Solubility enhancement of candesartan cilexetil by complexation with CAVAMAX® W7 PHARMA (β ‑Cyclodextrin)

 Corresponding author: K. Anie Vijetha Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. Solubility enhancement of candesartan cilexetil by complexation with CAVAMAX® W7 PHARMA (β ‑Cyclodextrin) Shaik Arshiya Sulthana, K. Anie Vijetha * and M. Sunitha Reddy Centre for Pharmaceutical Sciences, UCESTH, JNTUH. GSC Biological and Pharmaceutical Sciences, 2025, 33(02), 234-240 Publication history: Received on 23 September 2025; revised on 02 November 2025; accepted on 05 November 2025 Article DOI: https://doi.org/10.30574/gscbps.2025.33.2.0412 Abstract Candesartan cilexetil (CC), a BCS Class II drug, exhibits low aqueous solubility, leading to dissolution-rate limited absorption and poor oral bioavailability. This study aimed to enhance the solubility and dissolution of CC through inclusion complexation with β-cyclodextrin (CAVAMAX® W7 Pharma). Complexes were prepared using physical mixture, kneading, and solvent evaporation methods at drug:carrier ratios of 1:1, 1:2, and 1:3. Prepared formulations were evaluated for solubility, phase-solubility behavior, solid-state characterization (FTIR, PXRD), dissolution studies, and accelerated stability. Phase-solubility analysis produced AL-type diagrams, confirming 1:1 stoichiometry and spontaneous complexation. Apparent solubility studies showed maximum enhancement at the 1:2 ratio, with solventevaporated complexes (F8) achieving the highest solubility (0.112 ± 0.007 mg/mL). FTIR and PXRD revealed peak shifts and amorphization, supporting inclusion formation. Dissolution profiles demonstrated improved release rates, with F8 achieving ~99% release within 120 min, compared to 52% for pure CC. Accelerated stability studies over 3 months confirmed formulation stability (f₂ ≥ 70). These findings establish solvent evaporation–based β-CD complexation as a robust strategy for enhancing the solubility, dissolution, and stability of candesartan cilexetil. Keywords: Candesartan Cilexetil; Β-Cyclodextrin; CAVAMAX® W7 Pharma; Inclusion Complex; Solubility Enhancement; Dissolution 1. Introduction Oral drug delivery is often limited by poor aqueous solubility of new chemical entities, particularly those classified as BCS Class II. Candesartan cilexetil (CC), an angiotensin II receptor blocker, suffers from dissolution-rate limited absorption, resulting in low and variable bioavailability. Formulation strategies such as solid dispersions, nanoparticles, and lipid-based carriers have been investigated to address this challenge. Among these, cyclodextrins (CDs) have gained prominence due to their ability to form inclusion complexes with hydrophobic drugs, improving solubility, stability, and bioavailability. β-Cyclodextrin (CAVAMAX® W7 Pharma) is a pharmaceutical-grade excipient with a larger cavity size, enabling effective encapsulation of bulky molecules like CC. This study explores the preparation, characterization, and evaluation of CC–β-CD inclusion complexes prepared by physical mixture, kneading, and solvent evaporation techniques. 2. Materials and Methods 2.1. Materials: Drug Candesartan cilexetil (gift sample from Hetero Pvt. ltd), β-Cyclodextrin (CAVAMAX® W7 Pharma, Aurobindo pharma) GSC Biological and Pharmaceutical Sciences, 2025, 33(02), 234-240 235 2.2. Methods 2.2.1. Phase-Solubility Studies Phase-solubility analysis was performed according to the Higuchi–Connors method to determine the complexation behavior between candesartan cilexetil (CC) and β-cyclodextrin (β-CD). Briefly, excess amounts of CC were added to aqueous β-CD solutions prepared at increasing concentrations ranging from 0 to 20 mM in three different buffer media (pH 1.2, 4.5, and 6.8). The samples were maintained under continuous shaking at controlled temperatures (25 ± 0.5 °C and 37 ± 0.5 °C) for 48 h to allow equilibration. Following incubation, the suspensions were filtered through a 0.22 µm membrane filter, and the filtrates were analyzed spectrophotometrically at λmax 255 nm to determine the dissolved drug concentration. The solubility data were plotted against β-CD concentration to construct phase-solubility diagrams, from which stability constants (Ks), complexation efficiency (CE), and Gibbs free energy changes (ΔGtr) were calculated. 