drug release. Additionally, the release profile of the THN branded drug was assessed for its comparability with our developed formulations. The formulation demonstrating a release profile similar to that of the THN branded drug was then selected for further in vitro assessments across different pH environments (pH 1.2, 4.5, and 7.5).
3.2.1. In Vitro Drug Release: First-Series Analysis
In
Figure 3, the drug release profile of the branded THN drug, labelled as the THN reference, demonstrates a CR for up to 12 h. A significant variation in the drug release rate was observed among the first series of formulations (
p < 0.05).
The release rate decreased in the following order: THN branded drug > F4 > F3 > F2 > F1, which corresponds to the respective amounts of incorporated P-407: 70%, 60%, 50%, and 40%. An increase of 10% in the P-407 content resulted in at least a 1 h delay in drug release, indicating a clear correlation between the amount of P-407 and the decrease in release rate. Notably, formulation F4, containing 70% P-407, exhibited the most-extended controlled drug release within the first series, lasting up to 7 h. These findings underscore the significant role of P-407 in extending the drug release profile.
3.2.2. In Vitro Drug Release: Second-Series Analysis
To assess the effect of STA, HPMC, and their combination on drug release, the formulations in the second, third, and fourth series contained a constant amount of P-407. In the second series, an increase in the incorporated amount of STA led to a delay in the drug release, as shown in
Figure 4.
The longest periods of controlled drug release were observed in the following order: F8 > F7 > F6 > F5, with STA incorporated amounts of 3%, 9%, 17%, and 25%, respectively. F8, containing 45% P-407 and 25% STA, demonstrated the longest period of controlled drug release, up to 6 h.
3.2.3. In Vitro Drug Release: Third-Series Analysis
The substitution of STA with HPMC in the third series of formulations, as shown in
Figure 5, effectively extended the drug release duration. An increase in HPMC concentration was directly associated with a longer delay in drug release. Notably, formulation F12 exhibited the most prolonged drug release control, lasting up to approximately 7 h. This was followed by formulations F11, F10, and F9, in that order. While the first three series demonstrated a significant impact of P-407, STA, and HPMC in prolonging drug release, the maximum duration they achieved was 7 h.
3.2.4. In Vitro Drug Release: Fourth-Series Analysis
Figure 6 presents the release profiles of THN from the matrix systems in Series 4, demonstrating the predominant influence of STA content on THN release from P-407/STA/HPMC matrix systems. An inverse relationship is observed: as the STA proportion increases, the percentage of THN release correspondingly decreases. For instance, the drug release level after 9 h varied across different compositions: it was 100% in the 20/20 HPMC/STA composition (F13), but was reduced to 93% in the 15/25 HPMC/STA composition (F14), 83% in the 10/30 HPMC/STA composition (F15), and 80% in the 5/35 HPMC/STA composition (F16). Notably, the release profile of F15 did not significantly differ (
p > 0.05) from the reference THN product, maintaining THN release for up to 12 h.
Furthermore, the results indicate a high degree of similarity between the test (F15) and reference dissolution profiles, as evidenced by an f2 similarity factor of 80, which is within the acceptable range of 50–100. This suggests that the test (F15) and reference profiles are closely matched. Additionally, the f1 dissimilarity factor of 3, which falls within the desirable range of 0–15, further confirms the minimal dissimilarity between these two profiles. Together, these factors demonstrate a strong alignment between the test formulation and the reference.
Consequently, CRMS-F15 was selected as the candidate formulation for further analysis and characterization.
3.2.5. In Vitro Drug Release in Media of Different pH Levels (pH 1.2, 4.5, 7.5)
Figure 7 shows that the CRMS-F15 drug release profile did not significantly differ (
p > 0.05) from the reference product in simulated physiological pH media at pH 1.2, 4.5, and 7.5. The matrix system was effective in controlling drug release for over 12 h.
Figure 8 further illustrates the pH-dependent drug release from both CRMS-F15 and the reference product after 11 h. The highest drug release rate was observed at the water pH level, followed by pH 1.2, then pH 7.5, and it was lowest at pH 4.5, with only minor variations noted. The drug release rate from CRMS-F15 at 11 h was 97% in DW and 81%, 63%, and 68% at pH 1.2, pH 4.5, and pH 7.5, respectively.
