To Formulate and Evaluate of Rivaroxaban Immediate Release Tablets Using Super Disintegrants and Surfactant

Drug delivery system (DDS) is a strategic tool for expanding markets, extending product life cycles and generating opportunities. Tablet is a solid pharmaceutical dosage form containing drug substances with or without suitable diluent and prepared by compression or molding method. Rivaroxaban is anticoagulant. It inhibits the blood coagulation. It is used to treat and prevent deep vein thrombosis (DVT), which can lead to blood clots in the lungs (pulmonary embolism). Rivaroxaban is a direct factor Xa inhibitor. It works by blocking the process of formation of blood clots2.

1.1 Oral Drug Delivery3

The oral route is one of the most desirable routes for the systemic drug delivery due to its ease of ingestion, simple, safest, convenient, non-invasive, versatility and most importantly, patient compliance. Solid oral delivery systems are cheaply manufactured because they don’t require sterile conditions. Although, increased focus and interest generated in the area of controlled release and targeted drug delivery system in recent years, tablet dosage forms that are intended to be swallowed whole, disintegrate, and release their medicament fast and furiously in the gastrointestinal tract4.

1.2 Tablets5

Tablets is a solid preparation which contains a single dose of one or more active ingredients and obtained by compressing uniform volumes of particles. Some are dissolved or dispersed in water before being administered and some are retained in the mouth, where the active ingredient “liberated”5. Tablets remain popular as a dosage form because of the advantages like afforded both to the manufacturer (e.g., simplicity and economy of preparation, stability and convenience in packing, shipping and dispensing) and the patient (e.g., accuracy of dosage, compactness, portability, blandness of taste and ease of administration)6. Tablets may differ greatly in size and weight depending on the amount of drug substance present and the intended method of administration. Although tablets are more frequently discoid in shape, they also may be round, oval, oblong, cylindrical or triangular. They may have lines or break-marks and may bear a symbol or other markings. Tablets may be coated or non-coated7.

1.2.1 Mechanism of Tablet Disintegration8,9:

The mechanism by which the tablets are broken into small pieces and then produce a homogeneous suspension is based on the following steps: -

Figure 1: Mechanism of Tablet Disintegration

1.2.2 Super Disintegrants in Immediate Release Tablets10,11

A disintegrant is an excipient which is added to a tablet or capsule blend to aid in the breakup of the compacted mass when it is put into a fluid environment. This is especially important for immediate release products where rapid release of drug substance is required.

2. Drug Profile and Excipient Profile

2.1 Drug Profile

Rivaroxaban

Rivaroxaban is an anticoagulant and the first orally active direct factor Xa inhibitor. Unlike warfarin, routine lab monitoring is not necessary. However, there is no antidote available in the event of a major bleed. Only the 10 mg tablet can be taken without regard to food. The 15 mg and 20 mg tablet should be taken with food. FDA approved on July 1, 2011. Specifically, it is used to treat deep vein thrombosis and pulmonary emboli and prevent blood clots in atrial fibrillation and following hip or knee surgery. Rivaroxaban was patented in 2007 and approved for medical use in the United States in 2011. In the United States, it will not be available as a generic medication until 2024.

IUPAC Name:

5-chloro-N - ({(5 S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl] -1,3-oxazolidin 5-yl) - methyl) -2-thiophenecarboxamide.

CAS No.: 366789-02-8.

Molecular Weight: 435.9 g/mol. Molecular Formula: C19H18ClN3O5S Log P value: 1.5

Structural Formula:

Figure 6: Structure of Rivaroxaban

Properties:

Description: Rivaroxaban is a pure (S)-enantiomer. It is an odourless, non-hygroscopic, white to yellowish powder.

Solubility:

Rivaroxaban is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and is practically insoluble in water and aqueous media. DMSO 20 mg/mL; Water <1 mg/mL

Melting Point: 227-230°C.

Storage: Store in a well-closed container.

