DEVELOPMENT AND EVALUATION OF ORAL DISINTEGRATING TABLETS OF SPRAY-DRIED ARIPIPRAZOLE SOLID DISPERSIONS

DEVELOPMENT AND EVALUATION OF ORAL DISINTEGRATING TABLETS OF SPRAY-DRIED ARIPIPRAZOLE SOLID DISPERSIONS

Preethi Sudheer * and S. V. Rajendra

Department of Pharmaceutics, Krupanidhi College of Pharmacy, Bangalore, Karnataka, India.

ABSTRACT: Aripiprazole is a biopharmaceutics classification system (BCS) II drug used to treat schizophrenia and bipolar disorders. A fast-dissolving tablet will be an appropriate drug delivery route in these conditions. Therefore, the objective of the work was to convert aripiprazole into a solid dispersion via a spray drying process and further present it as an oral fast-dissolving tablet for improving patient compliance. The solid dispersion of the drug in mannitol from solvent evaporation via spray-drying forms porous amorphous solid dispersions. The spray drying trials were optimized using a custom design approach via Design Expert software version 13. Oral fast-disintegrating tablets containing optimized solid dispersions were evaluated for tableting properties, in-vitro drug release profile, and pharmacokinetic profile compared to aripiprazole. The optimized solid dispersion exhibited a 2-fold increase in solubility compared to pure aripiprazole. The tablet disintegrated in 27.1± 1.1seconds. The in-vitro drug dissolution showed a four-fold increase in drug release profile compared to pure aripiprazole in one h. The pharmacokinetic profile observed a two-fold increase in the bioavailability of solid dispersion in comparison to the pure drug suspension. The stability studies for six months assured the stability of the tablet. In conclusion, an orally disintegrating tablet of aripiprazole with improved solubility may increase the therapeutic efficacy of the drug.

Keywords: Aripiprazole, Solid dispersion, Spray drying, Mannitol, optimization

INTRODUCTION: The oral route is the most convincing route of drug administration. However, the oral route faces many challenges, such as the low therapeutic efficacy of the medication due to poor water solubility and permeability. The drugs belonging to BCS II and IV encounter solubility issues. Therefore, to prepare an appropriate dosage form, we require drug in soluble form, as the soluble fraction will be readily available for therapeutic efficacy ¹. Numerous pharmaceutical manipulations exist to combat the poor solubility of medications, such as micronisation, micelles, lipid-based systems, and solid dispersions ².

Solid dispersions are an exciting method to enhance the water solubility of poorly water-soluble drugs. Properties such as particle size reduction to a molecular level, increased wettability, porosity, and the property to exist in amorphous form add on solid dispersions ³. Solid dispersion is the dispersion of drugs in hydrophilic carriers. The methods to prepare solid dispersions include rapid melt cooling, rapid solvent evaporation, melt extrusion, spray drying etc. Spray drying involves drying atomized solution or suspension of drug -carrier in a stream of hot air to a finely divided powder.

API in spray-dried form increases the solubility by increasing surface area and porosity ^{4, 5}. Psychosis is a state of mind where an individual experiences things that no one else experiences, an impaired relationship with reality. Psychotic symptoms can be part of conditions such as schizophrenia, schizoaffective disorder, personality disorder, and bipolar disorder ⁶. Antipsychotic drugs tend to block dopamine D2 receptors in the dopaminergic pathways of the brain ⁷. Second-generation antipsychotic drugs are serotonin-dopamine antagonists under the class of atypical antipsychotics. Aripiprazole is an atypical antipsychotic that acts as a partial agonist at the dopamine (D2) receptors and an antagonist to the serotonin (5-HT2A) receptors. It is a BCS Class II compound with poor solubility and undergoes considerable metabolism with a bioavailability of about 60% ⁸. Oral disintegrating tablets (ODT) combine the advantage of liquid conventional tablet dosage forms with additional traditional benefits of both dosage forms ⁹. Moreover, in psychosis, ODT can be a convenient dosage form from in administration point of view. Therefore, the work is emphasized on preparing nanosized solid dispersion-based oral disintegrating tablets of aripiprazole for effective treatment of the disease.

MATERIALS: Aripiprazole procured from Watson India ltd. Mannitol, Crosspoidone from SD fine chemicals ltd. Mumbai. All the other chemicals and reagents used were of analytical grade.

METHODOLOGY:

Saturation Solubility Studies: An excess quantity of aripiprazole was added to 10 ml of water and kept under shaking for 72 hours in a bath shaker. The samples were filtered, diluted suitably, and analyzed spectrophotometrically at 255nm ¹⁰.

