INTRODUCTION:

Valsartan (VAL) (figure 1) is an angiotensin receptor blocker that is widely used in the treatment of hypertension, myocardial infarction and other cardiovascular diseases. Via its angiotensin receptor blockade mechanism, Valsartan directly affects the renin-angiotensin-aldosterone system (RAAS)¹. Due to the absence of dry cough or oedema as commonly associated with the use of ACE inhibitors, Valsartan exhibits milder side effects. Valsartan offers a broad therapeutic range, with paediatric doses as low as 10 mg and a maximum dose of 320 mg. Its safety and good tolerability make Valsartan a widely used medication for cardiovascular disease therapy^2,3.

The solubility of valsartan relies heavily on the pH of the gastrointestinal tract. As a weakly acidic drug, valsartan is quickly absorbed in the stomach and upper intestine. However, its solubility is low in these areas. Therefore, despite rapid gastrointestinal absorption, the bioavailability is limited due to poor solubility (approximately 23% after oral administration). Valsartan becomes more soluble at pH above 5 because all of its acid sites are ionised. However, ionisation leads to a significant decrease in the permeability of the drug^4,5. As solubility and permeability are two critical factors in the success of drug delivery systems, the unique properties of valsartan highlight the importance of improving its solubility at the site of absorption.

Figure 1: Chemical structure of valsartan

Some distinctive strategies in formulation technology have been developed to boost drug solubility, such as nanotechnology⁶, co-solvents^7,8, modification of salt structures⁹, co-crystal¹⁰ and amorphous solid dispersion (ASD)¹¹. Chemical modifications such as salt formation or particle reduction in the form of nanosize still encounter various obstacles such as complex synthesis pathways, unwanted by-products, and massive deposits of small particles^9,12,13. Amorphous solid dispersion (ASD) is a simple and straightforward drug solubility enhancement strategy by dispersing the drug in a carrier. In addition, ASD formulations have the advantage of being a non-toxic and easy-to-use method for most drugs as various water-soluble polymers are used to prepare these formulations. Amorphous Solid Dispersion (ASD) is a strategy used to enhance drug solubility by dispersing the drug in a carrier. Hydrophilic polymers are frequently used as carriers. Upon dispersion, the drug forms amorphous crystals that demonstrate greater stability than the pure amorphous form. The formulation is also capable of augmenting drug solubility by raising the drug saturation concentration. ASD systems inhibit nucleation by reducing the molecular mobility of the drug, thereby preventing the concentration of nucleation from being attained^14–16. Numerous studies related to ASD have been extensively conducted. Choi and Park (2017) successfully formulated solid dispersion of Tadalafil with a carrier of PVP-VA copolymer, resulting in a twofold increase in drug solubility compared to its pure form¹⁷. Eloy et al. (2015) conducted a study in which solid dispersion of ursolic acid was formulated based on poloxamer 407¹⁸. This formulation of solid dispersion led to an increased dissolution rate of ursolic acid, resulting in the complete dissolution of the drug within the initial 20 minutes. Solid dispersions can improve drug solubility and dissolution rate, which is controlled by the amount of polymer present in the system. Polymers play a crucial role by dispersing the drug uniformly and maintaining drug saturation in the medium¹⁹. However, excessive polymer does not always lead to a proportional improvement in the response. Instead, it can hinder drug release as found in case of povidone which at higher DL, both solubility and dissolution rate drastically plunged^20,21.

As technology advances, a new generation of solid dispersions incorporates surfactants in a ternary system. The use of surfactants is known to improve drug dissolution and ensure physical stability^20,21. Previous studies have shown that drug-polymer-surfactant systems exhibited more significant increases in dissolution rate compared to solid dispersions lacking surfactants^22–24. Nevertheless, other studies also indicated the adverse effects of surfactants on the stability of solid dispersion systems²⁵. Therefore, further study is needed regarding the significance of a ternary system in ASD. This study aims to optimize and characterize the solid dispersion of valsartan as a ternary system of drug-polymer-surfactant. Valsartan solid dispersion (VAL-SD) was prepared by spray drying method followed by several characterisations. Drug solubility, crystallography, and dissolution were measured to analyse the impact of formulation on the physicochemical properties of VAL-SD. Optimization was performed using full factorial design at α=0.05.

MATERIALS AND METHODS:

Materials:

Kolliphor P407 and Kollidon VA64 were provided as gift by BASF Pharma Solutions, Germany. Valsartan was provided as a gift from PT Kimia Farma, Indonesia. Other chemicals namely ethanol, hydrochloric acid 0.1M, sodium acetic acid, and acetic acid glacial were of analytical grade and purchased from PT Brataco, Indonesia.

