INTRODUCTION:

Although they are preferred, conventional dosage forms face significant challenges, such as low efficacy due to the low solubility of the molecules and bioavailability, rapid elimination, and systemic side effects¹. Drug developers consider the solubility of the class II category of the (BCS), as a significant challenge. These drugs typically exhibit low dissolution rates and poor oral bioavailability².

Self-micro/nano-emulsification systems, encapsulated nanoparticle systems, nanocrystal systems, and solid dispersion techniques such as spray drying, hot-melt extrusion, solvent evaporation, and melting are some of the strategies used to improve the bioavailability of these candidates^3,4.

Cocrystals are state-of-the-art approaches or polymorphic systems of different components in a system attached by hydrogen bonding in a stoichiometric pattern. Co-crystallization impacts the biopharmaceutic and biological properties of the drugs, such as solubility, bulk density, compressibility, and bioavailability⁵.

Nanocrystals, one of the traditional approaches in which nanosized particles exist in the system stabilized by surface stabilizers, significantly impact a drug candidate’s saturation solubility, dissolution rate, oral bioavailability, and therapeutic effect. However, this technique cannot substantially improve saturation solubility and cannot be applied to candidates where solubility-limited dissolution occurs. So, the current work combines nanonization and cocrystals for an improved therapeutic outcome^6,7.

Anticoagulant therapy using rivaroxaban, which is a direct, antithrombin-independent, orally active FXa inhibitor for deep vein thrombosis and pulmonary embolism, is widespread. In addition, its effect on acute coronary syndrome and thromboprophylaxis is well-recognized. Rivaroxaban inhibits free prothrombinase complex and clot-bound FXa⁷.

Rivaroxaban was classified as a BCS class II drug. Clinical studies suggest that the drug's Cmax and AUC are dose-proportional at lower doses, and from a dose of 10 mg and above, these parameters are dose-disproportional; the reason may be the solubility limited drug absorption process. The percentage of the initial dose that undergoes metabolism is up to 57%. Higher doses of anticoagulants can result in internal bleeding^8,9. Therefore, improving solubility reduces the dose, and presentation in film form is highly acceptable.

Oral disintegrating films or strips are water-soluble polymeric systems that can absorb water and hydrate, and undergo quick disintegration and dissolution in saliva. The high vascularity and highly permissible nature of the oral mucosa contribute to the bioavailability of these dosage forms.The enormous surface area contribution and ease of administration improve the onset of action, efficacy, and safety profile^10-12.

Therefore, this study is the first to address the poor water solubility of rivaroxaban by converting the drug into nanocrystals. This dosage form may reduce the dose and be present as an oral fast-dissolving film for effective delivery via the oral cavity.

MATERIALS AND METHODS:

Materials:

Rivaroxaban was provided by Symed Labs (Hyderabad). Gallic acid was procured from SD Fine Chemicals, Mumbai. This study involved all analytical-grade agents (chemicals and solvents).

Compatibility studies by attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR):

A Bruker alpha instrument operated at 250C±0.50C. A zinc selenoid crystal plate screwed into the anvil was used to place the sample. The scanning range was 4000-400 cm^-1.¹³

Saturation solubility studies:

A saturated drug solution was prepared in 10ml of water, 6.8 pH buffer, and hydrochloric acid (0.1N), and shaken for 24 h in a mechanical shaker. After filtration and suitable dilution, the concentration was determined spectroscopically^14,15.

Preparation of Rivaroxaban nano co-crystals:

An anti-solvent addition method was used for preparing cocrystals with the help of the co-former gallic acid, as given in (Figure 1)¹⁴.

Figure 1. Preparation of Rivaroxaban nano co-crystals

Optimization of the formulations:

A JMP software-assisted custom design approach led to optimization of the formulation. The co-former, stabilizer, and stirring time were selected as factors, and the solubility and dissolution rate were selected as responses (Table 1); the runs are given in (Table 2)^15,16.