Indication:

Rivaroxaban is indicated for the prevention of venous thromboembolic events (VTE) in patients who have undergone total hips replacements and total knee replacement surgery; prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE); to reduce risk of recurrent DVT and/or PE. Rivaroxaban is also indicated, in combination with aspirin, for reducing the risk of major cardiovascular events in patients with chronic coronary artery disease or peripheral artery disease. Due to a lack of safety studies, it is not recommended for use in those under 18 years old. Its use is also not recommended in those with severe renal impairment

Dosage and Administration Rivaroxaban

2.5 mg, 10 mg, 15 mg, 20 mg available as tablets. Indicated for reduction in risk of recurrence of DVT and/or PE in patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months 10 mg PO qDay, after at least 6 months of standard anticoagulant treatment

Reduction of Risk of Major Cardiovascular Events

In combination with aspirin, is indicated to reduce the risk of major cardiovascular events (cardiovascular [CV] death, myocardial infarction [MI] and stroke) in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD).

2.1.1 Pharmacokinetics:

2.1.1.1 Absorption: [Oral administration]

Rivaroxaban is rapidly absorbed and reaches peak plasma concentration in 2-4 hours. Bioavailability of the 10 mg dose is >80%. However, the 15-20 mg dose have a lower bioavailability if taken in the fasted state and consequently should be taken with food.

2.1.1.2 Distribution:

• The steady state Vd is 50 L
• Plasma protein binding is about 92% to 95%

2.1.1.3 Metabolism:

Approximately two-thirds of the dose is metabolized. It is metabolized by CYP3A4, CYP3A5, CYP2J2 and CYP independent mechanisms29.

2.1.1.4 Excretion:

Approximately two-thirds of rivaroxaban is excreted into urine (via active tubular secretion in which approximately 36% as unchanged drug and 30% as inactive metabolism). The remaining third of the administered dose is excreted via faeces in which 7% is in the form of unchanged drug and 21% as inactive metabolites. The terminal half-life is 5-9 hours in adults and 11-13 hours in the elderly. Systemic clearance is approximately 10 L/h, so rivaroxaban is considered a drug with low clearance. Renal clearance is ~3-4 L/h. 6.4.

2.1.2. Pharmacodynamics Mechanism of Action:

Rivaroxaban competitively inhibits free and clot bound factor Xa. Factor Xa is needed to activate prothrombin (factor II) to thrombin (factor IIa). Thrombin is a serine protease that is required to activate fibrinogen to fibrin, which is the loose meshwork that completes the clotting process. Since one molecule of factor Xa can generate more than 1000 molecules of thrombin, selective inhibitors of factor Xa are profoundly useful in terminating the amplification of thrombin generation. The action of rivaroxaban is irreversible30,31,32.

Figure 7: Mechanism of action of Rivaroxaban

3. Experimental Work

3.1. Procurement of API and Characterization

Rivaroxaban is official drug in United States Pharmacopoeia. API was procured from Lupin Pharmaceuticals limited, Mumbai as a gift sample. Before usage of the drug, identification of drug was done using various pharmacopeial parameters as per USP.

• Organoleptic Properties

The drug sample was analysed for physical appearance, colour and odour.

• Melting Point Determination

The melting point of rivaroxaban was recorded by capillary method using melting point apparatus and was compared with literature reported data.

• UV Visible Spectroscopy UV Spectrum (λmax)

A solution of rivaroxaban 10 ppm was prepared in acetate buffer and the maximum absorption wavelength was noted.

Construction of Calibration Curve of Rivaroxaban:

Preparation of Standard Stock Solution:

1000 µg/ml of rivaroxaban solution was prepared by dissolving 100 mg of rivaroxaban in few ml of pH 4.5 acetate buffer and the volume made upto 100 ml. From above solution, 10 ml solution was pipette out and dilute upto 100 ml with acetate buffer. Resulted solution was 10 µg/ml. The solution was further diluted to get various working solution.