Design of experiments (DoE):

Optimization was conducted using a full factorial design. The study was carried out with 2 independent variables and 3 levels. Design Expert was employed to generate 9 runs that were optimized (Table 1).

Table 1: Full factorial design for two variablesunt

Run	Valsartan (mg)	Kollidon VA64 (mg)	Kolliphor P407 (%)
1	80	80	1
2		240	5
3		240	3
4		80	5
5		160	3
6		80	3
7		160	1
8		160	5
9		240	1

Preparation of valsartan solid dispersion:

Valsartan loaded solid dispersion (VAL-SD) was prepared through spray drying method. Preparation procedure adapted that of Davis et al. (2017). The polymer, surfactant, and active substance were initially dissolved in 70% ethanol while stirring at 750rpm. The solution was subsequently identified as the feed solution (FS). The FS was then introduced into the spray dryer chamber for the drying process. The drying process was carried out at an inlet temperature of 80°C. The inlet-outlet temperature, FS concentration, aspiration rate and pumping speed remained constant for all formulations, leading to variations occurring only in the polymer and surfactant composition within the FS.

Solubility measurement:

The solubility of VAL-SD was measured using Chella et al. (2015) method with modifications. VAL-SD, which is equivalent to approximately 1 gram of valsartan, was added to 10mL of aquadest. The resulting mixture was stirred on a water bath at 25°C for 24hours. The mixture was centrifuged at 3000g for 10 minutes to precipitate the remaining insoluble valsartan. A 0.45µm filter paper was then used to remove the precipitate. The samples were analysed by means of the UV-Vis spectrophotometric method. Pure valsartan was used as a control with the same treatment²⁶.

VAL to SD equivalence assay:

Drug loading was assayed to determine the weight equivalence of the solid dispersion to valsartan. Approximately 100mg of VAL-SD was weighed and dissolved in 100mL of ethanol. Subsequently, the solution underwent filtration using a 0.45um filter. A 1 mL aliquot was taken and diluted to 20mL with ethanol. The sample was assayed quantitatively using UV spectrophotometry at 252nm. The drug content was expressed as the amount of valsartan in milligrams per gram of solid dispersion (mg/g). The aforementioned ratio was used to determine the amount of solid dispersion powder to be used in subsequent analyses.

Intrinsic dissolution test:

The intrinsic dissolution test was conducted using two different media: 0.1N HCl (pH 1.2) and acetate buffer (pH 4.5). VAL-SD were accurately weighed to approximately 100 mg of valsartan. The granules were then compressed into pellets and coated with liquid paraffin, allowing only the surface to come into contact with the dissolution media. The apparatus was operated at a constant speed of 100rpm. Sampling was performed every 10minutes until 10% of the drug was dissolved. The intrinsic dissolution rate was analyzed by plotting the cumulative amount of dissolved drug per unit area against time²⁷.

Solid state characterization of valsartan loaded solid dispersion:

a) Fourier transform infrared spectroscopy (FTIR):

A Thermo Nicolet iS10 FTIR spectrophotometer was used to analyse the molecular interactions in the solid dispersion system. 100mg of VAL-SD was mixed with dried KBr to give 2000mg total weight. Then, 100mg of the mixture was compressed into thin plates for analysis. The analysis was carried out in the wavenumber range of 4000-400 cm^-1. Pure valsartan, Kollidon VA64 and Kolliphor P407 were used as standards.

b) Differential scanning calorimetry (DSC):

The analysis was carried out following the method proposed by Himawan et al. (2022), with necessary adjustments. Samples of VAL-SD (approximately 5mg) were hermetically sealed with aluminium plate. The analysis was conducted over a temperature range of 0 to 300°C, with a heating rate of 10°C/minute under a constant flow of nitrogen (N₂). Pure valsartan, Kollidon VA64, and Kolliphor P407 were used as reference.

c) X-Ray diffraction (XRD):

XRD analysis was performed following Himawan et al. (2022) method with necessary modifications. A D8 Advance XRD analyser was used for the analysis. VAL-SD (approximately 50mg) were analysed in the angular range of 5° - 50° (2𝜃). The scan was carried out at a speed of 5°/minute with a sampling step size of 0.02°.