3.3. Kinetic Release Model Evaluation
The statistical analysis comparing the release kinetic model results of CRMS-F15 to those of the branded drug, as presented in
Table 5, revealed no remarkable difference (
p > 0.05). Among the evaluated models, both the zero-order and Hixson–Crowell models exhibited the highest goodness of fit, with
values of 0.9774 and 0.9976, respectively. These results suggest that these models accurately described the release behavior of our drug formulation. The Higuchi model also demonstrated a relatively high correlation, with a coefficient of 0.9702. Conversely, the first-order and Korsmeyer–Peppas models showed lower
values, indicating their limited suitability for describing the release kinetics of this formulation.
3.4. X-ray Diffraction
Figure 9 depicts the diffraction patterns for THN, P-407, STA, HPMC, and CRMS-F15. The diffractogram of THN featured several sharp peaks, with the most prominent at around 12° (2θ), and other less intense peaks at 2θ angles of 14.2, 24, and 25.3. This finding aligns with previous research demonstrating similar XRD patterns for THN (
Figure 9A) [
60].
P-407 exhibited sharp peaks indicative of a semi-crystalline structure, with the most intense peaks approximately at 19° and 23° (2θ) in addition to wider peaks 26.5° and 36° (2θ) (
Figure 9B) [
61,
62]. The XRD pattern of STA showed an exceptionally intense peak at about 21.5° (2θ), with a less intense peak at 24.1° (2θ); these sharp peaks indicate a high degree of crystallinity in STA (
Figure 9C) [
63]. In contrast, HPMC presented an amorphous halo, lacking discernible crystalline peaks, except for a broad characteristic peak across the 15–25° (2θ) range, which is typical for many polysaccharides (
Figure 9D) [
64,
65]. The XRD peak patterns of CRMS-F15, as illustrated in
Figure 9E, showed peak positions similar to those of the drug molecule and the excipients used. However, a notable reduction in peak intensity was observed, particularly for the peaks associated with the drug molecule.
3.5. Scanning Electron Microscopy
SEM images, as shown in
Figure 10, provided detailed morphological insights into the various studied materials, including THN, P-407, STA, HPMC, CRMS-F15, and the branded drug. The SEM micrograph of THN particularly highlights a distinctly crystalline structure (
Figure 10A). Most particles appear rod-like in shape, with uniform surfaces and sharp edges, indicative of significant crystallinity. The dimensions of these crystalline structures vary, with some particles measuring over 10 µm in length while maintaining a width of less than 10 µm [
66].
Contrastingly, SEM imagery showed the P-407 particles to be spherical with predominantly smooth surfaces, although some exhibit minor surface irregularities and are interspersed with smaller spheres (
Figure 10B) [
61]. The HPMC samples, however, significantly differed, displaying an assortment of irregular, non-crystalline structures. These are characterized by a coarse, heterogeneous surface texture, indicating an agglomerated state (
Figure 10C). The SEM images of STA reveal a compact, stratified arrangement, primarily flake-like in morphology. The surfaces of these laminar flakes are noticeably rough, with many visible edges and facets. Their sizes vary, with some extending several micrometers in length (
Figure 10D).
The SEM examination of CRMS-F15, as shown in
Figure 10E, reveals a composite microstructure. This arrangement is characterized by a uniform mixture of constituents, suggesting an integrated composite. The matrix of this formulation displays a slightly uneven texture, which is similar to that of the branded drug, depicted in
Figure 10F.
3.6. Fourier Transform Infrared
The spectral profiles generated via FTIR for the THN powder, P-407, STA, HPMC, and CRMS-F15 are illustrated in
Figure 11. The primary functional groups of THN, associated with various vibrational modes, exhibited clear signals at 1313 cm
−1, 1663 cm
−1, and 1564 cm
−1, representing the stretching of C-O, amide C=O, and aromatic C=C bonds, respectively. These findings were consistent with those of a prior study [
67].
The IR spectra of P-407 exhibited distinctive peaks, including a prominent absorption at 2875 cm
−1 corresponding to aliphatic C–H stretching vibrations. Furthermore, these spectra featured a well-defined peak at 1342.46 cm
−1, attributed to O–H bending, and a sharp absorption at 1099 cm
−1, indicating C–O stretching [
68].
The STA spectra displayed moderate-intensity peaks at 2846 and 2961 cm
−1, which are indicative of aliphatic –CH stretching vibrations. The absorption peak at 3321 cm
−1 corresponds to –OH stretching vibrations, while peaks at 1462 cm
−1 and 1060 cm
−1 represent –CH
2 and C–O stretching, respectively. An additional peak associated with C–O stretching was observed at 729 cm
−1 [
69].
