Preparation of Nimodipine Amorphous Solid Dispersion with Various Processes Based on Physicochemical Properties and In Vivo Exposure

2. Materials and Methods

2.1. Materials

Nimodipine (MW 418.8 g/mol) was purchased from Lusochimica S.p.A (Lomagna, LC, Italy). HPC (LS–11 grade, MW 140,000 g/mol), HPMCAS (M grade, MW 18,000 g/mol), and HPMCP (HP–50 grade, MW 78,000 g/mol) were provided by Shin–Etsu Chemical Co., Ltd. (Tokyo, Japan). PVP (K25 grade, MW 28,000 to 35,000 g/mol) was supplied from BASF (Ludwigshafen, Germany). Formic acid and lovastatin were purchased from Sigma–Aldrich (St. Louis, MO, USA). HPLC–grade water and methanol (MeOH), alongside acetone and dichloromethane were purchased from J.T. Baker® (Phillipsburg, NJ, USA). All other reagents were of analytical grade and used as received.

2.2. Drug–Polymer Miscibility

The drug–polymer miscibility is well understood in polymer science where each polymer component is amorphous in a stable state. The major complexity around the miscibility of ASD is that the amorphous drug is usually meta-stable and tends to recrystallize. Therefore, the composition of a system in equilibrium with regard to recrystallization would be the solubility of the crystalline drug in the polymer [15]. The miscibility in the ASD is associated with a meta-stable equilibrium and requires the drug to stay in super-cooled liquid state without recrystallization within the experimental time frame. It is measured mainly using thermal analysis (DSC for T_g), microscopy (AFM and SEM), and spectroscopy (NMR, FTIR, and Raman) to assess phase behavior and interactions in solid dispersions. Typical methods would Hansen solubility parameter, Gordon–Taylor equation, Flory−Huggins interaction parameters ($\chi )$ and melting point depression [16].

Hansen solubility parameter predictions were utilized to estimate drug–polymer (D/P) miscibility using the van Krevelen and Hoftyzer group contribution method [17]. Hansen solubility parameters (δ) utilized the group contribution method in drug–polymer systems based on different chemical fragments and their contribution to molecular forces and molar volume. Three primary Hansen parameters were calculated for each molecule: (i) dispersion forces (${\delta }_d)$, (ii) dipolar intermolecular forces (${\delta }_p)$, and hydrogen bonding energy (${\delta }_h).$ The total Hansen solubility parameter (${\delta }_t)$ was calculated by combining these parameters, as shown in equation (1).

$${{\delta }_t}^2={{\delta }_d}^2+{{\delta }_p}^2+{{\delta }_h}^2$$

(1)

These forces were determined using equation (2), where $F_{\mathit{di}}$ represents the dispersion forces, $F_{\mathit{pi}}$ denotes the polar forces, $F_{\mathit{hi}}$ is the hydrogen bond energy, and $V$ represents the group contribution to molar volume.

$${\delta }_{d }={\displaystyle \frac{\sum F_{\mathit{di}}}{V}}; {\delta }_p={\displaystyle \frac{\sqrt{\sum {F_{\mathit{pi}}}^2}}{V}};{ \delta }_h=\sqrt{{\displaystyle \frac{\sum F_{\mathit{hi}}}{V}}}$$

(2)

Gordon–Taylor equation (3) predicted the miscibility of drug in polymers theoretically based on the shift in the melting endotherm, T_g values, and weight fractions of the individual components. In this equation, $T_{g1}$ is the glass transition temperature of the drug, $w_1$ and $w_2$ are the weight fractions of the component (drug and polymer), and $K$is a constant calculated using the Simha–Boyer rule based on the true densities of the drug $\left({\rho }_1\right)$ and polymer$\left({\rho }_2\right)$ [18]. The true densities of the components were determined using a helium gas displacement pycnometer (Accupyc 1330, Micromeritics, Norcross, GA, USA).

$$T_{g \mathit{mix}}={\displaystyle \frac{w_1·T_{g1}+K·w_2·T_{g2}}{w_1+K·{ w}_2}}; K\approx {\displaystyle \frac{T_{g1}· {\rho }_1}{T_{g2}{· \rho }_2}}$$

