Assessment of Dose Proportionality of Rivaroxaban Nanocrystals

Demir, Huriye; Gülsün, Tuğba; Ozkan, Melike Hacer; Nemutlu, Emirhan; Şahin, Selma; Öner, Levent

doi:10.1208/s12249-020-01776-z

Cited by 5 publications

(6 citation statements)

References 42 publications

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“…RXB powder ( Figure 4 A,B) has a smooth surface with a rectangular and irregular crystalline shape [ 25 ]. However, the solid dispersions did not contain any RXB crystals except large particles, suggesting that the drug and polymer were homogeneously combined in the solid dispersions ( Figure 4 C–F) [ 28 ]. PVA-based solid dispersions ( Figure 4 C,D) appeared as irregular and flaky particles with a low polymer ratio, whereas the gelatin-based solid dispersions ( Figure 4 E,F) were spherical with a smooth surface.…”

Section: Resultsmentioning

confidence: 99%

“…DSC was used to verify the thermal behavior of drugs in the formulation ( Figure 6 ). The DSC curve of RXB powder (a) and physical mixtures (b, d) showed a sharp single endothermic peak appeared at about 228 °C, which corresponds to the melting point of RXB indicative of crystalline properties [ 28 ]. However, in the PVA-based and gelatin-based solid dispersions (c, e), the sharp characteristic peak corresponding to the melting point of the drug disappeared and the peak was not observed, indicating that the drug existed in an amorphous form [ 27 ].…”

Section: Resultsmentioning

confidence: 99%

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Effects of Polymers on the Drug Solubility and Dissolution Enhancement of Poorly Water-Soluble Rivaroxaban

Choi

Woo

Choi

et al. 2022

IJMS

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The purpose of this study was to investigate the efficacy of hydrophilic polymers in a solid dispersion formulation in improving the solubility and dissolution rate of rivaroxaban (RXB), a poorly soluble drug. The developed solid dispersion consisted of two components, a drug and a polymer, and the drug was dispersed as amorphous particles in a polymer matrix using the spray drying method. Polymeric solid dispersions were evaluated using solubility tests, in vitro dissolution tests, powder X-ray diffraction, differential scanning calorimetry, scanning electron microscopy, and particle size distribution analysis. To maximize physical stability against crystallization and improve the solubility and dissolution of RXB, it is important to select the appropriate polymer type and the optimal ratio of the polymer to the drug. The optimized polyvinyl alcohol (PVA)-based (1/0.5, w/w) and gelatin-based (1/5, w/w) solid dispersion formulations showed 6.3 and 3.6 times higher drug solubilities than pure RXB powder, respectively, and the final dissolution rate was improved by approximately 1.5 times. Scanning electron microscopy and particle size distribution analyses confirmed that the gelatin-based solid dispersion was smaller and more spherical than the PVA-based solid dispersion, suggesting that the gelatin-based solid dispersion had a faster initial dissolution rate. Differential scanning calorimetry and powder X-ray diffraction analyses confirmed that RXB had successfully changed from a crystalline form to an amorphous form, contributing to the improvement in its solubility and dissolution rate. This study provides a strategy for selecting suitable polymers for the development of amorphous polymer solid dispersions that can overcome precipitation during dissolution and stabilization of the amorphous state. In addition, the selected polymer solid dispersion improved the drug solubility and dissolution rate of RXB, a poorly soluble drug, and may be used as a promising drug delivery system.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Effects of Polymers on the Drug Solubility and Dissolution Enhancement of Poorly Water-Soluble Rivaroxaban

Choi

Woo

Choi

et al. 2022

IJMS

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“…In general, methods for obtaining nanocrystals can be divided into two groups: topdown methods and bottom-up methods. The first group includes grinding (dry and wet) and homogenization under high pressure, based on the principle of applying mechanical energy to break large crystals into smaller fragments [14][15][16][17]. As a rule, the resulting particles have an irregular shape, and the method itself has limitations on the size of the particles obtained, beyond which further grinding is impossible.…”

Section: Introductionmentioning

confidence: 99%

Modeling of the Aqueous Solubility of N-butyl-N-methyl-1-phenylpyrrolo[1,2-a] pyrazine-3-carboxamide: From Micronization to Creation of Amorphous–Crystalline Composites with a Polymer