Preparation of Solid Dispersion via Solvent Spray Drying Method: Aripiprazole was dissolved in an ethanolic mannitol solution. Based on preliminary studies, the drug: carrier ratio chosen was 1: 2 based on preliminary studies.   The solutions were spray dried using (Lab ultima; Model number LU 222 advanced). The process is optimized via a custom design approach. The factors chosen were inlet temperature, spray rate, and atomization pressure, and the responses studied were solubility and dissolution rate Table 1 ¹¹.

TABLE 1: THE EXPERIMENTAL DESIGN

Evaluation of Solid Dispersions: Spray-dried formulations (1:2 (Drug: carrier) at various conditions were selected per the experimental design and evaluated for practical yield, drug content solubility, and dissolution rate.

Practical Yield: The practical yield and the percentage yield were calculated. 

Drug Content Determination: Solid dispersions containing an equivalent amount of aripiprazole (10 mg) were weighed into a 10 ml volumetric flask and diluted using ethanol; 1 ml was diluted to 10 ml using PBS 6.8 and analyzed spectroscopically ¹².

Solubility Studies of Solid Dispersion: The solubility of solid dispersions is carried out by dissolving 25mg of drug equivalent solid dispersions in 10 ml of phosphate buffer PBS pH a 6.8 and subjected to shaking for 72 hours in a vortex shaker. After 72 hours, a filtrate volume of 1 ml was diluted to 10 ml in a volumetric flask, followed by a 0.5 ml to 10 ml dilution. The drug concentration was determined using a Shimadzu UV spectrometer at 255nm ¹².

In-vitro Drug Release Study: In-vitro drug release study for all solid dispersions was carried out using USP dissolution apparatus–II. The solid dispersions were introduced into the dissolution media, phosphate buffer solution pH 6.8 and stirred at 50 rpm. Samples were withdrawn at 5 15, 30, 45 and 60 minutes. The drug concentration in the samples was determined spectroscopically at 255 nm¹³.

Selection of Optimum Formula from the Experimental Design: The optimum formula was selected based on experimental design evaluation based on maximum desirability, and the optimum formulation was prepared and evaluated further. The optimum formulation was converted to ODT Table 2.

DSC Studies: To confirm the thermal behaviour of a pure drug in the presence of excipients, a DSC analysis was carried out. Approximately 5mg of the sample and drug equivalent formulations were precisely weighed into non-hermetically sealed aluminium pans and crimped. The samples were heated from 0°C to 350^oC at a heating rate of 10^oC/min. During the measurement, nitrogen was continuously purged at a flow rate of 40ml/min, and DSC thermograms were recorded in Shimadzu DSC-60, Japan ¹⁴.

X RD Studies: XRD pattern of neat sample and the crystal was studied using X-ray diffractometer D8 Discover, Bruker Axs, Germany). The pattern is collected between 10 to 900 angles at a gap of 0.010 ^{15, 16}.

TABLE 2: FORMULATION OF ODT

Precompression Parameters of the Blend:

Angle of Repose: The precisely weighed blend is taken in a funnel. The funnel height is adjusted to touch the funnel tip to the apex of the heap of the blend. The drug (Solid dispersions)-excipient blend can flow freely through the funnel onto the surface. The diameter/radius of the powder cone is measured, and angle of repose is calculated using the following equation ¹.

Tan Ө = h/r

Density Profiles of the Solid Dispersions: Apparent bulk density is determined after pouring a balanced quantity of blend into a graduated cylinder of bulk density apparatus. The sample was allowed to tap 100 times, and the tapped volume was noted. Various densities and flowability parameters were given by the formulas given below. The general formula gives a compressibility index ¹⁸.

Bulk Density = (Weight of powder) / (Volume of the powder)

Tapped Density = (Weight of powder) / (Tapped volume of the powder)

Compressibility index = (Tapped density - Bulk density) / (Tapped density) × 100

Hausner ratio = (Tapped density) / (Poured density) × 100

Evaluation of Oral Disintegrating Tablets:

Assay of Tablets: The assay of the tablets was studied by crushing ten tablets in a mortar and weighing 10 mg drug equivalent tablet triturate. The tablet triturate was further dissolved in ethanol and diluted suitably, and the absorbance was measured spectrophotometrically at 255 nm ¹⁹.