(3)

Flory–Huggins interaction parameter ($\chi )$ was used to evaluate drug–polymer miscibility and solubility based on thermodynamic principles. The parameters ($\chi )$ for drug–polymer systems were determined from the difference between the solubility parameters of the drugs and polymers, calculated using equation (3). In contrast, $T_{m, mix}$ represents the melting temperature of the solid dispersion, $T_{m, drug}$ is the melting temperature of the drug, $\Delta H_f$ denotes the heat of fusion of the drug, $m$ is the volume ratio of polymer to drug, and ${\varphi }_{\mathit{drug}}$ and ${\varphi }_{\mathit{polymer}}$ are the volume fractions of the drug and polymer [19].

$$\left({\displaystyle \frac{1}{T_m \mathit{mix}}}-{\displaystyle \frac{1}{T_{m }\mathit{drug}}}\right)=-{\displaystyle \frac{R}{∆H_f}}\left\{\mathit{In}{ \varphi }_{\mathit{drug} }+\left(1-{\displaystyle \frac{1}{m}}\right)·{\varphi }_{\mathit{polymer}}+\chi {\varphi }_{\mathit{polymer}}^2\right\}$$

(4)

2.3. Sample Preparation

Samples including physical mixtures were prepared using trituration, spray–drying, and melt–quenching methods. The physical mixtures of drug–polymer was prepared using a mortar and pestle. The components were manually triturated for 5 min, and the final blend was passed through a sieve (Sieve No. 40). Drug-to-polymer ratios were of 1:1, 1:2, 1:3, and 1:4, and the resulting samples were stored in airtight Eppendorf tubes until further analysis [20,21].

Another method was spray–drying with a Mini Spray Dryer (Buchi Corp., Newcastle, DE, USA). NIM (0.25 g) and each polymer (0.75 g) were dissolved in a 1:1 (v/v) mixture of acetone and dichloromethane at a solid content of 10%. The spray-drying was conducted under nitrogen gas at a flow rate of 700 L/h, with an aspirator setting of 35 m³/h and a feed rate of 3 mL/min [22]. The other method was melt–quenching. Each polymer (0.75 g) was melted at approximately 180 °C on a hotplate stirrer (MSH–20A; Daihan Scientific Co. Ltd., Wonju, Korea), and NIM (0.25 g) was added to the molten polymer. Following thorough mixing, the hot liquid dispersion was immediately transferred to a refrigerator (DF8510; IlShin BioBase Co. Ltd., Dongducheon, Korea) at a temperature of –30 °C for 2 h and then vacuum–dried at room temperature overnight (Isotemp® 280A, Fisher Scientific, MO, USA) to remove residual solvent [23]. The particle size of the solid dispersion was reduced using a ball mill (Pulverisette 23, Fritsch GmbH., Idar–Oberstein, Germany) to achieve samples with size range of 180−250 µm.

The optimized drug-to-polymer ratio (1:3) was chosen for the preparation of solid dispersions, as no detectable recrystallization was observed during analysis of the individual drug–polymer systems. This ratio was determined using DSC, where the mixtures at different ratios were heated to 200 °C at a scan rate of 10 °C/min. The absence of sharp melting endothermic events suggested that ratios at or below 1:3 did not exhibit detectable crystallization.

2.4. Thermodynamic Properties

The drug and ASDs were analyzed using a differential scanning calorimetry, DSC Q2000 (TA Instrument, New Castle, DE, USA). Approximately 2 mg of sample was placed in a Tzero aluminum pan crimped with a pierced lid and scanned over a temperature range of 20−200 °C at a heating rate of 10 °C/min, while purged with nitrogen gas at 50 mL/min. An empty Tzero aluminum pan with a pierced lid was used as the reference. The instrument was calibrated using indium as a standard [24,25]. Thermodynamic parameters, including T_o (onset temperature), T_g (glass transition temperature), T_m (melting temperature), and T_e (endset temperature), were determined using TA Universal Analysis 2000 software (Version 4.5A, TA Instruments, New Castle, DE, USA).