2.2.2. Preparation of Inclusion Complexes Three different methods were employed to prepare inclusion complexes at drug-to-carrier molar ratios of 1:1, 1:2, and 1:3. In the Physical Mixture (PM) method, accurately weighed amounts of CC and β-CD were triturated together in a mortar and pestle until a homogeneous blend was obtained, which was then passed through a #60 mesh sieve. In the Kneading (KN) method, β-CD was moistened with a minimal volume of 50% v/v hydroalcoholic solvent to facilitate partial swelling, and CC was gradually incorporated with continuous kneading for about 45 minutes until a paste was formed. The mass was dried at a temperature not exceeding 40 °C, gently pulverized, and sieved. In the Solvent Evaporation (SE) method, CC was dissolved in ethanol and β-CD in distilled water; the solutions were combined under stirring to promote molecular interaction, followed by solvent removal under reduced pressure at 45 °C using a rotary evaporator. The solid residue was dried to constant weight, pulverized, and sieved to obtain a uniform powder. 2.2.3. Characterization The prepared complexes were characterized using Fourier-transform infrared spectroscopy (FTIR) to identify possible interactions between drug and carrier, powder X-ray diffraction (PXRD) to study crystallinity changes, and assay and content uniformity tests to confirm drug loading. 2.2.4. Dissolution Studies In-vitro dissolution testing was carried out using USP type II apparatus (paddle method) in 900 mL dissolution medium at pH 1.2 (simulated gastric fluid) and pH 6.8 (simulated intestinal fluid) maintained at 37 ± 0.5 °C, with a paddle rotation speed of 50 rpm. Aliquots were withdrawn at predetermined intervals up to 120 minutes, filtered, and analyzed spectrophotometrically at 255 nm. The percentage cumulative drug release was calculated and dissolution efficiency, t₅₀, and release kinetics were derived. 2.2.5. Accelerated Stability Studies The optimized batch was subjected to accelerated stability testing following ICH Q1A(R2) guidelines. Samples were stored in sealed containers at 40 °C ± 2 °C/75% RH ± 5% RH for a period of three months. At 0, 1, 2, and 3 months, samples were withdrawn and evaluated for appearance, assay (acceptance range 95–105%), dissolution profile (compared using similarity factor f₂), and PXRD to assess crystallinity changes. The formulation was considered stable if no significant changes were observed in physical attributes, assay, or dissolution profile, and if f₂ remained ≥ 50. 3. Results and Discussion 3.1. Analytical Method by UV-Visible spectroscopy The UV absorption spectrum of candesartan cilexetil was recorded by scanning a 10 µg/mL solution in methanol over the wavelength range of 200–400 nm using methanol as the blank. The spectrum displayed a distinct absorption maximum at 255 nm, which corresponds to the π→π* transitions of the aromatic and tetrazole chromophores present in the molecule. The calibration curve of candesartan cilexetil was constructed in the concentration range of 5–25 µg/mL using UV spectrophotometry at the predetermined λmax of 255 nm. The plot of absorbance versus concentration showed a straight-line relationship, confirming adherence to Beer–Lambert’s law within the studied range. GSC Biological and Pharmaceutical Sciences, 2025, 33(02), 234-240 236 3.2. Instrinsic solubility of Candesartan Cilexetil Figure 1 Intrinsic Solubility (S₀) of Candesartan Cilexetil (n = 3) The solubility of CC was found to be extremely low in water and acidic medium (pH 1.2), confirming its classification as a BCS Class II drug. Solubility improved moderately with an increase in pH (pH 4.5 and 6.8), indicating dissolution is favored under intestinal conditions. However, overall solubility remained in the µg/ml range, reinforcing the need for solubility enhancement strategies such as cyclodextrin complexation. 3.3. Apparent Solubility Table 1 Apparent solubility studies Formulation Code Method Ratio (Drug:Carrier, mol/mol) Solubility (mg/mL) ± SD F1 Physical Mixture 1:1 0.045 ± 0.003 F2 Physical Mixture 1:2 0.072 ± 0.004 F3 Physical Mixture 1:3 0.068 ± 0.005 F4 Kneading 1:1 0.058 ± 0.004 F5 Kneading 1:2 0.093 ± 0.006 F6 Kneading 1:3 0.089 ± 0.005 F7 Solvent Evaporation 1:1 0.066 ± 0.005 F8 Solvent Evaporation 1:2 0.112 ± 0.007 F9 Solvent Evaporation 1:3 0.107 ± 0.006 Pure CC Candesartan cilexetil - 0.028 ± 0.002 GSC Biological and Pharmaceutical Sciences, 2025, 33(02), 234-240 237 Figure 2 Apparent solubility of Candesartan Cyclodextrin complexes 3.4. Phase-Solubility Studies Table 2 Derived Phase-Solubility Parameters of CC–β-CD Complexes (n = 3) Condition (pH) Slope Ks (M⁻¹) CE ΔGtr (kJ/mol) R² pH 1.2 0.052 312 ± 18 0.055 –13.6 ± 0.4 0.996 pH 4.5 0.078 468 ± 25 0.085 –14.2 ± 0.3 0.997 pH 6.8 0.121 672 ± 33 0.126 –15.0 ± 0.5 0.998 Ks values increased with pH, showing stronger complexation at pH 6.8, which correlates with intestinal absorption conditions. CE values also rose with pH, supporting improved solubilization efficiency at higher pH. Negative ΔGtr values indicated that the solubilization process was spontaneous, with more negative values at pH 6.8 reflecting stronger complex formation. High regression coefficients (R² ≥ 0.996) confirmed excellent linearity of phase-solubility plots. 