Weight Variation: The weight variation test is carried out to ensure uniformity in the weight of tablets in a batch. Weight variation is carried out by weighing 20 formulation tablets; the average is calculated; the individual weight is also determined. The percentage deviation is calculated ¹⁹.

Hardness: The crushing strength of the tablets was measured using a Monsanto hardness tester. Five tablets from the formulation batch were tested randomly, and the average reading was noted. The hardness is measured in kg/cm^{2 19}.

Friability: Ten tablets were weighed, and weight was noted down. The pre-weighed tablets were subjected to 25 rpm for 4 min in a Roche friability reweighed after the studies. The percentage of friability is calculated using the formula.

% Friability = (W₁- W₂) / (W₂) × 100

Where, W₁ is the initial weight and W₂ is the final weight after the studies ¹⁹.

Disintegration Test: The USP disintegration apparatus contains six glass tubes, "3 long, open at the top, and held against a ten-mesh screen at the bottom end of the basket rack assembly. After placing the tablet in the glass tube, the basket rack is poisoned in 1-litre distilled water at 37±2°C. Assisted by up and down movements, the time taken by the tablet to disintegrate is noted ¹⁹.

In-vitro Dissolution Test: The formulation's in-vitro drug release study was carried out using the USP type II dissolution apparatus. The ODT formulation was introduced into the dissolution media, phosphate buffer solution (PBS) pH 6.8, stirred at 100 rpm, and maintained at 37 °C. Samples were withdrawn in 5, 15, 30, 45, 60 minutes intervals, diluted suitably using the same media. The drug concentration in the samples was determined via UV spectroscopic method ¹⁹.

Stability Studies: The stability studies of the optimized formula were carried out at two stability conditions such as 25°C± 5°C for 65%RH and 45°C± 5°C 75%   for 3 m. After storage, the formulations were studied drug content and disintegration time ²⁰.

Pharmacokinetic Studies: Male Wistar rats weighing 140–160 g (6 weeks) were maintained under environmentally controlled conditions of temperature (23°±1°C) and humidity (55 ± 5%) and with a 12h light/dark cycle, having free access to water and regular lab diet for five days. The animals were divided into two groups (n=6). The first group was administered oral suspension of aripiprazole (2.65mg/kg) in sodium carboxy methyl cellulose (0.1%w/v) suspension, and the second group was administered dispersion of solid dispersion (2.65mg/kg). The blood samples were collected at the intervals of 0.5 h, 1 h, 2 h, 3 h, 4 h, 7.5, 12 h 24 h 48 h and 96 h and tail vein puncture. Blood samples were collected in an Eppendorf tube containing an anticoagulant sodium citrate solution. After centrifugation at 3000 rpm for 30 minutes, the plasma samples were stored at -80°C. The drug concentration in the sample was analyzed by the HPLC method. The pharmacokinetic parameters such as Cmax, tmax, and area under the curve (AUC) were determined and compared using suitable PK software ²¹.

RESULTS AND DISCUSSION:

Saturation Solubility Studies: The saturation solubility of aripiprazole in water was found to be 0.0073 mg/ml.

Preparation of Solid Dispersion of Aripiprazole via Spray Method: The solid dispersions of aripiprazole were prepared via the spray drying method using mannitol. The spray drying trials were optimized via custom experimental design. The factors such as inlet temperature, spray rate and atomization pressure were studied on responses such as solubility and dissolution rate. The system generated 18 experimental trials.

The solubility ranged between 0.086±0.008mg/ml - 0.179±0.09 mg/ ml. In comparison to pure drug, there was a 10-17 fold increase in the solubility for all the formulation trials Table 3. The controlled and reduced particle size, the corresponding increase in surface area, and perhaps a change in the crystal lattice to a less orderly pattern and conversion to nanosuspension to a more porous structure. The dissolution rate was in the range of 83.12±0.91% - 88.76±0.90. Results suggested the increase in solubility might have resulted in a subsequent rise in the dissolution rate. However, we could not conclude a solubility-assisted drug dissolution. The results of experimental trials were substituted to the model to obtain the model fit. At a maximum desirability of 0.854, suggesting an optimum formula with a solubility of 0.064 mg/ ml and dissolution rate of 87.87% on experimentation 0.078 mg/ml and dissolution rate of 87.23± 1.22 % was observed. The X-ray pattern exhibited a distinct peak pattern, wherein the formulations and the intensity of the peaks were reduced, and a more random pattern was observed in Fig. 1 and 2. The results suggested reduced crystallinity of the drug when prepared as solid dispersions. This is evident that the spray dying in the presence of a hydrophilic carrier increased the effective surface area, which would have contributed to the increased dissolution rate.