2.5. Spectroscopic Measurement

The possible drug–polymer interactions were investigated using a Fourier–transform infrared (FTIR) spectrometer (Nicolet iS5, Thermo–Fisher Scientific, Waltham, MA, USA) [26]. The samples were crushed before analysis, and a small quantity of each sample was placed at the center of the diamond ATR crystal. A stainless–steel pressure bar was positioned over the sample and tightened with a screw to ensure optimal contact with the powder. The IR spectra of all ASDs were recorded with an average of 64 scans over a spectral range of 4000–500 cm⁻¹ with a resolution of 4 cm⁻¹. The most suitable polymers were identified based on the presence, shift, or disappearance of characteristic peaks in the ASDs [27].

2.6. Water Content with Thermogravimetric Analysis

The percentage moisture content of each sample was determined using a thermogravimetric analyzer (TGA; Pyris TGA N–1000, Scinco, Korea). Approximately 5 mg of the sample was accurately weighed and placed into an aluminum pan, which was heated from 20−200 °C at a constant rate of 10 °C/min. The weight loss during the heating process was recorded and analyzed to quantify the moisture content in the sample [28].

2.7. Crystalline Properties

The crystalline properties of ASDs were analyzed using an X–ray diffractometer (Ultima IV, Rigaku Corp., Tokyo, Japan) with a scintillation counter detector and Cu–Kα radiation (λ = 1.5409 Å) operated at 40 kV and 30 mA. Approximately 1 mg of each sample was placed on a zero-background (0–BG) sample holder. Data were obtained at a scanning speed of 3°/min over an angular range 5 to 45° (2θ) with a step size of 0.02° [29]. Crystallinity was calculated by dividing the area of the crystalline peak by the total area of the powder X–ray diffractometry (PXRD) spectrum using OriginPro 9.0 (OriginLab Corporation, Northampton, MA, USA) [30,31].

2.8. Scanning Electron Microscope (SEM)

The surface morphology of NIM and its corresponding solid dispersions was examined using a field emission scanning electron microscope (Clara LMH, Tescan, Brno, Czech Republic) operated at 15 kV and equipped with an Everhart–Thornley (ETH) detector. Each sample was mounted on an aluminum stub using double–sided adhesive carbon tape. Prior to imaging, samples were sputter–coated with a thin layer of gold for approximately 40 s under vacuum in an argon atmosphere to enhance the conductivity and image resolution [32].

2.9. Solubility

The saturation solubility was evaluated across a pH range of 3.0−6.8. Subsequently, 2 mL of each pH solution was transferred into an individual vial, and an excess amount of drug (approximately 5 mg) was gradually added and vortexed until no further dissolution occurred. All vials were shaken for 48 h at 75 rpm and 37 °C using a multi–mixer (SLRM–N1.5, Seongnam, Gyeonggi, Korea) and subsequently left undisturbed for 6 h to reach equilibrium. The suspensions were centrifuged at 13,000 rpm for 30 min (Centrifuge 5420, Eppendorf AG, Hamburg, Germany) to separate undissolved drug. The supernatant was collected, diluted with the corresponding buffer, and the drug concentration was quantified using a UV–Vis spectrophotometer at 238 nm [33].

2.10. In Vitro Dissolution

The drug release profiles or dissolution were evaluated using a USP Apparatus II dissolution tester (Varian 705, Cary, NC, USA). A reference sample containing 10 mg of NIM and a solid dispersion equivalent to 10 mg were dispersed in 700 mL of phosphate buffer (pH 5.0, 6.0, and 6.8) maintained at 37 ± 0.5 °C with a stirring speed of 75 rpm. At predetermined time intervals (5, 10, 15, 30, 45, 60, 90, and 120 min), 2 mL aliquots were withdrawn and filtered through a 0.45 μm membrane to remove undissolved particles. The absorbance of filtrate was measured at 238 nm using a UV–Vis spectrophotometer (Optizen, Seoul, Korea), and the percentage of drug release was calculated using linear regression equations derived from calibration curves prepared in the respective release media [34,35].