Table 1. Factors levels

Factors	Upper limit	Lower limit
Amount of co-former (mg)	1000	125
Amount of stabilizer (ml)	5	0.5
Stirring time (h)	5	1

Table 2. Formulation Table for Nano co-crystals of Rivaroxaban via Custom design approach

Sl. No	Amount of co-former (mg)	Amount of stabilizer (ml)	Stirring time (h)
1	1000	0.05	1
2	125	2	1
3	125	0.05	5
4	562.5	1.025	3
5	125	2	5
6	1000	2	5
7	562.5	1.025	3
8	1000	2	5
9	125	0.05	5
10	1000	2	1
11	125	2	1
12	1000	0.05	5

Evaluation of Nano co-crystals:

Saturation solubility studies:

Solubility was determined by preparing a saturated solution of nano-co-crystals in 10ml of water, 6.8 pH buffer, and hydrochloric acid (0.1N) under mechanical shaking for 24h; the sample was filtered. A filtrate volume of 1ml was diluted to 10ml in a volumetric flask. Drug concentration was determined using a Shimadzu UV spectrometer at an observed λ max¹⁷.

Drug content determination:

Accurately, 50mg of the cocrystal was weighed into a 10 ml volumetric flask, diluted with methanol to obtain Beer’s concentration range, and analyzed using a UV spectrophotometer. The drug concentration was determined accordingly¹⁸.

In vitro drug release study:

Drug release from cocrystals was carried out at a pH of 6.8 in phosphate buffer under stirring at 50rpm after withdrawing the samples at 10, 30, 45, 60, and 120-min intervals. After suitable dilution, drug concentration was determined by UV spectroscopy¹⁹.

Evaluation of the experimental trials and selection and Evaluation of the optimized formulation:

The optimal formula was determined by analyzing the outcomes following the model's adjustment using the desirability function.

Surface electron microscopy (SEM):

A model (JSM-7500F, JEOL Ltd., Japan) was used to capture the surface photographs. The procedure was performed after gold coating of the samples and vacuum drying. An acceleration voltage of 10.0 kV was used in this study²⁰.

X-ray diffraction (XRD):

The diffraction profiles for the drug and F6 formulation were obtained at ambient temperature using a Bruker D8 Advance model equipped with Ni-filtered Cu Kα radiation (wavelength 1.540 Å). Scanning was conducted within the 2θ- to 2o- to 80^o21,22.

Particle size analysis:

The Horiba SZ-100 nanoparticle dynamic light scattering system operates on the dynamic light scattering (DLS) technique used in this study. After dilution with water, measurements were carried out at a suitable scattering angle of 90° and a temperature of 25.2°C^23,24.

Differential scanning calorimetry (DSC):

Approximately 5mg of the pure drug, physical mixture, and formulation were weighed into non-aluminum pans that were non-hermetically sealed and crimped. Thermograms recorded at 0°C to 200°C at a rate of 10°C/min, and nitrogen was continuously purged at a flow rate of 40ml/min in a Shimadzu DSC-60 Japan instrument^25,26.

Preparation of Rivaroxaban nano co-crystals based ODF:

Table 3. Formula for Method of preparation of ODF

S. No	Excipients	Qty taken
1	Nano co-crystal	4 mg drug equivalent
2	HPMC	2% w/v
3	PEG-400	0.5 ml
4	Sodium Starch Glycolate	30 mg
5	Citric acid	30mg
6	Mannitol	20mg
7	Peppermint oil	2 drops
8	Water	Q. S

Figure 2. Preparation of nano cocrystal ODF using solvent casting method

The formula and method of film preparation are given in (Table 3) and (Figure 2). depicts the method of preparation²⁷

Evaluation of Rivaroxaban ODFs:

Drug content, Film thickness, Folding endurance:

Rivaroxaban was extracted from different locations and dissolved in methanol. After filtration, a suitable dilution drug concentration was determined using triplicate spectroscopic method¹⁹. Film thickness and content uniformity are directly related. Using a micrometre screw gauge at different strategic locations throughout the patch, the thickness of the film was²⁰. Folding endurance was obtained by repeated folding of the strip at the same place until the strip broke, indicating the flexible nature^30,31

Disintegration time:

Each patch area of 6.2 cm² contains 4mg of the drug was placed in 10ml of phosphate buffer (pH 6.8) on a petri plate. The time required for complete solution formation was noted to be down³²

In vitro dissolution study:

The release study used a USP type II apparatus with 900 ml phosphate buffer pH 6.8 as the dissolution medium, which was maintained at 37±0.5°C at an RPM of 50. After introducing the pure drug and ODF of the optimized formula, samples were obtained at 10, 30, 45, 60, and 120-min samples were obtained by maintaining an equal buffer volume to maintain the concentration gradient. The samples were subsequently filtered and analyzed at the observed λmax via spectrophotometry to determine the drug concentration³³.

