Effect of pH Modifiers on the Solubility, Dissolution Rate, and Stability of Telmisartan Solid Dispersions Produced by Hot-melt Extrusion Technology

Abstract

The aim of the current study was to investigate the dual effect of an amorphous solid dispersion generated by hot melt extrusion and the addition of pH modifiers on the solubility and stability of telmisartan. Hydroxypropyl methylcellulose acetate succinate L grade was used as a polymeric carrier and recrystallization inhibitor, and meglumine, sodium carbonate, or Neusilin S2 were incorporated as pH modifiers to generate a desirable microenvironmental pH in the solid dispersions. Differential scanning calorimetry, powder X-ray diffraction, and Fourier transform infrared spectroscopy were incorporated to obtain the solid-state characterizations of telmisartan, and the results confirm a partial transformation of telmisartan to an amorphous state. An in vitro release study revealed that the transformation of telmisartan to an amorphous material improved its dissolution rate by 2-fold compared to pure drug and by up to 5-fold with the incorporation of pH modifiers. Results of the stability studies demonstrated that the samples have no significant degradation under accelerated stability conditions at 40 °C/75% RH.

Graphical Abstract

1. Introduction:

Poorly soluble active pharmaceutical ingredients have been investigated to improve their bioavailability by manipulating their solubility and dissolution rate behavior. Several widely known approaches have been explored to achieve these goals, such as solid dispersion, pH adjustment, size reduction, salt formation, and nanoparticle approaches [1]. Due to their low cost and feasibility, solid dispersions have been shown to be superior to other methods. Therefore solid dispersions have been used extensively to enhance the solubility and bioavailability of poorly soluble drugs [2]. The carrier in a solid dispersion may play several roles, although major functions are to transform the drug from a crystalline state to an amorphous state, while also inhibiting recrystallization over time. Additionally, the carrier improves the drug solubility of poorly soluble drugs by enhancing drug wettability and decreasing particle size [3], [4].

Hot-melt extrusion (HME) is one of the approaches to formulate an amorphous solid dispersion (ASD) and has gained popularity within the pharmaceutical industry over the past three decades. Additionally, HME has the ability to produce several versatile formulations and its ability to tailor processing materials through modifications in the screw design and mixing and shearing forces or by controlling the material feed rate; additionally, HME allows processing at multiple temperatures and screw speeds. HME has advantages over traditional pharmaceutical processing techniques, including its ability for continuous operation and ability to implement quality by design (QbD) and process analytical technology (PAT) strategies; furthermore, HME is a solvent-free method, has few processing steps, is inexpensive, and is feasible for industrial scale-up and processing of drugs with high melting points and viscous materials [1], [5]–[10]. The selection of an amorphous solid dispersion carrier depends on the formulation and its ability to maintain the amorphous state for a given shelf life. Hydroxypropyl methylcellulose acetate succinate L grade (HPMCAS LG) has been reported to efficiently prevent recrystallization and improve the solubility of poorly soluble drugs at ≥ pH 6.8 [4], [11], [12].

Another important approach to improve the solubility of pH-dependent, poorly soluble drugs is pH adjustment. Incorporating a pH-modifying material into formulations or tablets is a promising way to create a suitable microenvironment pH that leads to improved solubility and the release of pH-dependent drugs. For example, poorly soluble weakly basic drugs can solubilize more when using acidifiers and vice versa [13], [14]. Nevertheless, the drawback of this method is that a high drug load formulation requires a large amount of pH modifying agent inside the formulation, which could affect its stability if a hygroscopic material is used, such as sodium hydroxide. Therefore, the selection of the pH modifier is a crucial factor to balance drug solubility and formulation stability [15], [16]. Meglumine, sodium carbonate, and Neusilin S2 are alkaline in nature, therefore, they were chosen in this research to investigate their ability to generate a potential suitable microenvironmental pH and the possibility to improve the drug solubility and dissolution rate [17], [18].

Telmisartan (TEL) is an angiotensin II type 1 receptor blocker and has been used to treat hypertension. Its bioavailability is 42% and 58% at 40 and 160 mg doses, respectively. TEL is chosen as a model drug for this research because it has poor aqueous solubility and pH-dependent solubility, in which it is highly soluble in strongly acidic (466 μg/mL in pH 1.2) and basic media (491 μg/mL in pH 10) but is insoluble between pH 3–7 (< 1μg/mL)[13], [18]. Several methods have been reported to enhance its aqueous solubility and dissolution rate by using the salt formation method, adjusting the pH using alkalizers, crystal engineering approaches, nanoparticles, comilling techniques, and solid dispersion [13], [17], [19]–[24].