The in vitro release profiles of the drug and its solid dispersion were evaluated using percentage dissolution efficiency (DE) and mean dissolution time (MDT). Mathematical modeling of the release profiles was performed using DD solver software. Model parameters were determined, and the best-fit model was selected by comparing the correlation coefficient (R²), model selection criteria (MSC), and Akaike information criterion (AIC). The experiment was conducted under three pH conditions (5.0, 6.0, and 6.8) to simulate the gastrointestinal tract [31].

2.11. In Vivo Pharmacokinetics

The in vivo pharmacokinetic studies of NIM, physical mixture, and solid dispersion were conducted in male Sprague–Dawley rats housed at 23 ± 2 °C, 50 ± 5% relative humidity, under a 12 h dark/light cycle. The study protocol was approved by the Institutional Animal Care and Use Committee (IACUC) of Mokpo National University, Republic of Korea (Approval no. MNU–IACUC–2025–015). Sixteen 2–month–old rats (average weight 260.54 ± 25.00 g) were divided into four groups. The rats were fed a standard diet with free access to drinking water. All rats were fasted for 12 h before the experiment, with free access to drinking water. Group 1 received an oral gavage of control NIM (60 mg/kg body weight), whereas Group 2, Group 3 and Group 4 received an oral gavage of the respective physical mixture, NIM.CP.SM, and NIM.CP.HM (240 mg/kg body weight) using a feeding needle or tube.

Approximately 250 µL blood was collected from the oculi chorioideae vein at pre-dose and at 0.25, 0.5, 2.5, 3, 4, 8, 12, and 24 h post–administration. Blood samples were collected using polyethylene tubes, immediately transferred into the sodium heparin Eppendorf tubes and centrifuged at 10,000×g for 10 min. The resulting plasma was carefully separated and stored at −70 °C until further analysis [36,37]. Pharmacokinetic parameters included peak plasma concentration (C_max), time to peak concentration (T_max), area under the plasma concentration (AUC) vs. time curve from dosing to the last quantifiable concentration (AUC_0–24), AUC from 0 h to infinity (AUC_0–∞), and terminal half–life (t_1/2).

2.12. Statistical Analysis

Experiments were performed in triplicate and reported as mean ± standard deviation (SD). Statistical analysis was performed using Microsoft Excel (Microsoft Corporation, Malvern, PA, USA), with the DDSolver Add-In program. Mean comparisons were conducted using Student’s t-test. p-value < 0.05 was considered statistically significant.

3. Results and Discussion

3.1. Drug–Polymer Miscibility

Before designing ASD, it may require information on the miscibility of the drug within the polymeric matrix and the thermodynamic miscibility of NIM with various polymers was investigated by calculating the Hansen solubility parameter using the van Krevelen and Hoftyzer group contribution method. In this method, a drug and a polymer are considered miscible if their solubility parameter differs by less than 7 MPa^0.5, or if both compounds have similar $∆\delta$ values. In contrast, a system is immiscible if $∆\delta$ exceeds 10 MPa^0.5. The estimated solubility parameters of NIM, HPC, HPMCAS, HPMCP, and PVP K25 calculated using the Hansen group contribution theory (Table 1). NIM with HPC, HPMCAS, HPMCP, and PVP K25 showed $∆\delta$ values ranging from 0.22–3.23 MPa^0.5, below the 7 MPa^0.5 threshold, suggesting favorable miscibility.

Moreover, the drug was physically mixed with various polymer ratios, and the resulting thermograms were evaluated. The observations might suggest that the crystalline drug dissolves into the polymer at low drug loading ratios (Figure 1). The endothermic peak of the drug in all the physical mixtures broadened and shifted to lower temperatures with decreasing drug concentration. The melting point (T_m) was not observed at a D/P ratio < 1:3. Therefore, a D/P ratio of 1:3 was selected for ASD preparation. This was supported by Flory–Huggins analysis using the melting–mixing method and melting point depression (Figure 1S). The model ($\chi )$ used equation (4) to determine drug–polymer solubility parameters. This equation indicates that $\chi \ge 0.5/M$ corresponds to unfavorable drug–polymer interaction. Conversely, $\chi \le 0.5/M$ indicates stronger favorable interactions at the micro level. However, the interaction values for NIM with HPC, HPMCAS, HPMCP, and PVP K25 (Table 2) are below 0.5/M, indicating miscibility between the drug and polymers.