Regarding HPMC, the absorption peak at 3466 cm−1 is attributed to the stretching frequency of the -OH group. Additional stretching vibration bands associated with C-H and C-O were detected at 2897 cm−1 and 1049 cm−1, respectively.
The main peaks of THN remained evident in the IR spectra of CRMS-F15, exhibiting only negligible shifts in wavenumber. For instance, peaks at 1342 cm−1 (C-O stretch), 1664 cm−1 (C=O stretching amide), and 1562 cm−1 (C=C stretching aromatic) were consistent in both spectra.
3.7. Differential Scanning Calorimetry
Figure 12 presents the thermal profiles from DSC analyses of the pure THN, P-407, STA, and HPMC. The DSC thermogram of THN shows two prominent endothermic peaks. The first peak initiated at an onset temperature (
Tonset) of 269.89 °C, peaked at 272.39 °C, and exhibited a heat absorption of 153.43 J/g. The second peak began at a
Tonset of 324.85 °C, reached a peak temperature of 335.89 °C, and had an enthalpy of 74.849 J/g. For P-407, DSC analysis revealed a significant endothermic peak. This thermal event began at a
Tonset of 55.02 °C, peaked at 58.63 °C, and showed an enthalpy flow of 227.78 J/g.
The DSC thermogram for STA displays a prominent endothermic peak, beginning at a Tonset of 57.71 °C with an enthalpy of 435.56 J/g, and peaking at 60.84 °C. In contrast, no characteristic peak was observed for HPMC.
In the DSC analysis of the CRMS-F15, three distinct endothermic peaks were observed, as shown in
Figure 13. The initial peak had an enthalpy of 180.20 J/g and a peak temperature of 60.31 °C. This was followed by a secondary peak with a peak temperature at 264.82 °C, exhibiting an enthalpy of 56.848 J/g. The tertiary peak had a peak temperature of 351.75 °C with an enthalpy of 60.464 J/g.
These peaks indicate the thermal behavior of the incorporated excipients and the drug molecule. Notably, the enthalpy values, represented by the area under the curve of each peak, showed a decrease when compared to those of the individual constituents. The peak at 60.31 °C is hypothesized to arise from the combined melting points of P-407 and STA. The peak at 264.82 °C likely represents the melting point of THN; additionally, the peak at 351.75 °C is assumed to be attributed to degradation of THN.
3.8. Thermogravimetric Analysis
The TGA results showed that THN, as well as all the materials used in developing the matrix system, underwent a single stage of thermal decomposition and exhibited relatively high decomposition temperatures, as shown in
Figure 14. For THN, the decomposition began at 285 °C, resulting in a residual weight of 84.296%. The decomposition of THN completed at 336.55 °C, leaving a final weight of 1.014%. The recorded decomposition temperatures for P-407, STA, and HPMC were 363 °C, 190.01 °C, and 325 °C, respectively. In contrast, the thermal decomposition of CRMS-F15 occurred in two stages: the first stage at 204 °C with a remaining weight of 94.07%, followed by the second stage at 363 °C, with a remaining weight of 44.27%.
The temperatures required to induce a 50% weight loss in the samples, ranked from highest to lowest, were as follows: P-407 at 390.97 °C, HPMC at 360.38 °C, CRMS-F15 at 346.91 °C, THN at 314.93 °C, and STA at 238.27 °C.
3.9. Stability Assessment
Figure 15 demonstrates the release profile of CRMS-F15 during a 72 h storage period under varying temperatures (8 °C, 20 °C, 40 °C) with consistent humidity (60%). These results indicate that there were no significant differences in the drug release profiles of CRMS-F15 when stored under different temperatures (
p > 0.05). A slight increase in drug release was observed for the formulation stored at the highest temperature of 40 °C; however, this increase remained within permissible limits.
Figure 15 also illustrates the drug release profile of CRMS-F15 stored under different humidity conditions (0%, 25%, 60%) under a constant temperature, compared to the release profile of a fresh CRMS-F15 sample. There was no significant difference in drug release before 72 h across these various storage conditions (
p < 0.05).
Regarding drug content, no significant differences were observed when stored under varying temperature or humidity conditions (
p > 0.05), as shown in
Table 6. The minor variations in drug content following these storage conditions remained within the permissible limits [
59].
Figure 16 illustrates the in vitro release of CRMS-F15 when stored at 20 °C and 25% relative humidity, with assessments conducted after storage durations of 1, 2, and 3 months. The release profiles showed minimal variation across the different storage periods when evaluated at specified time points over a 12 h duration. Similarly, the drug content over the full three-month period was within the range of 294 to 302 ± 3.5.