The aim of the current investigation was to produce amorphous solid dispersion formulations with HMPCAS LG as a recrystallization inhibitor carrier, with and without the incorporation of pH modifiers. The design of experiment (DoE) strategy was employed in the development of ASDs by HME techniques. The impact of pH modifiers on the TEL solubility at pH 6.8 and its stability was studied. Furthermore, investigation of the novel use of a silica excipient Neusilin S2 (NEU) as an alkaline excipient and as an amorphous carrier on the solubility and stability of TEL was evaluated.

2. Materials and methods:

2.1. Materials:

Telmisartan (TEL) was kindly gifted by Hanmi Pharm. Co. (Suwon, Korea), meglumine (MEG) was generously gifted by Millipore Sigma (Tokyo Chemical Industry Co., Ltd., Japan), sodium carbonate anhydrous (SC) was purchased from Fischer Scientific (Fair Lawn, NJ), and Neusilin S2 (NEU) was generously provided by Fuji Chemical Industries Co., Ltd. (Toyama, Japan). AquaSolve™ HPMCAS LG was generously donated by Ashland Specialty Ingredients (Wilmington, DE).

2.2. Methods:

2.2.1. Phase solubility study:

The solubility of TEL in 0, 2, 4, 6, 8, 10, and 12% (w/v) aqueous solutions of meglumine and sodium carbonate was investigated by adding an excess amount of TEL to a vial with 10 mL of each concentration (n=3). The vials were agitated at 180 rpm for 72 h at ambient temperature. Withdrawn samples were centrifuged at 15000 rpm for 15 min, the supernatant was filtered through a 0.45 μm membrane filter before being suitably diluted. Then, the dissolved drug was analyzed by using a UV spectrophotometer at 297 nm. The Gibbs free energy of transfer (ΔG°_tr) provides a description on the good or unfavorable conditions of drug solubilization in an aqueous medium. The ΔG°_tr of TEL was calculated using this equation:

$$\Delta \text{G}{°}_{\text{tr}}=-2.303RT\mathrm{Log}\frac{S_0}{S_S},$$ (1)

where (S_s) is the ratio of molar solubility of TEL in an aqueous solution with a pH modifier, S₀ is the molar solution of drug in distilled water, R is the gas constant (8.31 JK⁻¹ mol⁻¹), and T is the temperature in Kelvin.

The apparent stability constant value (K_s) of the drug-polymer was calculated from the phase solubility graphs according to this equation.

$$K_s=\frac{Solpe}{S_0}(1-Slope),$$ (2)

2.2.2. Solid dispersion preparation:

2.2.2.1. Design of experiment

Preformulation studies were conducted to reach the most suitable and feasible formulations of different drug loads (10, 20, 30, and 40%) combined with HPMCAS LG for extrusion by HME. After investigating the effect of drug load on the amorphous nature of the tested formulations, 10 formulations (Table 1) with one drug load were generated. Furthermore, the effects of the type and percent of pH modifiers on the dissolution and stability of TEL were assessed by using the design of experiment (DoE) software (Design-Expert). A three-level full factorial design was used to investigate the effect of independent factors (type of pH modifier and % of pH modifier) on the formulation behavior toward the dissolution and stability of TEL (dependent factors). One-way analysis of variance (ANOVA) was applied to identify the model suitability and factor significance (p < 0.05). The model suitability was based on how the data fit the model and was represented by the R² value, in which a value closer to 1 is considered a good fit.

Table 1.

Design of Experiment suggested formulations

Formulation
Combinations (% w/w)	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10
TEL	10%	10%	10%	10%	10%	10%	10%	10%	10%	10%
HPMCAS LG	90%	87.5%	85%	80%	87.5%	85%	80%	87.5%	85%	-
MEG	-	2.5%	5%	10%	-	-	-	-	-	-
SC	-	-	-	-	2.5%	5%	10%	-	-	-
NEU	-	-	-	-	-	-	-	2.5%	5%	90%*

^*F10 with 10% NEU was modified to have 90% NEU and 10% TEL only

2.2.2.2. Hot melt extrusion

Telmisartan (10%) was mixed with HPMCAS LG (80–90%), SC (0–10%), MEG (0–10%), or NEU (0–5%, 90%) using a V-shell blender (MaxiBlendTM, GlobePharma, North Brunswick, NJ, USA) at 25 rpm for 15 min. The physical mixtures were extruded successfully using a corotating twin-screw extruder (11 mm Process 11™, Thermo Fischer Scientific, Karlsruhe, Germany) with a Thermo Fischer standard screw design at 180 °C, 50 rpm, and a 5-set feed rate (1.7 g/min). Triethyl citrate (TEC) was used as a plasticizing agent (10% w/w in regard to HPMCAS LG).