RESULT:

Optimization of VAL-SD:

a) Solubility of VAL-SD:

Two-factor interaction (2FI) model was recommended by program, which generates equation shown in Table 2. From the provided model equation, it can be observed that all factors have positive coefficients. The study found that both the proportion of Kollidon VA64 and Kolliphor P407, as well as their interaction, had a positive influence on the response. Specifically, the saturated solubility of VAL-SD was increased. Figure 2A demonstrates that the solubility of VAL-SD increases proportionally with the concentration of the polymer and surfactant. At the maximum proportion of polymer and surfactant, the solubility of valsartan reached its maximum point.

b) Intrinsic dissolution of VAL-SD:

The program recommended a quadratic model for intrinsic dissolution at both pH 1.2 and 4.5, which in turn provided the equations showed in Table 2. From the given model equations, it clearly showed that all factors have positive coefficients. Results revealed that the response was positively affected by the proportion of Kollidon VA64 and Kolliphor P407, as well as their interaction. This led to an increase in the dissolution rate, to be specific. The coefficient of Kollidon VA64 was the largest, indicating that the proportion of polymer has the most prominent effect on the dissolution rate of valsartan. The dissolution profiles of VAL-SD at pH 1.2 and pH 4.5 showed a similar trend as shown in figure 2.

The stretching of aromatic C=C bonds was represented by a sharp peak at 1471 cm^-1, and finally a sharp peak at 759 cm^-1 corresponded to a fingerprint band for aromatic compounds in the ortho position^4,26,28. Kollidon VA64 showed a broadened absorption band at 3200 - 3600 cm^-1, which was a typical peak of polymeric OH group. Some other absorption bands shown by Kollidon VA64 were 1737 cm-1 (Carboxylate stretching), 1642 cm^-1 (amide stretching) while the absorption band at 1021 showed the stretching of vinyl-terminal at the end of the polymer chain. Kolliphor P407 showed a band at 2885 cm-1 showed C-H stretching and the sharp peak at 1103 cm^-1 showed C-O stretching¹⁹. The FTIR spectra of VAL-SD showed shifts in the absorption bands. The absorption bands of valsartan and Kollidon VA64 at 1642 cm^-1 and 1605 cm^-1, respectively, shifted to an absorption band at 1660 cm^-1, accompanied by a decrease in the intensity of the vinyl terminal absorption at 1022 cm^-1²⁹. The carboxylate absorption bands on valsartan and Kollidon VA64 did not shift, indicating that hydrogen bonding was more dominant between the NH group on valsartan and the C=O carbonyl group on the vinyl pyrolidone structure. The loss of the absorption band at 759 cm-1 and changes in the spectrum in the fingerprint region indicated that hydrophobic interactions between the components also occurred in addition to hydrogen bonding³⁰. Results showed that there were molecular interaction within the ASD system.

b) Crystallography:

The crystallography of the valsartan solid dispersion was confirmed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis. Figure 3 shows the thermal profile of valsartan solid dispersion. Valsartan showed a sharp endothermic peak at 116^oC, indicated its melting point. Kolliphor P407 showed a sharp endothermic peak at 58^oC. Kollidon VA64 as an amorphous polymer did not show an endothermic peak, but it showed a decrease in heat flow at 106^oC due to softening of the polymer. This temperature was also known as the glass transition temperature (Tg)¹⁹.

The DSC pattern of the VAL-SD did not show any endothermic peaks related to valsartan and Kolliphor P407. However, the thermogram shows Tg of 86^oC, as shown in Figure 3D. It indicates complete transformation of valsartan into an amorphous form. Since the amorphous material does not undergo melting, it shows no endothermic peak but rather softens with increasing temperature. Figures 3E, 3F, and 3G illustrate that the amount of polymer in the ASD system was directly proportional to the increase in the glass transition temperature (Tg). These results confirm the antiplastization effect of Kollidon VA64. Similar results were obtained where PVP-VA co-polymer exerted an antiplastization effect on ezetimibe solid dispersion systems¹⁹. The amorphization of valsartan was further confirmed through X-ray diffraction (XRD) results. Valsartan has an XRD pattern with many sharp peaks showing the crystalline characteristic of it (Figure 4). The XRD pattern of VAL-SD did not show the sharp peaks of pure valsartan, confirming the amorphization of valsartan.

Figure 3: DSC thermograms of (A) Valsartan, (B) Kolliphor P407, (C) Kollidon VA64, (D) Optimized VAL-SD, (E) VAL-SD with polymer-drug ratio 3:1, (F) VAL-SD with polymer-drug ratio 2:1, and (G) VAL-SD with polymer-drug ratio 1:1. Scanning was performed using Shimadzu DSC-60 plus. Approximately 5 mg of sample was hermetically sealed using an aluminium plate. The sample was then heated from 30 to 300°C at a rate of 10°C per minute while maintaining a continuous stream of nitrogen gas (N₂). OriginLab was then used to process and present the data.