On the other hand, incomplete miscibility may lead to the formation of concentrated drug domains, resulting in recrystallization and phase separation. The Gordon–Taylor equation suggests that a binary mixture of drug–polymer exhibits a single T_g that ranges between the T_g of the polymer and melting point of the drug (Table 3). The calculated T_g with the equation was similar to the experimental T_g values.

3.2. Thermodynamic Evaluation

DSC was used to determine the physical properties of NIM and to investigate potential drug–polymer interactions in ASDs prepared by spray–drying and melt–quenching. Figure 1 shows the DSC thermograms of NIM and its solid dispersions with HPC, HPMCAS, HPMCP, and PVP, prepared using the spray–drying method. NIM exhibited a sharp endothermic peak at 124.92 °C, confirming its crystalline property [37]. Figure 1a shows the thermograms of NIM.HP.SM, NIM.AS.SM, NIM.CP.SM, and NIM.PK.SM, suggesting that the drug was solubilized in the polymer and converted to the amorphous state. Figure 1b illustrates the NIM thermogram and its solid dispersion prepared using the melt–quenching method. The thermograms of NIM.HP.HM, NIM.AS.HM, and NIM.CP.HM showed no melting peaks, indicating that the drug was miscible with the polymers. However, NIM.PK.HM thermogram exhibited peak broadening due to the highly hygroscopic nature of PVP K25, where the drug gets trapped into its polymer matrix (amorphous state) without melting and remain thermodynamically stable at a lower humidity [38]. The thermogram revealed a single T_g for each solid dispersion, located below the T_m of NIM and T_g of polymers, suggesting that spray– drying produced homogeneous and uniform solid dispersion [39]. Additionally, the DSC thermogram showed no notable change in peaks or thermodynamic events (Table 4).

3.3. Spectroscopic Evaluation

The potential drug–polymer interactions within ASD were investigated using FTIR spectroscopy. The IR spectra were properly labeled (Figure 2a,b). The IR spectra of crystalline NIM showed an N–H stretching vibration at 3293 cm⁻¹, confirming the presence of hydrogen bonding associated with the pyridine ring and carboxylic acid groups. Conversely, the N–H stretching vibration was absent in the spectra of NIM.AS.SM, NIM.CP.SM, NIM.PK.SM, NIM.AS.HM, NIM.CP.HM, and NIM.PK.HM solid dispersions. This suggests that the N–H bonds are involved in inter-molecular hydrogen bonding with the polymer matrix. The aromatic and aliphatic C–H stretching vibration at 2981 cm⁻¹ was attributed to NIM. The IR spectra of the solid dispersion (NIM.HP.SM, NIM.CP.SM, NIM.PK.SM, NIM.AS.HM, NIM.HP.HM, NIM.CP.HM, and NIM.PK.HM) showed broader peaks shifted to lower wavenumbers. The slight shift in specific vibrational bands across the solid dispersions confirms crystalline lattice disruption and molecular dispersion induced by the polymer. The carbonyl C=O stretching band of NIM appeared at 1691 cm⁻¹. The FTIR spectra of NIM.HP.SM, NIM.AS.SM, NIM.CP.SM, NIM.AS.HM, NIM.HP.HM, NIM.CP.HM, and solid dispersion showed a shift to higher wavenumbers, whereas NIM.PK.SM, NIM.PK.HM exhibited a more intense peak. The C=C bending vibration of the aromatic ring and nitro groups was observed in the 1550–1710 cm⁻¹. Other functional groups, including CH₃ bending, nitro groups and substituents, showed vibration in the 1344–1118 cm⁻¹ (Table 5).