2.2.3. Drug content

An amount equivalent to 10 mg of TEL of each extruded formulation (n=3) was dissolved in 4 mL of 0.1 N NaOH and 16 mL of methanol; this mixture was sonicated for 30 min and then centrifuged. Next, the supernatant was collected and diluted suitably before the TEL concentrations were detected by UV spectrophotometry at 297 nm. A calibration curve of TEL was conducted over a concentration range of 1–10 μg mL⁻¹, and the regression coefficient (R²) was 0.998.

2.2.4. Saturation solubility studies

Excess quantities of solid dispersed formulations were added to sealed glass vials containing 10 mL of pH 6.8 phosphate buffer to evaluate the saturation solubility of TEL; these samples were shaken for 48 h at room temperature (n=3). A 0.45 μm membrane filter was used to filter samples before being suitably diluted. The dissolved amount of TEL was analyzed by UV spectrophotometry at 297 nm. Three determinations were performed for each sample.

2.2.5. Differential scanning calorimetry (DSC)

The thermal behavior of TEL, HPMCAS LG, and other excipients was studied by a DSC 25, TA instrument, which was calibrated with indium. Samples (4–5 mg) were crimped in standard aluminum pans and sealed with a standard aluminum lid. After that, they were heated and scanned from 50 to 300 °C at a heating rate of 20 °C/min at a flow rate of 50 mL/min in a dry nitrogen atmosphere. An empty aluminum pan was placed as a reference. The degree of crystallinity (DC) of the drug in PM and SD was calculated by using Eq. 3:

$$DC=f\frac{\Delta H_{SD}}{\Delta H_{Drug}}\times 100,$$ (3)

where f is the fraction of drug present in the mixture, ΔH_SD is the heat of fusion of the drug in formulation (SD/PM) and ΔH_Drug is the heat of fusion of the pure drug [25].

2.2.6. Powder x-ray diffraction (PXRD):

PXRD was performed using a Rigaku Miniflex 600 diffractometer. The generator was set to a voltage of 40 kV and a current of 15 mA. The scan ran from 5° to 50° (2θ) with a 0.02 scanning step and a scanning step duration of 0.5 seconds. The relative degree of crystallinity (RDC) was calculated by using Eq. 4:

$$RDC=\frac{I_{SD}}{I_{Drug}},$$ (4)

where I_SD is the peak height of the SD or PM under investigation and I_Drug is the peak height at the same angle for pure TEL [26].

2.2.7. Fourier transform infrared spectroscopy (FT-IR)

FT-IR analysis was conducted in the spectral range of 4000–650 cm⁻¹ using a Cary 660 instrument (Agilent Technologies, Santa Clara, CA, USA). The bench was equipped with a MIRacle ATR accessory (Pike Technologies, Fitchburg, WI, USA) that was fitted with a single bounce, diamond-coated ZnSe internal reflection element. FT-IR was performed to determine the molecular interactions of pure TEL alone and in the presence of SC, MEG, NEU and HPMCAS LG in the formulations before and after applying high shear forces and elevated temperatures.

2.2.8. In vitro dissolution

Dissolution studies were conducted using a USP II paddle method (75 rpm, 37 °C, and 900 mL of dissolution medium) with a Hanson SR8-Plus™ dissolution test station. An amount of SD powder equivalent to 40 mg of TEL was exposed for 1 h to pH 6.8 phosphate buffer plus 0.05% sodium lauryl sulfate (SLS) (n=3). A 2 mL sample was withdrawn from the dissolution medium at predetermined intervals (10, 20, 30, 45 and 60 min), and then the drug concentration was determined using a UV spectrophotometer at 297 nm; additionally, 2 mL of fresh medium was added to maintain a constant dissolution volume. Additionally, F1, F4, F7, and F10 powders equal to 20 mg of TEL were subjected to the same dissolution conditions to investigate the impact of dose on the TEL dissolution behavior.