Preparation of standard dilutions:

For linearity study, dilutions were made for rivaroxaban in the concentration range of 2, 4, 6, 8, 10 µg/ml by diluting the stock solution with acetate buffer. The calibration curve was established at 248 nm by plotting the graph between concentration verses absorbance. graph was plotted and linear equation and regression analysis (r2) was noted in Figure 14 and 15.

• Saturation Solubility Studies

The solubility of rivaroxaban was determined in various solvents like hydrochloric acid (pH 1.2), phosphate buffer (pH 6.8) and acetate buffer (pH 4.6 with 0.4% SLS). The solvents were taken in 5 mL glass vial. An excess amount of drug was added in each vial and closed with stopper. These glass vials were attached in an orbital shaking water bath. The shaking was carried out for 24 hours with the speed of 50 rpm and in the entire study the temperature was maintained around 37±0.5°C. The solution was kept aside for 6 hours for equilibrium. The solution was filtered through Whatman filter paper and the supernatant was analysed spectrophotometrically at 248 nm. The saturation solubility study data is noted in Table 21.

IR Analysis

The FTIR spectrum of rivaroxaban was recorded using Prestige-21 (SHIMADZU) with IR resolution software. The doing sample was placed in FTIR sample holder and scanned ever the range of 400 – 4000cm-1. The spectrum obtained was shown in Figure 16 and structural assignments for the characteristic absorption bands were listed in Table 22.

7.1.1. Compatibility Studies

It is very important to perform physicochemical evaluation of all excipients which are probably used in the formulations. Interactions in the solid state between the active ingredient and excipients in pharmaceutical dosage forms can give rise to changes in the stability, solubility, dissolution rate and bioavailability for stable dosage forms. A compatibility study for rivaroxaban was carried out with potential formulation excipients to determine possibility of any drug-excipient interaction. Drug and excipients mixed in 1:1 ratio was stored at 40oC for 10 days. After 10 days the samples were analysed for chemical interaction by FTIR noted in Figure 17

7.2.1. Preliminary Trial Batches:

For preliminary study the tablet was formulated using HPMC E5, with SLS and without SLS. The formulated tablet was evaluated for drug release, the tablet shows variation in drug release as the concentration of SLS change from batch to batch. The composition and percent drug releases of preliminary batches are shown in Table 5, 6, and 7 respectively.

Table 5: Composition of Preliminary Batches

Table 6: Preliminary Batches with % Drug Release

Table 7: In-vitro % Drug Release from Preliminary Batches

Figure 12: In-vitro % Drug Release from Preliminary Batches

7.2.2. Factorial Design

It is desirable to develop an acceptable pharmaceutical formulation in shortest possible time without wastage of raw materials. Traditionally pharmaceutical formulations after developed by changing one variable at a time approach. The method is time consuming in nature and requires a lot of imaginative efforts. Moreover, it may be difficult to evolve an ideal formulation using this classical technique since the joint effects of independent variables are not considered. It is therefore very essential to understand the complexity of pharmaceutical formulations by using established statistical tools such as factorial design. In addition to the art of formulation the technique of factorial design is an effective method of indicating the relative significance of a number of variables and their interaction the number of experiments required for these studies is dependent on the number of independent variables selected. Factor is simply a categorical variable with 2 or more values, referred to as level. Factorial design in which 2 factor with three levels are present is called as 32 factorial designs. Factorial design is used to evaluate two or more factor simultaneously. A 32 full factorial design was constructed where HPMC and SLS were selected as factors and the level of 2 factors were selected on the basis of preliminary studies carried out before implementing the experimental design all the other formulations and processing variables were kept constant throughout the study. Two independent variables selected were HPMC E5 and SLS. As per experimental design nine formulations were formulated. From the in- vitro drug release of trial batch it was observed with the increase in SLS concentration % drug release also increased.

Table 8: Experimental Design Layout