Markeev,

Tishkov,

Vorobei

et al. 2023

Polymers

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N-butyl-N-methyl-1-phenylpyrrole[1,2-a] pyrazine-3-carboxamide (GML-3) is a potential candidate for combination drug therapy due to its anxiolytic and antidepressant activity. The anxiolytic activity of GML-3 is comparable to diazepam. The antidepressant activity of GML-3 is comparable to amitriptyline. GML-3 is an 18 kDa mitochondrial translocator protein (TSPO) ligand and is devoid of most of the side effects of diazepam, which makes the research on the creation of drugs based on it promising. However, its low water solubility and tendency to agglomerate prevented its release. This research aimed to study the effect of dry grinding, the rapid expansion of a supercritical solution (RESS), and the eutectic mixture (composite) of GML-3 with polyvinylpyrrolidone (PVP) on the particle size, dissolution rate, and lattice retention of GML-3. The use of supercritical CO2 in the RESS method was promising in terms of particle size reduction, resulting in a reduction in the particle size of GML-3 to 20–40 nm with a 430-fold increase in dissolution rate. However, in addition to particle size reduction after RESS, GML-3 began to show signs of a polymorphism phenomenon, which was also studied in this article. It was found that coarse grinding reduced particle size by a factor of 2 but did not significantly affect solubility or crystal structure. Co-milling with the polymer made it possible to level the effect of the appearance of a residual electrostatic charge on the particles, as in the case of grinding, and the increased solubility in the resulting mechanical mixtures of GML-3 with the polymer may also indicate the dissolving properties of polymers (an increase in 400–800 times). The best result in terms of GML-3 solubility was demonstrated by the resulting GML-3:PVP composite at a ratio of 1:4, which made it possible to achieve a solubility of about 80% active pharmaceutical ingredient (API) within an hour with an increase in the dissolution rate by 1600 times. Thus, the creation of composites is the most effective method for improving the solubility of GML-3, superior to micronization.

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“…However, RIV is an un-ionized neutral molecule with low and pH-independent solubility. It suffers from poor oral bioavailability, as low as 60% at the 20 mg dose under fasting conditions ( Bae et al, 2019 ; Demir et al, 2020 ; Takács-Novák et al, 2013 ; Xue et al, 2018 ). The bioavailability of RIV is dose-dependent (100% for 5 mg dosage, 90% for 10 mg dosage, and 60% for 20 mg dosage) ( Demir et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…It suffers from poor oral bioavailability, as low as 60% at the 20 mg dose under fasting conditions ( Bae et al, 2019 ; Demir et al, 2020 ; Takács-Novák et al, 2013 ; Xue et al, 2018 ). The bioavailability of RIV is dose-dependent (100% for 5 mg dosage, 90% for 10 mg dosage, and 60% for 20 mg dosage) ( Demir et al, 2020 ). This low bioavailability due to low solubility leads to problems such as increased variations between fasting and fed conditions, delayed effect, and failure to achieve dose proportionality.…”

Section: Introductionmentioning

confidence: 99%

Preparation, characterization, and pharmacokinetics of rivaroxaban cocrystals with enhanced in vitro and in vivo properties in beagle dogs

Meng¹,

Tan²,

Yao³

et al. 2022

International Journal of Pharmaceutics: X

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Assessment of Dose Proportionality of Rivaroxaban Nanocrystals

Cited by 5 publications

References 42 publications

Effects of Polymers on the Drug Solubility and Dissolution Enhancement of Poorly Water-Soluble Rivaroxaban

Effects of Polymers on the Drug Solubility and Dissolution Enhancement of Poorly Water-Soluble Rivaroxaban

Modeling of the Aqueous Solubility of N-butyl-N-methyl-1-phenylpyrrolo[1,2-a] pyrazine-3-carboxamide: From Micronization to Creation of Amorphous–Crystalline Composites with a Polymer

Preparation, characterization, and pharmacokinetics of rivaroxaban cocrystals with enhanced in vitro and in vivo properties in beagle dogs

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