Stability studies:

Stability studies of the film formulation were carried out at 40O C± 2 ± 75± 5% and 25o C± 2± 65± 5% relative humidity for one month. The drug content and physical properties were observed at the end of the storage period³⁴.

RESULTS AND DISCUSSION:

Pre-formulation studies:

Compatibility studies by FTIR:

The IR spectra of rivaroxaban and its physical mixture are shown in (Figure 3). The peaks were observed in the stretching range of 3350 to 3310 for -N-H- stretching, 1900 to 1600 for C=O bending, 850 to 550 for -C-Cl- stretching, 1600-1650 for Aro C=C stretching, 1650-1700 for Aro C-C stretching, 2580-3300 for C-H stretching, 750-685 for C-S stretching, 1400-1350 for OH bending group. Observing drug-like peaks in the physical mix and formulation ensured the safety of the components in the film.

Figure 3. FTIR Spectrum of a) Rivaroxaban b) Physical mixture of Rivaroxaban and Excipients c) Film

Saturation solubility and release of drug from cocrystals:

The pure drug in water, PBS 6.8 and 0.1 N HCl, had saturation solubilities of 0.069±0.00027, 0.135±0.00026 and 0.089±0.00015mg/ml, respectively. The cocrystals obtained as per the experimental trials were evaluated for both responses, such as solubility and in vitro drug release; the results are shown in (Table 4) and Fig 9—the % CDR of 30±0.14 to 77.1.1±0.015 at 10min. 49.4±0.18 to 99±0.25% at 60 min was observed. USP standards specify solubility criteria as very soluble (<1:1 part of solute: solvent to >1:10,000 solvent: solute as insoluble). The solubility of the cocrystals ranged from 0.151mg/ml to 1.83mg/ml, which shows a two-fold increase to a twenty-six-fold increase in solubility compared to the Rivaroxaban. The ability of the cocrystal to change the crystal packing, thereby reducing the lattice energy, may be one of the reasons for the hydrophilic nature of gallic acid and consequent changes in solvation barrier reduction correlated with the dissolution rate of the cocrystal. The improved cocrystal solubility compared with rivaroxaban is attributed to the hydrophilic nature of gallic acid and its hydrogen bonding capacity. Moreover, in a crystallized form, there is no covalent interaction, and an ionic bond exists between the drug and the coformer. This solubility enhancement led to an increased dissolution rate of the cocrystals compared to that of the pure drugs. (Figure 4).

Table 4. Solubility Studies of Rivaroxaban Nano co-crystals in PBS pH 6.8.

Sl. No	Formulation	Solubility mg/ml
1	F1	0.443
2	F2	0.151
3	F3	0.149
4	F4	1.166
5	F5	0.683
6	F6	0.437
7	F7	0.158
8	F8	0.443
9	F9	0.182
10	F10	1.504
11	F11	0.269
12	F12	1.830

Figure 4. In vitro drug release from nano co-crystal formulations (F1-F12)

Experimental runs and optimum formula selection:

The significance of the factors on the responses at a level (p< 0.05) using ANOVA was evaluated. The effect of each factor on the reactions, such as the solubility and dissolution rate, was studied. (Figure 5) Both the quantity of both coformers and stabilizers greatly influenced the responses. However, stirring time was found to be the least influential factor. The desirability function addresses multiple responses simultaneously, providing the best solution. The desirability was found to be 0.97 when the gallic acid concentration was 1000 mg, with a stabilizer of 2ml and a stirring time of 5h, which assisted in choosing the optimum formula. The predicted responses were a solubility of 1.61mg/ml and a release of 90% of the drug in 2h. (Figure 6).

Surface morphology:

Irregular crystal morphology and uniformly scattered particles were observed using surface electron microscopy (Figure 7). The uniformity in size may account for the selection of the coformer and the methodology chosen for preparing the cocrystals in the study.

