The development of an innovative method to improve the dissolution performance of rivaroxaban

Introduction

Recently, the pharmaceutical industry has faced significant challenges in formulating drugs with poor aqueous solubility, such as rivaroxaban (RIV), a potent anticoagulant. Despite their therapeutic potential, these drugs often exhibit limited bioavailability due to their low solubility, which can lead to suboptimal therapeutic outcomes. Cyclodextrins, particularly hydroxypropyl-β-cyclodextrin (HPβCD), have emerged as promising excipients for enhancing the solubility and bioavailability of poorly soluble drugs by forming inclusion complexes. The preparation and characterization of these inclusion complexes are crucial for optimizing their performance and application. Several studies have investigated the preparation of cyclodextrin-based inclusion complexes to improve the solubility of guest molecules [1, 2, 3, 4, 5]. The inclusion of different active pharmaceutical ingredients (API) in the cavity of various cyclodextrins (CDs) has been an important topic for many studies aimed at increasing the solubility, bioavailability, stability, or other disadvantages of the drugs [6, 7, 8, 9, 10, 11]. Still, despite numerous data collected in the literature, there are not yet many commercial products based on cyclodextrins inclusion complexes available in the pharmaceutical market. Several reasons stand between the research findings and the pharmaceutical industry production.

Several studies have demonstrated the efficacy of cyclodextrin-based inclusion complexes in improving the solubility and dissolution rates of various drugs. For instance, in a study by Gu and Liu [12], the inclusion of hydroxypropyl-β-cyclodextrin (HPβCD) significantly enhanced the solubility of a hydrophobic compound, thereby improving its bioavailability. Similarly, Lincón-López et al. [13] highlighted the potential of cyclodextrins in pharmaceutical applications, emphasizing their ability to enhance the solubility and stability of drug molecules. Cyclodextrins offer unique molecular structures with hydrophilic exteriors and lipophilic interiors. Many molecules can penetrate the cavity CD to form an inclusion compound. These molecules must meet an important condition, called full or partial conformability to the CD cavity [14, 15, 16]. β–CDs are most suitable for pharmaceutical technology because the size of their cavity allows the entrapment of drug molecules. α – CD is generally too small for this purpose, and γ – CD, which is actually a byproduct of the enzymatic degradation of β – CD, is too large [17, 18]. The special configuration of CDs gives them the property of being able to trap hydrophobic molecules or the apolar part of amphiphilic molecules in their cavity [19]. Since all APIs have well-established therapeutic dosages that cannot be changed, when incorporating them into the CDs cavity, the complexation phenomenon must take place at minimum molar ratios between API and CD. Taking into account that CDs have a much higher molecular mass than APIs, they become part of the binary system in a larger amount, meaning a greater amount of material must be included in a pharmaceutical form. The inclusion complex turns into the new active ingredient of the product and other excipients must be added to obtain a suitable pharmaceutical system that can be administered to humans. Unfortunately, at low molar ratios (API:CD) the API incorporation is not complete, but usually only partial complexation is achieved. Most of the data demonstrate that increasing the amount of CD in the complex leads to better inclusion [20, 21, 22], but the complex cannot be able to be included in a proper drug, especially an oral solid dosage form. Even if a convenient complexation degree in a low molar ratio is achieved, by using modern technologies such as freeze-drying [23], other disadvantages are encountered. Cyclodextrins are hygroscopic and can easily absorb moisture when exposed to humidity [24]. Therefore, regardless of the method used to prepare the complex, it has a certain water content, which is an important factor in the mechanical properties of materials and in obtaining samples with a specific concentration [25].

Also, all CDs and solid-state inclusion complexes (IC) have very poor flowability, probably due to the enclosed moisture [26, 27, 28, 29, 30, 31], which always affects the flow properties of the compression materials and requires either large quantities of fillers and lubricants in the formulation, either the use of advanced excipients which are very expensive or the application of complicated technologies. However, while cyclodextrins offer promising solubility enhancement properties, the integration of inclusion complexes into solid dosage forms remains a challenge. Traditional methods, such as direct compression or wet granulation, may compromise the stability or bioavailability of the drug, limiting its efficacy in achieving optimal dissolution rates. Additionally, the hydrophobic nature of many drugs poses difficulties in achieving uniform dispersion within solid dosage forms. Considering the above drawbacks, the present study aimed to develop a new method that can solve the current problems of pharmaceutical technology and bridge the gap between science and the drug industry regarding the use of CDs in oral solid dosage forms. Our study aims to address this gap by investigating the potential of liquid-state inclusion complexes to enhance API entrapment and formulation characteristics. Specifically, we seek to develop liquid-state inclusion complexes of rivaroxaban (RIV) with hydroxypropyl-β-cyclodextrin (HPβCD) and assess their suitability for oral solid dosage forms.
Rivaroxaban (Figure 1a), a hydrophobic compound with limited aqueous solubility, possesses functional groups such as aromatic rings and carbonyl groups, which contribute to its hydrophobicity and propensity for interactions with other molecules [32]. HPβCD (Figure 1b), on the other hand, is a hydrophilic derivative of cyclodextrin characterized by its hydroxyalkyl substituents, which impart water solubility and facilitate interactions with hydrophobic guest molecules [33].