In the FTIR spectra of solid dispersion, these vibration bands appeared at similar region but with narrower and lower intensity [40]. The drug–polymer interactions and molecular mobility in the dispersion system slightly shifted specific intensities compared to the NIM spectrum. A few FTIR spectra showed peak shifting due to crystalline structure disruption and electrostatic effects of the polymer. Additionally, no significant changes were observed in the spectra of the solid dispersion compared to NIM.

3.4. Effect of Water Content on Stability

Water content can affect T_g of ASD as it can play a role similar to plasticizers, increase molecular mobility, promote recrystallization, and cause phase separation [38]. The moisture may affect hydrogen bonds and hence drug-polymer interactions. The presence of moisture in solid dispersions was confirmed by TGA, which may significantly influence the recrystallization of the amorphous form. Figure 3a and Figure 3b shows the TGA profiles of ASDs prepared by spray–drying and melt–quenching, respectively. NIM exhibited a major weight loss of ~0.98% at ~175 °C, attributed to thermal decomposition. The TGA curve of NIM.HP.SM showed two events: 73 °C (4.86%) from surface-absorbed water loss, and 83 °C (0.48%) from thermal degradation. TGA curve for NIM.AS.SM showed three events: 70 °C (2.02%) for oxidation, 100 °C (0.34%) for heat-induced decomposition, and 180 °C (0.06%) indicating complete degradation. TGA curve for NIM.CP.SM revealed two events: 95 °C (2.01%) and 135 °C (0.35%) suggesting moisture and residual solvent loss [41]. TGA curve for NIM.PK.SM revealed two events: 100 °C (10%) from surface moisture, and 180 °C (1.63%) from thermal degradation. TGA curve for NIM.HP.HM revealed mass loss at 80 °C (1.66%) from surface moisture. TGA curve for NIM.AS.HM showed a mass loss at ~ 170 °C (0.19%) from oxidation and decomposition. TGA curve for NIM.CP.HM showed a mass loss at 180 °C (2.84%) from moisture and residual solvent. TGA curve for NIM.PK.HM showed a mass loss at 80 °C (6.14%) from surface moisture. Overall, spray-drying and melt-quenching were effective for ASDs preparation. Polymer selection significantly influenced thermal stability. ASD containing PVP K25 and HPC showed higher mass loss, indicating lower stability compared to HPMCAS and HPMCP. PVP K25 showed the highest moisture-related mass loss due to its hygroscopic nature. In contrast, HPMAS and HPMCP provided superior moisture protection due to their hydrophobicity and formation of moisture-resistant surface layers [22].

3.5. Evaluation of crystallinity

The PXRD Spectrum of NIM exhibits multiple sharp diffraction peaks at specific 2θ angle suggesting its crystalline nature and lattice arrangement. Figure 4a,b shows the PXRD patterns of NIM and its solid dispersions prepared by spray–drying and melt–quenching. NIM exhibited characteristic peaks at 2θ angles (6.38, 12.78, 15.3, 17.32, 19.64, 20.24, 20.58, 22.12, 23.48, 24.88, 26.20, 27.12, 28.78, 30.24, 30.68, 32.08, 33.06, 36.3, 37.27, 38.62, 39.68, 41.52, and 43.36), confirming its highly crystalline nature [42]. The diffraction pattern of ASDs showed diffuse halo peaks and no characteristic NIM peaks, confirming conversion to the amorphous state within the polymer matrix. However, NIM.HP.SM and NIM.HP.HM diffractogram showed distinctive peaks compared to other solid dispersions, likely due to the hygroscopicity of HPC inducing recrystallization [39]. Similarly, solid dispersion of NIM with HPMCAS and HPMCP was confirmed as amorphous, consistent with DSC results. Crystallinity was calculated as the ratio of the individual peak area of the entire curve [43]. All prepared ASDs exhibited crystallinity below 30%, confirming their amorphous nature. Spray-dried ASDs of NIM with HPMCAS and HMPCP showed crystallinity below 15%, suggesting superior molecular-level dispersion of the drug within the polymer [44].