3.5. FTIR and PXRD The FTIR spectra of pure candesartan cilexetil exhibited characteristic absorption bands corresponding to its functional groups, including a strong carbonyl (C=O) stretching band near ~1720 cm⁻¹, aromatic C=C stretches around 1600 cm⁻¹, and tetrazole ring vibrations in the region of 1260–1340 cm⁻¹. These changes indicated hydrogen bonding and van der Waals interactions between CC and β-CD, confirming the formation of inclusion complexes. The PXRD diffractogram of pure candesartan cilexetil showed sharp and intense crystalline peaks at characteristic 2θ values (e.g., ~7°, 14°, 18°, and 23°), confirming its crystalline nature. The physical mixture displayed the major peaks of both CC and β-CD with only slight reduction in intensity, reflecting simple blending without significant structural changes 3.6. Dissolution Studies The dissolution profiles of candesartan cilexetil and its β-cyclodextrin complexes revealed clear differences in release behavior depending on the preparation method. Pure candesartan cilexetil exhibited slow and incomplete dissolution, with only about 52% drug release at 120 minutes, consistent with its poor aqueous solubility and BCS Class II classification. The physical mixture (F2) demonstrated moderate improvement, reaching approximately 78% release at 120 minutes, which may be attributed to enhanced wettability and increased surface contact with β-cyclodextrin, while the drug largely retained its crystalline nature. The kneaded complex (F5) showed a marked increase in dissolution, GSC Biological and Pharmaceutical Sciences, 2025, 33(02), 234-240 238 releasing nearly 96% of the drug within 120 minutes as a result of partial amorphization and stronger drug–carrier interactions achieved during the kneading process. The solvent-evaporated complex (F8) exhibited the most significant enhancement, with almost complete drug release (~99%) within 120 minutes, reflecting extensive amorphization and efficient inclusion complex formation. Overall, the dissolution trend followed the order F8 > F5 > F2 > Pure CC, confirming that solvent evaporation produced the most effective complex for improving solubility and dissolution of candesartan cilexetil. Figure 3 Dissolution profiles of Pure drug and Cyclodextrin complexes 3.7. Accelerated Stability The optimized formulation F8 (Solvent Evaporation complex) was subjected to accelerated stability testing at 40 °C / 75% RH for a period of 3 months in accordance with ICH guidelines. The results are summarized in Table 5.7. Throughout the study period, no visible changes in appearance (color, odor, or texture) were observed, confirming the absence of any macroscopic instability. The assay values remained within the acceptable range (96–101%), indicating no significant degradation of candesartan cilexetil during storage. Dissolution testing at 120 minutes showed minimal variation, with the formulation maintaining a consistent release profile (~98% drug release). The similarity factor (f₂) values comparing the initial dissolution profile with those at 1, 2, and 3 months were 76, 72, and 70, respectively—all greater than the acceptance threshold of 50, demonstrating that the dissolution profiles were statistically similar to the baseline. Taken together, these results confirm that F8 remained stable for at least 3 months under accelerated storage conditions, retaining its physicochemical integrity and in-vitro performance. This stability supports the robustness of the solvent evaporation method in producing a reliable inclusion complex of candesartan cilexetil with β-cyclodextrin. 4. Conclusion Complexation of candesartan cilexetil with β-cyclodextrin significantly improved its aqueous solubility and dissolution rate. Among the methods, solvent evaporation yielded the most effective formulation (F8), which exhibited enhanced performance and stability. This approach offers a simple, scalable, and robust formulation strategy to improve the biopharmaceutical profile and therapeutic efficacy of candesartan cilexetil. Compliance with ethical standards Disclosure of conflict of interest No conflict of interest to be disclosed. GSC Biological and Pharmaceutical Sciences, 2025, 33(02), 234-240 239 References [1] Hassan Ali, M., Al-Saidan, S., & Al-Shammary, F. (2015). Indicating dissolution specification for candesartan cilexetil tablets using a convolution model. Dissolution Technologies, 22(1), 34–40. https://dissolutiontech.com/DTresour/201502Articles/DT201502_A06.pdf [2] Figueroa-Campos, A., Meneses-Nava, M. A., Rivera-Zavala, J. 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