2.2.9. In vitro dissolution data

The dissolution parameters were calculated to assess and understand the fate of TEL during the dissolution study. The dissolution efficiency (DE) is determined as the area under the dissolution graph to a specific point in time (t); this parameter is expressed as a percentage of the area of the rectangle described by 100% dissolution at the same time. The DE at 10 and 30 min 199 was calculated by using Eq. 5: [27]

$$DE=\frac{{\int }_0^{t}y\times dt}{y_{100}\times t}\times 100\%$$ (5)

The initial dissolution rate (IDR) was calculated over the initial 10 min of dissolution using Eq. 6:

$$IDR=\frac{\%Dissolved}{minute}$$ (6)

The dissolution rate can be expressed by another parameter, which is the mean dissolution time (MDT), and it is the mean time for the API to dissolve under in vitro conditions and can be calculated using Eq. 7:

$$MDT=\frac{{\sum }_{j=1}^n{t}_j\Delta Mj}{{\sum }_{j=1}^n\Delta Mj}$$ (7)

where n is the number of dissolution time points, j is the dissolution sample number, and tj is the middle point of the jth time period, which is calculated with (t + [t − 1]/2). ΔMj is the excess amount dissolved between t and t − 1.

The mean dissolution rate (MDR) was calculated using Eq. 8: [28], [29]

$$MDR=\frac{{\sum }_{j=1}^n\Delta Mj/\Delta t}{n}$$ (8)

where Δt is the midpoint time between t and t − 1 {(t + t −1)/2}.

The relative dissolution rate (RDR) is the ratio between the amount of dissolved drug from a formulation and the pure drug at 60 min [30].

2.2.10. Stability study

Physical and chemical stability studies were investigated for 1 month at accelerated conditions of 40 °C/75% RH. Formulations F4, F7, and F10 were loaded and sealed in vials with screw caps. The drug content, crystallinity, and dissolution studies were conducted on the first day and after 1 month. The dissolution results of the stability samples were compared with the profile of the initial samples at 0 days. A similarity factor (f2) was calculated using the dissolution results according to Eq. 9:

$$f2=50\log \left\{{\left[1+\left(\frac{1}{n}\right)\Sigma {\left(R_t-T_t\right)}^2\right]}^{-0.5}\times 100\right\}$$ (9)

where R_t and T_t are the percentages of the dissolved samples in fresh samples and the test batch at 30 days, respectively, and n is the number of sampling points (n = 5).

3. Results and Discussion

3.1. Solubility study:

The aqueous solubility of TEL was 0.12 ± 0.002 mg/mL, and the effect of adding a pH modifier on its aqueous solubility is shown in Fig. 1. According to the Higuchi and Connors phase solubility method, the solubility of TEL showed an improvement by adding small percentages of a pH modifier, and the increase was linear, suggesting an A_L-type pattern with multiple-fold increases [31]. The increased solubility of TEL in the presence of increasing pH modifier concentrations indicated that creating a suitable microenvironment pH could improve the pH-dependent drug solubility (Table 2). The relative solubilizing ability of pH modifiers was represented by the slope value, which indicated that MEG (0.0888) had a greater ability to solubilize TEL than SC (0.0743), and this conclusion was confirmed by the 9-fold increase in solubility of TEL with MEG compared to the 7-fold increase in solubility with SC. Moreover, the capability of MEG to improve acidic drug solubility is in accordance with an already reported publication where the solubility of naproxen was enhanced using MEG [32].

Figure 1.

TEL phase solubility study

Table 2.

Phase Solubility and Gibbs free energy of TEL at different concentrations of MEG and SC

pH-modifier (% w/v)	TEL Conc. in MEG (mg/ml)	ΔG°tr (J/mol)	TEL Conc. in SC (mg/ml)	ΔG°tr (J/mol)
0	0.13 ± 0.002		0.13 ± 0.002
2	0.36 ± 0.004	−2.52	0.31 ± 0.011	−2.15
4	0.59 ± 0.008	−3.75	0.41 ± 0.012	−2.85
6	0.82 ± 0.005	−4.57	0.63 ± 0.008	−3.91
8	1.03 ± 0.009	−5.14	0.84 ± 0.016	−4.62
10	1.08 ± 0.027	−5.25	0.93 ± 0.032	−4.88
12	1.15 ± 0.033	−5.41	0.96 ± 0.028	−4.95
Stability constant (ml/g)	622.42		529.07
R2	0.9537		0.9686
Slope	0.0888		0.0743