3.6. Scanning Electron Microscope (SEM)

The surface morphology of ASDs was examined by SEM. Figure 5a–5i show ASD prepared by spray-drying and melt-quenching methods. NIM showed large crystalline agglomerates with defined shapes and sizes. SEM images confirmed the disappearance of the original crystalline drug particles and the formation of a homogenous amorphous system. Both methods effectively transformed the crystalline drug into an amorphous form, with slight differences in shape due to polymer properties. SEM images of Figure 5d (NIM.CP.SM) and Figure 5h (NIM.CP.HM) show comparatively smaller particles, which facilitate drug dissolution in the release medium. Spray–drying produced smaller HPMCP solid dispersions, supporting polymer selection to maintain the amorphous and bio-available form.

3.7. Solubility

NIM saturation solubility and its solid dispersions were determined across pH 3.0–6.8 to evaluate drug release under physiological conditions. The standard calibration curve (2.5–12.50 µg/mL) showed excellent linearity (R² ≈ 0.9995), with a limit of quantification of 0.296 µg/mL and a limit of detection of 0.0976 µg/mL. Figure 6 shows the pH-dependent solubility of NIM and its solid dispersions, with a marked increase at phosphate buffer pH 6.0. At lower pH (3.0–5.0), the drug showed limited solubility, indicating poor release under acidic conditions. In contrast, solubility increased significantly at pH 6.0, suggesting that this pH provides favorable conditions for drug release. The improved solubility at pH 6.0 was observed in solid dispersion, attributed to HPMCP, a pH-dependent polymer insoluble in acidic environment. In other words, HPMCP protects the drug in acidic environments and facilitates its release at weak basic conditions. These findings suggest that NIM solid dispersion with HPMCP effectively improves solubility at pH 6.0, potentially supporting controlled drug release and improved bioavailability.

3.8. In Vitro Dissolution

The in vitro dissolution testing was performed for pure NIM as a reference and solid dispersions across different pH (pH 5.0, 6.0, and 6.8). Figure 7 shows the in vitro release profiles of the solid dispersion prepared by the spray–drying method. At phosphate buffer pH 5.0, 6.0, and 6.8, the NIM.CP.SM formulation exhibited high drug release of 53.07%, 89.50%, and 56.27%, respectively, after 120 min, consistent with the performance of the HPMCP-based system. The drug release rate was the highest for the HPMCP-based solid dispersions, followed by HPMCAS, PVP K25, and HPC (HPMCP > HPMCAS > PVP K25 > HPC). Figure 8 illustrates the in vitro release profiles of the solid dispersion prepared using the melt-quenching method. This method did not result in the release of the desired drug amount from the solid dispersion. The NIM.CP.HM formulation exhibited high drug release of 63.39%, 66.24%, and 65.80% with the HPMCP polymer in respective phosphate buffer at pH 5.0, 6.0, and 6.8, after 120 min. This release profile indicated that spray–drying method produced a more consistent solid dispersion with HPMCP than the melt-quenching method. Overall, the NIM.CP.SM showed the drug release at pH 6.0, as HPMCP limits drug release under acidic conditions and enhances solubility near neutral pH (6.8).

In addition, bulk density data revealed that ASD prepared by spray–drying (0.23, 0.14, 0.13 and 0.16 g/mL with HP, AS, CP and PK, respectively) had lower bulk density than the melt–quenching (0.24, 0.15, 0.15 and 0.20 g/mL with HP, AS, CP and PK, respectively). The lower density solid dispersion might give higher capillary channel by wicking, wetting, and penetration mechanisms, therefore rapid in vitro drug release might be observed [45].

The release kinetics of NIM and its solid dispersions prepared with HPMCP, HPMCAS, HPC, and PVP using spray–drying (SM) and melt–quenching (HM) methods were comparatively evaluated in phosphate buffer media at pH 5.0, 6.0, and 6.8. Table S1 and S2 summarize the results of the in vitro release profiles. The release data were fitted to the Korsmeyer–Peppas (KP) model, showing that the NIM.CP.SM formulation exhibited the highest k_KP value (98.12) at pH 6.0. Pure NIM showed negligible dissolution under all tested conditions. In contrast, HPMCP-based ASDs exhibited a pronounced and superior enhancement of drug release. Specifically, the NIM.CP.SM (spray dried) was the top performer, achieving the highest overall DE (0.901) at pH 6.0, while the NIM.CP.HM (melt–quenching) formulation showed robust performance. These findings identify HPMCP as the optimal carrier and confirm the presence of the spring–parachute effect.