FIG. 1: X-RAY DIFFRACTION PATTERN OF PURE DRUG                

FIG. 2:  X-RAY DIFFRACTION PATTERN OF  SOLID DISPERSION

TABLE 3: EVALUTION OF SOLID DISPERSIONS

FIG. 3: NUMERICAL OPTIMIZATION FOR SELECTION OF OPTIMIZAIED FORMULA

FIG. 4: CONTOUR PLOTS FOR RESPONSES SOLUBILITY AND DISSOLUTION RATE

TABLE 4: PRECOMPRESSION PARAMETERS OF THE TABLET BLEND

The Selection of Optimum Formula and Preparation of Oral Disintegrating Tablets: The optimum formula was converted to oral disintegrating tablets Fig. 3 and 4. The optimum formula was equivalent to 5 mg of blended microcrystalline cellulose, PVP, cross povidone, and magnesium stearate to obtain a compressible tablet blend. The tableting properties such as flowability, density profiles, and compressibility index were studied. The compressibility index of 10.25 assures good flowability, and the Hausner ratio assures flowability tableting property Table 4.

With promising tablet properties, the tablets were compressed, and various post-compression properties were studied. As given in the table, a compressibility index of 10 .25 and an angle of repose of 30.23 recommended good tableting properties, therefore, easily compressed to a tablet. The compressed tablets were studied for drug content, hardness, friability, and disintegration time. A hardness of about 3.23±0.5 Kg indicates reasonably good tableting properties. The comparatively low hardness might have been the reason for the friability of the higher side. The disintegration time of tablets was found to be 27.1± 1.1 Table 5. The optimum formulation exhibited a drug content of 97.51±1.02%. The disintegration time was found to be 27.1±1.1 sec. The solubilizing effect of solid dispersion and additive effect of cross povidone super disintegrant resulted from faster disintegration.

TABLE 5: EVALUATION OF ODT

FIG. 5: COMPARATIVE DRUG RELEASE PROFILE OF ODT AGAINST ARIP (MARKETED FORMULATION)

The comparative dissolution profile indicates a four-fold increase in drug dissolution compared to the marketed tablet Arip 5mg. Fig. 5 The increased solubility contribution from spray-dried powder, due to the maximum effective surface area contribution from the spray-dried powder, helps dissolve the drug.

Stability Testing: The stability studies at two different temperatures show no appreciable change in the physical appearance. There were no apparent changes observed in drug content. However, the disintegration time slightly increased after three months of storage. The results recommend room conditions for storage of the formulation.

 Pharmacokinetic Evaluation of the Data: The pharmacokinetic studies after oral administration of prepared solid dispersion against the pure drug suspension indicated a remarkable change AUC parameter. The AUC_{zero - inf} of the pure drug was found to be 89.07µg/mlh at a dose level of 0.5 mg/kg, whereas the formulation exhibited a bioavailability of 94.07 µg/ml h at half the dose level. The results suggest an increased solubility-assisted dissolution profile and the corresponding increase in the plasma concentration of the drug. The t_max of 5h suggests the rate of absorption; however, no changes were observed in comparison to pure drug. C_max of the solid dispersion observed a one-fold increase. The results suggest solid dispersion via spray drying can potentially improve the therapeutic efficacy Fig. 6.

FIG. 6: COMPARATIVE PLASMA CONCENTRATION-TIME PROFILE OF SOLID DISPERSION AGAINST PURE DRUG

CONCLUSION: The solid dispersion of aripiprazole was successfully achieved via the spray drying method. The optimized formulation was converted to oral disintegrating tablets. The pharmacokinetic profile of the optimized solid dispersion compared to pure drug indicated a higher solubility of the formulation, therefore, a larger AUC. The short disintegration time ODT suggested the same could be an alternative to conventional oral therapy via an economical approach; the therapeutic efficacy of the aripiprazole may be improved.

ACKNOWLEDLMENTS: We acknowledge RGUHS, Bangalore, for the research grant. The authors thank the principal and management of Krupanidhi College of Pharmacy for the facilities provided for carrying out the research work.

CONFLICTS OF INTEREST: The authors declare no conflict of interest

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    How to cite this article:

    Sudheer P and Rajendra SV: Development and evaluation of oral disintegrating tablets of spray dried aripiprazole solid dispersions. Int J Pharm Sci & Res 2023; 14(9): 4658-65. doi: 10.13040/IJPSR.0975-8232.14(9).4658-65.

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