Development of Orally Disintegrating Tablets from Solid Dispersions Containing Tolvaptan/ Cyclodextrin Complexes

Abstract

Objectives: Tolvaptan is a compound that is practically insoluble in water and poorly soluble at physiological pH, and is used to treat low blood sodium levels in adults with conditions such as heart failure and certain hormonal imbalances. Increasing the water solubility and dissolution rate of tolvaptan could increase its bioavailability and, consequently, its efficacy. This study aimed to increase the efficiency of tolvaptan by enhancing its solubility and dissolution rate, and to develop a fast-acting dosage form that improves convenience for patients with swallowing difficulties.

Materials and Methods: Solid dispersion (SD) formulations were developed by the rotary evaporation method using hydrophilic polymers (polyvinylpyrrolidone and polyethylene oxide), solubility enhancers (Solutol HS-15 and Gelucire 44/14), and complexing agents (β-cyclodextrin and hydroxypropyl-β-cyclodextrin). Various characterization studies were performed on developed formulations, including solubility studies, X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy, and scanning electron microscopy analyses, in vitro dissolution tests, and release kinetics studies.

Results: The solubility of tolvaptan in the 2-hydroxypropyl-beta-cyclodextrin (HPβCD)-SD2 formulation containing 2-hydroxypropyl-β-cyclodextrin, was the highest at 0.2314 mg/mL, which was approximately 8.7 times that of pure tolvaptan. Based on the results, HPβCD was selected as the complexing agent as the optimal SD formulation. In the dissolution study, at least 90% of the tolvaptan in the HPβCD-SD2 formulation dissolved in all buffer solutions within 25 min. Orally disintegrating tablets (ODTs) were prepared using the HPβCD-SD2 formulation; formulation code 59, which had a friability of ≤1% and a disintegration time of ≤180 s, was selected as the final tablet.

Conclusion: A new SD formulation with increased solubility and dissolution rate compared with pure tolvaptan was developed. The developed ODTs may be an alternative to the current commercial product.

Introduction

Solid dispersion (SD) is an important formulation development strategy defined as the dispersion of one or more active substances in a solid, inert carrier or matrix prepared by solvent evaporation, melting, or solvent melting.1–3 In the solvent evaporation method, an SD is obtained after the solvent evaporates from the solution containing the drug and carrier; the resulting solid mass is then pulverized and milled.4,5 In this method, heat degradation of drugs or carriers can be prevented because organic solvents evaporate at low temperatures.5,6 Methods such as hot-plate heating, vacuum drying, rotary evaporation, spray drying, freeze drying, sprayfreeze drying, and ultra-fast freezing are used to remove the solvent quickly.7 The rotary evaporation method is a solvent evaporation technique that involves evaporating a dispersion or solution under vacuum in a rotating flask for a specified period, resulting in the formation of a solid film on the inner glass surface of the flask when it is heated. This method is rapid, relatively inexpensive, and readily available.

Cyclodextrins (CDs) can form inclusion complexes with active substances that have low solubility and dissolution rates, thereby improving their properties owing to their hydrophilic outer surfaces.8,9 In terms of formulation development, CDs offer advantages, such as reducing particle size to the molecular level, increasing wettability and porosity, and converting the drug’s crystalline state into an amorphous form.7,10,11 The aim of a study was to increase the oral bioavailability of sulfamethoxazole, which has low solubility and a low dissolution rate, by enhancing its solubility and dissolution rate. For this purpose, 2-hydroxypropyl-beta-cyclodextrin (HPβCD): sulfamethoxazole (1:1) complexes were prepared, and SDs were prepared using polyethylene glycol 20000 and polysorbate 20. The solubility of sulfamethoxazole was increased by forming complexes with CDs and by preparing SDs of these complexes.12