3.9. In Vivo Pharmacokinetics

The in vivo pharmacokinetic study was conducted to evaluate the oral bioavailability of NIM, the physical mixture, and the solid dispersions. The method validation showed acceptable reliability, with Table S3 summarizing the inter-day and intra-day precision and accuracy values. Linearity was confirmed using a correlation coefficient (R²) of 0.994. Figure 9 illustrates the plasma drug concentration–time profiles of NIM, the physical mixture, NIM.CP.SM and NIM.CP.HP following intragastric administration to Sprague–Dawley rats. Table 6 summarizes the pharmacokinetic parameters associated with these outcomes. The time to reach maximum plasma concentration (T_max) for NIM, the physical mixture, the NIM.CP.SM, and the NIM.CP.HP was 3.13 ± 3.01 h, 1.0 ± 0.41 h, 0.25 ± 0.12 h, and 0.31 ± 0.13 h, respectively. The maximum plasma concentration (C_max) for NIM, the physical mixture, the NIM.CP.SM, and NIM.CP.HM was 74.93 ± 10.23 ng/mL, 73.62 ± 75.95 ng/mL, 2480.80 ± 1629.26 ng/mL, and 777.56 ± 1448.63 ng/mL, respectively. The AUC_0–t of NIM.CP.SM was 4672.92 ± 3395.65 ng⋅h/mL, significantly higher than that of NIM (332.50 ± 120.21 ng⋅h/mL), indicating significantly improved systemic exposure.

The physical mixture could not release the NIM at gastric pH and in the small intestine because the components were not uniformly mixed at the molecular level. Consequently, NIM likely underwent recrystallization and could not maintain supersaturation. In contrast, NIM.CP.SM exhibited a 33-fold increase in C_max (2480.80 ng/mL) and a 15-fold increase in AUC_0–t compared to NIM, indicating that the solid dispersion significantly enhanced systemic exposure after oral administration (p-value < 0.05). Although NIM.CP.HM exhibited improved bioavailability compared to NIM, its pharmacokinetic performance was inferior to that of NIM.CP.SM. This finding confirms that the spray-drying method is more effective than melt-quenching for preparing HPMCP-based solid dispersions. The superior performance of NIM.CP.SM may be attributed to its smaller particle size, uniform drug distribution, and stronger intermolecular interactions between NIM and HPMCP, enhancing stability and preventing recrystallization. Therefore, the in vivo release profile demonstrated that the spray-dried HPMCP-based solid dispersion-maintained supersaturation, prevented recrystallization in gastrointestinal fluids, and significantly enhanced the oral bioavailability of NIM.

4. Conclusion

In this study, solid dispersions of NIM were prepared with HPC, HPMCAS, HPMCP, and PVP K25 as carriers using spray-drying and melt-quenching methods. The DSC thermograms showed the presence of T_g in all prepared ASDs, confirming their amorphous state. Drug–polymer compatibility and interactions were evaluated using FTIR spectroscopy, and the results showed no significant peak shifts in the spectra of the solid dispersions. The crystallinity in the ASDs was evaluated using PXRD, revealing no significant diffraction peaks, thereby confirming their amorphous nature. The in vitro and in vivo drug release profiles showed rapid, complete drug release from NIM.CP.SM suggesting complete dispersion. Supersaturation without recrystallization was maintained for 120 min in the release medium (phosphate buffer, pH 6.0). A significant improvement in drug release was observed for NIM.CP.SM compared to NIM as a reference. Furthermore, the findings suggest that HPMCP is a promising carrier and spray-drying method is a feasible method for achieving the amorphous form and enhancing in vitro drug release and bioavailability.