3.1.1. Gibbs-free energy (ΔG°_tr) study

The negative Gibbs free energy (ΔG°_tr) value provides an improved indication of TEL dissolution, and a decreasing value indicates more suitable conditions for the solubilization of TEL. All ΔG°_tr values (Table 2) were negative and decreased with an increasing amount of pH modifier; furthermore, MEG showed the lowest (ΔG°_tr) value, confirming the high solubilization of TEL with MEG. Moreover, the stability constants (K_s) of TEL with MEG and SC were 622.42 and 529.07 mL/g, respectively. According to Mukne and Nagarsenker, a stability constant value between 100 and 1000 mL/g is ideal and stable [33]. The observed stability constant values were well within 100 to 1000 mL/g, suggesting the ideal stability of the solutions. Three concentrations (2.5, 5, and 10%) of pH modifiers were chosen to investigate their ability to improve the dissolution of a pH-dependent drug combined with the influence of solid dispersion.

3.2. Drug content

The HME method was highly efficient for the preparation of all solid dispersion formulations while retaining a high content uniformity of 99%± 0.09 to 102% ± 0.70. This result suggests the suitability of this method for the development of ASDs.

3.3. Saturation solubility

All extruded formulations showed an improved TEL solubility compared to the pure drug (Fig. 2). The F1 formulation, a solid dispersion formulation without a pH modifier, increased the TEL solubility 6-fold compared to pure TEL, while the TEL solubility further improved as pH modifiers were added and this improvement increased as the percentage of pH modifier increased; thus, F4 showed higher solubility than the other formulations (13-fold increase). The enhanced TEL solubility may be attributed to the decreased TEL crystallinity, increased wettability, microenvironment pH and high HPMCAS LG hydrophilicity at pH 6.8.

Figure 2.

Saturation solubility study

3.4. Hot melt extrusion

In preliminary studies, HPMCAS LG could not be extruded alone without a plasticizer (TEC) below 160 °C further incorporating TEL made the extrusion unfeasible below 180 °C. The influence of the screw speed and residence time was investigated using speeds of 50, 100, and 150 rpm, and the HME process torque and DSC results showed no influence. The capacity of HPMCAS LG to transfer TEL to an amorphous state was evaluated using 10, 20, 30, and 40% drug loads with the polymer including 10% (w/w) TEC as the plasticizer. All batches were successfully extruded, milled, sieved, and tested by DSC. As the drug load increased more than 10%, the polymer was not able to transform TEL completely to the amorphous state, which might be because TEL has a relatively high molecular weight of 514.6 g/mol. As a result, a 10% drug load was fixed and established for this study, 180 °C was chosen for HME extrusion, 10% (w/w) TEC in regard to HPMCAS LG was used, and 50 rpm was set as the final speed. All formulations were extruded, milled using a laboratory grinder, sieved, and stored in a desiccator for further analysis.

To understand the effect of the NEU concentration on drug release, the F10 formulation with 10% TEL and 90% NEU replacing HPMCAS LG was investigated. The extrusion was conducted without plasticizer at 140 °C and 50 rpm. The main reason behind this modification was the low in vitro release profiles of F8 and F9 compared to pure TEL, which guided us to investigate the role of NEU as an amorphous carrier to improve the solubility and stability of TEL [34], [35].

3.5. Solid-state characterization study

3.5.1. DSC

The DSC thermograms of a pure TEL, solid dispersions (extrudates), and their corresponding physical mixtures (PM) are shown in Fig. 3A and B. The DSC curve of pure TEL showed a sharp endothermic peak at 267 °C with an enthalpy of fusion (ΔH) of 112.44 J/g, corresponding to its intrinsic melting point. The DSC of the PMs showed that TEL was present in a crystalline state, and the partial or complete absence of the peak with the SDs indicated that the drug was transformed either partially or completely into an amorphous state. The degrees of crystallinity of the F4 and F7 PMs were 0.21% and 0.39%, respectively, indicating that the drug was present in its crystalline form. The SD formulations did not show any endothermic melting peak except F10 (Fig. 4) and these results explain the ability of HPMCAS LG to decrease the degree of TEL crystallinity during the HME process. Moreover, F1, which only contains TEL and HPMCAS LG, showed an absence of a distinct TEL peak, which could occur due to a transformation to the amorphous state. This transformation occurred in all other formulations (F2-F9), and this was attributed to the presence of HPMCAS LG. However, F10 showed a small endothermic peak of TEL, indicating that TEL was partially transformed to an amorphous state.