Figure 7. SEM of optimum formula of co crystals

Particle size analysis:

The particle size distribution via the dynamic light scattering technique was 50 nm to 200nm. The poly dispersibility index of all the formulations was less than 0.522. The influence of the formulation variables and processing conditions was suitable for obtaining nanosized particles, as evidenced by the poly dispersibility index. A low polydispersity value indicates minimum aggregation of nanoparticles and their consistency and efficiency. Particle size analysis data and graphs are shown in (Figure 8).

Figure 8: Particle size of the optimum formula

Powder X-ray diffraction Method (PXRD):

The PXRD patterns (Figure 9) showed sharp and prominent peaks, confirming the crystalline nature of rivaroxaban. Meanwhile, in the optimum formula, the intensity and number of peaks were substantially lower than those of the pure drugs, indicating the reduced crystallinity of the formulation when converted into cocrystals.

Figure 9. PXRD of a) pure drug, b) Optimum formulation

Differential Scanning Colorimetry (DSC):

A sharp endothermic peak of rivaroxaban was observed at 232.66°C with an onset peak at 230.33°C and ended at 239.78°C, corresponding to the melting point of rivaroxaban. In the physical mixture, two endotherms were observed: one corresponded to gallic acid at 188.83°C with an onset peak at 186.66°C corresponding to the melting point of the former and the other peak at 221.8° for rivaroxaban. In addition, an additional endotherm may represent the flash temperature of Tween 80 used in the formulation. In optimum formulations, only one endotherm observed at 228°C corresponded to the drug in the cocrystal form. Therefore, the study shown in (Figure 10) confirms the changes in the crystalline nature of rivaroxaban when presented in the cocrystal form.

Figure 10. DSC Thermogram of A) pure drug B) formulation

Evaluation of Rivaroxaban ODFs:

Physical Evaluation:

In films, drugs may be present in either dissolved or dispersed forms. The drug content uniformity of the oral film formulation of rivaroxaban was estimated to be above 94.85±1.55% for the oral film formulation. The thickness provides proper disintegration and drug release in oral film formulations. The thickness of the rivaroxaban film formulations was 12±1.3mm. A folding endurance of 85±1.25 folds for the oral film formulation proves its pliable nature— a disintegration time of 47±0.5 S, USP standards of less than 30 seconds.

In vitro drug release profile:

Drug release from rivaroxaban was compared against an oral film made of pure drug and an oral film made by the addition of nanocrystals. There was a significant improvement in the dissolution rates compared to the pure drug in the oral film formulation. The %CDR in the final film formulation was 60.62±0.25 at 10 mins and 98.1±0.25 at 60min (Figure 11).

Figure 11. In vitro drug release profile of ODF, optimum cocrystal formulations and Rivaroxaban

Stability studies:

The stability study for 30 days under the conditions mentioned above indicated a slight reduction in the drug content and slight opacity in the film appearance under accelerated storage conditions, as shown in (Table 5).

Table 5. Stability study data

Parameters		40^OC±2/75±5% RH	2525^OC±2±65±5% RH
	0 days	30 days
Physical evaluation	Clear, Transparent film	Slightly opaque	Slightly opaque
Drug content (%)	94.85±1.25	94.20± 1.80	94.75±1.80

CONCLUSION:

In this study, rivaroxaban co-crystals were successfully prepared and characterized. The high dissolution rate and solubility of the prepared formulation suggested the possibility of reducing the dose and feasibility of converting the same into an orodispersible film. A comparative dissolution profile of pure drug against nanocrystals and the films of the nanocrystals showed a fourfold increase in release rates for both formulations compared to the pure drug. The study findings suggest that combining nanocrystals of poorly soluble drugs with orodispersible films is a promising approach to improve the bioavailability and therapeutic potential of this class of drugs.

ACKNOWLEDGEMENTS:

We thank our institution for the facility in carrying out the research work.

CONFLICT OF INTEREST:

Nil.

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Received on 08.10.2024 Revised on 05.04.2025

Accepted on 13.07.2025 Published on 01.12.2025

Available online from December 06, 2025

Research J. Pharmacy and Technology. 2025;18(12):5785-5792.

DOI: 10.52711/0974-360X.2025.00834

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