The structural compatibility between rivaroxaban and HPβCD arises from the complementarity of their molecular structures. The hydrophobic regions of rivaroxaban align with the hydrophobic cavity of HPβCD, allowing for favorable interactions such as van der Waals forces and π-π stacking interactions [34]. Additionally, the hydrophilic exterior of HPβCD promotes aqueous solubility and stabilizes the resulting inclusion complex in solution [35]. Hydrophobic interactions play a crucial role in facilitating the encapsulation of rivaroxaban within the cavity of HPβCD. As rivaroxaban molecules diffuse into the aqueous solution containing HPβCD, they are encapsulated within the hydrophobic cavity through hydrophobic interactions between their hydrophobic moieties and the inner wall of HPβCD. This encapsulation process is driven by the hydrophobic effect, wherein the hydrophobic molecules seek to minimize their exposure to the surrounding aqueous environment by associating with other hydrophobic surfaces [36]. The above-mentioned discussion highlights the structural and molecular basis for the inclusion of rivaroxaban within HPβCD and provides insights into the mechanisms governing inclusion complex formation.
In the proposed method a liquid-state IC, which is intended to have a better entrapment of the API [37, 38], is sprayed onto the surface of cellulose pellets, which are then encapsulated in hard gelatin capsules for oral administration. The selected active ingredient was rivaroxaban (RIV) because it has low water solubility, and is included in class II by the Biopharmaceutics Classification System (BCS), meaning its dissolution is the rate-limiting step for absorption [39].
Rivaroxaban, a nonionizable neutral molecule, exhibits consistent solubility across different pH levels. Experimental measurements at 298.15 K have determined its mole fraction solubility in water to be approximately 2.89 × 10⁻⁷ [40], while solubility tests in distilled water have yielded a similar value of 3.02 × 10⁻⁷ [41]. Khan et al. determined a 5.11 μg/mL solubility in distilled water of RIV. When it was prepared with β-cyclodextrin (βCD) at a molar ratio of 1:2 using the kneading method, the solubility of RIV increased significantly to 42.21 μg/mL, which is 8.26 times higher than that of the pure drug. Additionally, using Soluplus and the solvent evaporation method, the solubility of RIV was dramatically enhanced to 281.27 μg/mL [42]. Also, RIV, a potent anticoagulant substance, was found to have a food-dependent release profile [43]. To increase RIV aqueous solubility and avoid the use of surfactants such as sodium lauryl sulfate in the dosage formulation, it was incorporated in an IC with hydroxypropyl-beta-cyclodextrin (HPβCD), at a minimal molar ratio of 1:1. HPβCD is a synthetic hydroxyalkyl derivative that possesses a very good solubility in water (45% m/V), due to the presence of hydrophilic alcohol groups [44].

HPβCD is also well tolerated, being suitable for oral administration [45]. The novelty of our approach lies in leveraging liquid-state inclusion complexes as a means to overcome existing challenges in pharmaceutical technology. By encapsulating rivaroxaban within HPβCD at minimal molar ratios, we aim to enhance its solubility without the need for surfactants. Additionally, to increase the viscosity of the coating dispersion, hydroxypropyl cellulose (HPC) was used at a concentration of 2%. HPC, a cellulose derivative with film-forming properties, acts as a binder and helps to form a protective polymeric film around the cellulose pellets [46]. Although both HPC and HPMC were considered because both are valuable cellulose derivatives in pharmaceutical formulations and offer film-forming properties, binding capabilities, and solubility-promoting characteristics, the choice between them depended on the specific requirements of the formulation, such as solubility requirements, temperature sensitivity, and desired viscosity [47, 48], among other factors. One of the main reasons for choosing HPC in the studied formulation is its remarkable solubility in the solvent. HPC dissolves readily in various solvents, allowing efficient formulation preparation. In addition, the solubility-enhancing properties of HPC are of great importance, as they ensure that the API is evenly dispersed throughout the formulation. This improved solubility is crucial to achieve the desired therapeutic effect and consistency of the final product.

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Materials

Micronized RIV (form I) manufactured by Neuland Laboratories Limited was donated by Labormed-Pharma SA, HPβCD was purchased from Global Holding Group Co., Ltd., (Ningbo, China) and HPC from Sigma-Aldrich Chemie GmbH, Germany. Microcrystalline cellulose spheres (Cellets® 780) manufactured by IPC – International Process Center GmbH & Co. KG, Germany, were donated by Harke Romania SCS. All used chemicals and solvents were of analytical reagent grade. A Mettler Toledo AT261 balance (with 0.01 mg sensitivity) was used for weighing the samples.

Emma Adriana Ozon, Erand Mati, Oana Karampelas, Valentina Anuta, Iulian Sarbu, Adina Magdalena Musuc, Raul-Augustin Mitran, Daniela C. Culita, Irina Atkinson, Mihai Anastasescu, Dumitru Lupuliasa, Mirela Adriana Mitu, Received Date: 5 March 2024, © 2024 Published by Elsevier Ltd., The development of an innovative method to improve the dissolution performance of rivaroxaban, HELIYON, https://doi.org/10.1016/j.heliyon.2024.e33162.

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