Figure 3.

DSC thermograms: A: MEG formulations and B: SC formulations

Figure 4.

DSC thermograms of pure TEL and the SD formulations

3.5.2. PXRD

The PXRD patterns of the pure TEL and SD formulations are shown in Fig. 5. The PXRD pattern of pure TEL had three intense crystallinity peaks at 6.74°, 14.12°, and 22.26°. Moreover, the complete or partial disappearance of these crystalline peaks determine the suitability of HME process conditions and HPMCAS LG ability to reduce TEL degree of crystallinity. The PXRD of formulations showed a decrease in the intensity of pure TEL peaks, indicating its partial amorphization and crystallinity within formulations. The relative degree of crystallinity (RDC) was calculated by comparing the representative peak heights of pure TEL at the 6.74°, 14.12°, and 22.26° positions with those of SD and the results are shown in Table 3. This reduced crystallinity was attributed to HPMCAS LG and the HME process in which the high temperature and mixing shear led to the partial transformation to an amorphous state.

Figure 5.

PXRD of Telmisartan and formulations F3, F4, F6 and F7

Table 3.

Relative Degree of Crystallinity at PXRD peaks of TEL

Formulation	6.74 Pos. [°2Th.]		14.12 Pos. [°2Th.]		22.26 Pos. [°2Th.]
	(Height cts)	RDC	(Height cts)	RDC	(Height cts)	RDC
TEL	4300		2450.0		2011.0
F3	443	0.089	675	0.132	1063	0.146
F4	510	0.102	661	0.129	1156	0.158
F6	557	0.112	679	0.133	1126	0.154
F7	419	0.084	566	0.111	897	0.123

3.5.3. FT-IR

The FT-IR spectra of pure TEL, other excipients, and formulations (F1, F4, and F7) are shown in Fig. 6A–C. Pure TEL showed characteristic peaks at 3060 cm⁻¹ (O—H band) and 1692 cm⁻¹ (carbonyl group C==O). [13] F1, which had no pH modifier, showed a shift in the carbonyl stretching band from C==O (1692 cm⁻¹), suggesting a strong hydrogen bonding interaction, thus leading to the absence of an O—H peak at 3060 cm⁻¹ [36], [37]. This molecular interaction between TEL and HPMCAS LG improved TEL dissolution at least 1-fold and inhibited TEL recrystallization [11], [38]. This interaction was also present in the other formulations. Specifically, the FT-IR spectra of F4 and F7 showed the most prominent TEL dissolution enhancement, which may be due to the presence of MEG and SC; MEG and SC modified the microenvironment of the ASDs and did not interact with TEL or HPMCAS LG.

Figure 6.

A: FT-IR of TEL, HPMCAS LG, MEG, and SC. B: FT-IR of TEL and F1 PM vs Ext. C: FT-IR of the formulations

3.6. In vitro study

The dissolution of pure TEL and all formulations was performed in pH 6.8 phosphate buffer with 0.05% SLS (Fig. 7A–C). Figure 8A–B shows the release of the 20 mg dose compared to the 40 mg dose, and no dose dependency was noticed. The summary of dissolution parameters in Table 4 shows that the DE of F4, F7, and F10 improved TEL dissolution by 4-, 5-, and 3-fold compared to pure TEL, respectively. In regard to F10, TEL dissolution was improved compared to F1 because NEU might play a role as an ASD carrier and a pH modifier (Figs. 4 and 7). The MDT of pure TEL was 13.8 min, and that of F4 decreased to 6.93 min. The Q10 values of F2 to F7 showed the effect of the pH modifier and solid dispersion on the enhancement of TEL dissolution compared to F1, no pH modifier, and pure TEL. Furthermore, the RDR increased as the concentration of the pH modifier increased. Additionally, the IDR of formulations improved compared to the pure TEL and showed the same pattern as the RDR, where increasing the concentration of the pH modifier led to an improved IDR. The phase solubility study and the release profile data demonstrated that TEL released from SD formulations showed a biphasic drug release profile. Initially, the amorphous dispersed drug molecules were released followed by the residual TEL [39]. F8 and F9 showed no prominent improvement in TEL dissolution, which might be due to the low content of NEU being unable to impact the microenvironment pH in the ASD.