Although tablets are widely used today, many elderly individuals and children may have difficulty swallowing them. Orally disintegrating tablet (ODT) formulations are being developed for these patients. The Food and Drug Administration (FDA) defines an ODT as a solid dosage form that disperses rapidly, usually within a few seconds, when placed on the tongue, and contains a medicinal substance or an active ingredient.13 According to the European Pharmacopoeia, ODTs disperse in vitro in water within 3 min.14 ODTs have many advantages, such as applicability to patients who have difficulty swallowing or who refuse to swallow, rapid drug effects, no water requirement, improved stability, and increased bioavailability.15 In general, excipients such as fillers, superdisintegrants, glidant-lubricants, sweeteners, and salivary-stimulating agents are used in ODT formulations.16 In a study, orally disintegrating risperidone tablets were developed using SD and CD technologies. An SD of risperidone was prepared using methyl-CD; an increased dissolution rate was observed. They found that the disintegration time of SD ODTs containing risperidone prepared with Ac-Di-Sol and mannitol was 22.83 ± 3.66 s.17

Hyponatremia can occur frequently in older adults, especially in those who are hospitalized or living in long-term care facilities,18 as well as diarrhea that occurs in childhood.19 Tolvaptan, a vasopressin V2 receptor antagonist, is used to treat hyponatremia by increasing low blood sodium levels in adults with conditions such as heart failure and certain hormonal imbalances, and it plays a role in regulating renal fluid excretion.20,21 Tolvaptan is a BCS 4 drug that is practically insoluble in water, with low solubility at all pH values.22 It is important to improve its efficacy by enhancing the solubility and dissolution rate in water. In a study, SDs of tolvaptan were prepared by hot-melt extrusion and spray-drying techniques using hydrophilic polymers such as Soluplus, Kollidon VA64, and Kollidon 30. In the solubility study conducted in distilled water, the solubilities of pure tolvaptan, tolvaptan in SD prepared by spray drying, and tolvaptan in SD prepared by hotmelt extrusion were 0.04 ± 0.02, 0.32 ± 0.10, and 0.29 ± 0.05 mg/mL, respectively. In the in vitro dissolution test performed in distilled water containing 0.22% sodium lauryl sulfate (SLS), 39.60% of pure tolvaptan, 93.50% of tolvaptan in SDs obtained by hot-melt extrusion method, 91.40% of tolvaptan in SDs obtained by spray drying, and 94.20% of tolvaptan in the commercial product were released within 60 min.23 Inanother study, conventional ODTs containing pure tolvaptan and superdisintegrants were prepared by wet granulation. As a result of the study, the disintegration time ranged from 40 ± 0.01 to 105 ± 0.01 s, and friability ranged from 0.64 ± 0.02 to 0.86 ± 0.02%.24

It is important to increase the efficacy of tolvaptan in elderly and pediatric patients by enhancing its solubility and dissolution rate, and by improving patient compliance through reduction of side effects. Developing innovative dosage forms, such as ODTs rather than conventional solid dosage forms, increases patient compliance in older adults and pediatric patients. This study aimed to prepare CD-free and CD-containing SD formulations of tolvaptan using hydrophilic polymers and solubility enhancers by rotary evaporation, and to compare the solubility and dissolution rates of these formulations. After comparing the SD formulations for solubility and dissolution rate, the optimum formulation was prepared as an ODT using various excipients and rendered suitable for patient administration. To the best of our knowledge, no studies in the literature have reported formation of CD complexes with tolvaptan, preparation of SDs of these complexes, or development of ODT dosage forms.

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Materials

Tolvaptan was donated by Abdi İbrahim Pharmaceutical Company (Türkiye). Gelucire 44/14 was obtained from Gattefossé (France). HPβCD was provided by Roquette (France). βCD was purchased from Central Drug House (P) Ltd. (India). Polyvinylpyrrolidone (PVP) and Solutol HS-15 were acquired from BASF (Germany). SLS and methanol were purchased from Sigma-Aldrich (Germany).

KARA AA, TORT S, ACARTÜRK F. Development of Orally Disintegrating Tablets from Solid Dispersions Containing Tolvaptan/Cyclodextrin Complexes. Turk J Pharm Sci. 2026 Apr 15. doi: 10.4274/tjps.galenos.2026.20666. Epub ahead of print.

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