Figure 4: XRD patterns of (A) Valsartan, (B) Kolliphor P407, (C) Kollidon VA64, and (D) VAL-SD. Analysis was carry out using Bruder AXS D8 Advance Eco XRD. Approximately 50 mg of sample coated with gold and scanned over 5^o to 50^o with 5^o/min rate and 0.02 sampling step size. OriginLab was then used to process and present the data.

DISCUSSION:

In the study, valsartan was formulated as a spray-dried amorphous solid dispersion in Kollidon® VA 64 and Kolliphor® P 407. The aim of this study was to improve the solubility and dissolution speed of Valsartan especially at its absorption site (pH 1.2 - 4.5). The main finding of this research study was the triumphant development of the ASD system, which has considerably enhanced the solubility and dissolution of valsartan at pH of 1.2 and 4.5. The optimum formula had a solubility 39-fold that of pure valsartan (3.709±0.086 and 0.095±0.003mg/mL respectively), simultaneously accelerating its dissolution rate. Similar findings were also noted in a prior study where the VAL-HPMC-SLS ASD system increased Val's solubility to 220µg/mL. The solubility of VAL-ASD obtained in this study, however, was significantly higher, up to 17 times (3.709mg/mL compared to 0.220mg/mL, respectively). In the earlier study, VAL was formulated as ASD with a drug-polymer ratio of 3:1 to 2:1. In contrast, ASD was prepared with a drug-polymer ratio of 1:1 to 1:3 in this study. These results suggest that the amount of polymer in the system may have an impact on the final solubility of the ASD³¹. This also supports the findings in this study where polymers affect the solubility of valsartan in an amount-dependent manner. The addition of Kolliphor P407 as surfactant has a synergistic effect on enhancing the solubility of valsartan, as it increases wettability and functions as a co-solubilizer by virtue of its amphiphilic properties^21,32. Consequently, an increased proportion of Kollidon VA64 and Kolliphor P407 results in higher solubility of VAL. Increasing the solubility directly affects dissolution. According to the Noyes-Whitney equation, the difference between drug solubility and dissolved drug concentration determines the dissolution rate³³. Improving solubility and dissolution can potentially enhance absorption, as drug permeation through the intestinal mucosa is driven by a concentration gradient³⁴.

Both polymer and drug undergo dissolution, which can be congruent. Regardless, it is only satisfied if the amount of polymer is sufficient to have an effect on the dissolution rate. If the polymer amount is adequate, the ASD system becomes thermodynamically stable due to the low mobility of drug molecules, preventing recrystallization or resulting in a much higher dissolution rate compared to the drug crystallisation rate²⁰. As illustrated on the figure 5, Kolliphor P407 enhances the dissolution rate of VAL through a synergistic effect. During the dissolution process, water molecules are inserted into the matrix, causing it to swell and increasing the molecular mobility, thereby increasing the possibility of recrystallization^24,35. Kolliphor P407 encapsulates drug molecules forming a physical barrier that hinders interactions and, as a result, prevents drug recrystallization during the dissolution. Similar results were obtained with ledipasvir, indicating that the inclusion of surfactant, the dissolution rate was maintained at a drug load of up to 30%³². Nevertheless, in spite of the proportional relationship between dissolution rate and polymer amount obtained from various studies^36–38, increasing the quantity of polymer did not always exhibit a positive effect on the drug's dissolution rate, as illustrated in Figure 2. A decrease in dissolution rate was observed in the amorphous solid dispersion (ASD) formulation with a polymer to drug ratio of 3:1. It can be attributed to the formation of a viscous diffusive layer by the polymer, delaying the release of the drug from the matrix²⁶.