Figure 7.

Dissolution profiles of TEL and the formulations; A. F1 has no pH modifier and the rest are MEG formulations, B. SC formulations, and C. NEU formulations.

Figure 8.

TEL dose dependency study: A has 40 mg of TEL and B has 20 mg of TEL

Table 4.

Dissolution parameters summary

Formulation	Q10	Q30	DE10	DE30	MDT	MDR	IDR	RDR
Pure TEL	11.69	13.56	5.84	10.41	13.8	0.50	1.17	-
F1	18.55	26.77	9.27	18.49	11.50	0.84	1.86	1.71
F2	22.81	29.96	11.4	22.13	9.38	1.01	2.28	1.88
F3	29.30	32.61	14.64	25.85	9.39	1.23	2.93	2.14
F4	38.57	43.61	19.28	34.40	6.93	1.61	3.86	2.66
F5	24.75	26.67	12.37	21.62	7.07	1.07	2.61	1.73
F6	27.76	33.66	13.88	25.28	8.46	1.18	2.78	2.09
F7	31.45	36.04	25.72	27.62	12.16	1.33	3.15	2.53
F8	14.97	18.35	7.48	13.89	7.74	0.64	1.50	1.12
F9	14.00	16.75	6.99	12.77	8.38	0.6	1.4	1.04
F10	31.07	32.76	15.53	26.58	6.7	1.27	3.11	2.01

3.7. Design of experiment

Design-Expert software was used to investigate the impact of factors and levels of excipients on the dissolution and stability of TEL (Table 5). All 10 formulations were fit to the model with an R² of 0.933, and the difference between the adjusted R² (0.8991) and predicted R² (0.8056) was less than 0.2, as suggested by the software. Additionally, the results showed a significant effect on the dissolution of TEL with a p-value of 0.0006. On the other hand, the results showed no significant effect on TEL stability, with a p-value of 0.3558 and R² of 0.6535.

Table 5.

DoE formulations and the responses

Std	Run	X1	X2	Y1	Y2
		pH-M %	pH-M type	Dissolution ug/mL	Stability (DC) %
10	1	2.5	NEU	6.966	101.244
1	2	2.5	SC	11.6135	103.186
5	3	2.5	MEG	13.4048	104.356
2	4	0	SC	12.235	101.264
7	5	5	MEG	14.2734	100.474
4	6	10	SC	18.09	101.422
9	7	5	NEU	7.366	100.133
3	8	5	SC	14.226	99.763
6	9	10	MEG	19.0609	98.5782
8	10	10*	NEU	14.4025	100.578

^*Run 10 with 10% NEU was modified to have 90% NEU and 10% TEL only

3.8. Stability study

The formulations (F4, F7, and F10) were subjected to stability testing using DSC, drug content, and a dissolution study after 1 month under accelerated conditions at 40 °C/75% RH. The DSC in Fig. 9A showed no recrystallization of TEL compared to that at the initial time for F4 and F7; however, F10 showed slight recrystallization. The drug contents of F4, F7, and F10 were 100.47% ± 0.6, 101.42% ± 0.9, and 100.58% ± 0.7 at the initial time point, and after one month of storage, the drug contents were 98.31% ± 1.2, 101.20% ± 0.9, and 99.64% ± 1.3, respectively. Therefore, there was no significant loss in the drug content, and the dissolution results in Fig. 9B were similar to that at the initial time. The stability results showed that the significant drug-polymer interactions between TEL-HPMCAS LG and TEL-NEU were able to carry the amorphous drug and improve its solubility and stability. The similarity factor (f₂) between 50 and 100 was considered similar when comparing the two release profiles; thus, F4, F7, and F10 were 89.98, 83.83, and 88.91, respectively, and considered similar to the initial release profiles [40], [41].

Figure 9.

Initial formulations and 1-month stability comparison: A is the DSC thermograms and B is the release profiles

4. Conclusion

HPMCAS LG played a major role in enhancing the in vitro dissolution rate of TEL due to hydrogen bond formation, which occurred during the transformation of TEL to an amorphous state; this mechanism was affected by the addition of pH modifiers. Furthermore, HPMCAS LG prevented the recrystallization of TEL during the stability study. Meglumine and sodium carbonate did not interact with TEL and HPMCAS LG and increased the TEL solubility and dissolution rate as their concentrations increased. Additionally, their presence inside the formulation had no significant effect on TEL stability.