The ASD system impacts the thermodynamic equilibrium of the drug, where molecular interactions hold significant importance. DSC analysis had shown that VAL has a high melting point (116^oC), which was a characteristic of its crystalline form, which was further confirmed by the XRD pattern of VAL. Due to its orderly molecular arrangement, the crystalline form has a high lattice energy. This is one reason for its low solubility. In this study, VAL was dispersed in Kollidon VA64 matrix, leading to an amorphous dispersion. As a result, it interacted with the carrier at a molecular level, replacing its intermolecular interactions resulting in an irregular molecular arrangement, which leads to a loss of its crystalline structure. Consequently, the crystal lattice energy was reduced, making valsartan more soluble³⁹. Furthermore, amorphous solid dispersion (ASD) is a reversible pharmaceutical modification. During the process and storage, amorphous dispersions tend to crystallize to reach stability. Two mechanisms contribute to the stability of ASD: crystallization inhibition and antiplastization effect¹⁴. Drug crystallization occurs in two simultaneous stages. It begins with nucleation and continues with crystal growth as more drug molecules migrate to the surface of the nucleus. Hence, molecular mobility play a crucial role in this process⁴⁰.

The mobility of drug molecules is directly influenced by molecular interactions. Molecular interaction in the system limits the mobility of the drug molecules and reduce free drug concentration, resulting in stabilisation of the amorphous solid dispersion (ASD)^41,42. Therefore, increasing the amount of Kollidon VA64 enhances drug-polymer interactions, inhibit the recrystallization, thereby increasing its saturation solubility. FTIR analysis showed that ASD results in drug-polymer intermolecular interactions, facilitated by hydrogen bonding and hydrophobic interactions indicated by shifted band in the FTIR spectra. The shifts occurred because the amorphous dispersion disrupted internal hydrogen bonds in the crystalline structure of valsartan and allowed hydrogen bonding between valsartan and Kollidon VA64¹⁹. In keeping with prior findings, PVP-VA-based ASD models demonstrate that the carbonyl groups of Kollidon VA64 serve as hydrogen bond acceptors, facilitating hydrogen bond formation with hydroxyl and amine groups on drug molecules. Additionally, the polymer can participate in other types of interactions, including van der Waals forces³⁰. However, in this study carboxylate absorption bands on valsartan and Kollidon VA64 did not shift, indicating that hydrogen bonding was more dominant between the NH group on valsartan and the C=O carbonyl group on the vinyl pyrolidone structure. In this case, the carbonyl group acted as a hydrogen bond acceptor while the NH group acted as a hydrogen bond donor.

Figure 5: Dissolution process of the ASD and impact of the polymer and surfactant. During the dissolution process, water molecules are inserted into the polymer matrix, causing it to swell and increasing the mobility of the molecules, thereby increasing the possibility of recrystallization (A to B). Surfactant encapsulates drug molecules forming a physical barrier that hinders interactions and, as a result, prevents drug recrystallization during the dissolution (C to D).

CONCLUSION:

The ASD system successfully enhanced the solubility and dissolution rate of valsartan in this study. Both the polymer and surfactant had a positive synergistic effect in an amount-dependent manner, as observed in this study. It is noteworthy that using excess polymer may decrease the dissolution rate due to the extended release effect. Amorphization and molecular interactions are important factors that influence the characteristics of the resulting VAL-SD. The amorphous dispersion of valsartan in the matrix reduces lattice energy, thereby increasing solubility. Valsartan primarily interacts with Kollidon VA64 through hydrogen bonding and hydrophobic interactions. Due to the low amount of Kolliphor P407 in the system, the interaction may be less likely to be observed in this study.

CONFLICT OF INTEREST:

The authors declared there is no conflicts of interest.

ACKNOWLEDGMENTS:

The authors would like to thank BASF Pharma Solutions for providing Kollidon VA64 and PT Dexa Medica for providing Valsartan in support of this study.

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Received on 02.11.2023 Modified on 23.01.2024

Research J. Pharm. and Tech 2024; 17(8):3717-3724.

DOI: 10.52711/0974-360X.2024.00578

Responses (Y_i)	Equation	*p-value*	*Lack of Fit*	R² *Adjusted*	R² *Predicted*
Solubility (Y₁)	1,26A+1,12B+1,02AB	0,0002	0,6873	0,9990	0,9965
Intrinsic dissolution (pH 1.2) (Y₂)	+0,134A + 0,081B + 0,044AB – 0,191A² + 0,055B²	<0,0001	3,8127	0,9999	0,9996
Intrinsic dissolution (pH 4.5) (Y₃)	+0,141A + 0,093B + 0,054AB – 0,189A² + 0,072B²	<0,0001	3,3018	0,9999	0,9998

Characteristics	Predicted	Observed (n=3)	p value
Solubility (mg/mL)	3,747	3,709±0,086	0,0899
Dissolution rate at pH 1,2 (mg/min)	0,493	0,488±0,012	0,1054
Dissolution rate at pH 4,5 (mg/min)	0,507	0,518±0,023	0,0792