FORMULATION AND IN VIVO EVALUATION OF RISPERIDONE SPHERICAL AGGLOMERATES PREPARED FOR EARLIER ABSORPTION OF RISPERIDONE

www.wjpr.net Vol 8, Issue 13, 2019. 1641

FORMULATION AND

IN VIVO

EVALUATION OF RISPERIDONE

SPHERICAL AGGLOMERATES PREPARED FOR EARLIER

ABSORPTION OF RISPERIDONE

Moataz Farid*1,2 and Mohamed Jaffer3

1

Department of Pharmaceutics, Batterjee Medical College, Jeddah, Saudi Arabia.

2

Department of Pharmaceutics, National Organization for Drug Control and Research, Cairo,

Egypt.

3

Department of Pharmacology, Batterjee Medical College, Jeddah, Saudi Arabia.

ABSTRACT

Risperidone (RES) is a second generation antipsychotic drug with

potent serotonin-5HT2 and potent dopamine-D2 antagonistic

properties. RES belongs to class II of the Biopharmaceutical

Classification System (BCS) meaning that it has low water solubility

and high permeability and the dissolution rate is the limiting factor for

its absorption. The main aim of this study was to improve the

solubility, the dissolution rate and hence the bioavailability of

risperidone using spherical agglomeration technique with methanol,

water and chloroform as good solvent, poor solvent and bridging

liquid, respectively. The quasi emulsion solvent diffusion technique

was used as a method for spherical agglomeration. Polyethylene

Glycol 4000 and inutec SP1 were used as hydrophilic polymer in agglomeration process. The

agglomerated crystals were evaluated by water solubility, drug content, in-vitro release

studies, Powder X- Ray diffraction (PXRD), Differential Scanning Calorimetry (DSC),

Fourier Transform Infra Red Spectroscopy (FT-IR) and Particle size analysis. The water

solubility of all RES agglomerated crystals was improved, it was found to be in the range of

15.6 ± 0.27 to 188.2 ± 0.2 µg/ml when compared with the solubility of raw risperidone 2.16 ±

0.12 µg /ml. The dissolution rate of risperidone agglomerates within 60 minutes increased to

about 3 - 6 folds in simulated gastric fluid. DSC and FT-IR outcome showed no chemical

alteration in the recrystallized drug. DSC and PXRD studies showed that crystallinity of RES

was retained in all of the prepared agglomerated crystals. The in vivo activity of F2 (showing

Volume 8, Issue 13, 1641-1655. Research Article ISSN 2277– 7105

Article Received on 22 Oct. 2019,

Revised on 11 Nov. 2019, Accepted on 01 Dec. 2019,

DOI: 10.20959/wjpr201913-16539

*Corresponding Author

Moataz Farid

Department of

Pharmaceutics, Batterjee

Medical College, Jeddah,

highest dissolution rate in simulated gastric fluid) was assessed in mice. The selected formulae

showed significantly higher activity in comparison to the pure drug and control.

KEYWORDS: Risperidone, Spherical agglomeration, Solubility, Dissolution rate.

INTRODUCTION

It is well-known that the active ingredient in a solid dosage form must go into solution before

it is available for absorption and it is estimated that between 40% and 70% of all new

chemical entities identified in drug discovery programs are insufficiently soluble in aqueous

media[2] and the oral delivery of such drugs is frequently associated with low bioavailability, high intra- and inter-subject variability and a lack of dose proportionality.[3] Often, poor drug dissolution and solubility rather than limited permeation through the epithelia of the

gastrointestinal tract are responsible for low bioavailability of orally taken drugs and as these

compounds have low solubility, limited bioavailability is observed.[4-5] Therefore, the solubility of a drug is an important factor in determining the rate and extent of its

absorption.[6]

At the present time, most of importance is given to enhance the dissolution rate of the poorly

soluble drugs, so, it increases the bioavailability of drugs[7-8] as it is recognized that dissolution of a drug from a solid dosage form is frequently the rate-limiting step in

gastrointestinal absorption. Thus, when considering a drug of low solubility, the relationship

between dissolution rate and absorption is particularly distinct. Consequently, numerous

attempts have been made to attain more rapid and more complete absorption. When

dissolution is the controlling step in the overall process, absorption is said to be dissolution

rate-limited. Since the dissolution process precedes the absorption process, any factor

influencing the rate of dissolution must influence also the rate of absorption. Consequently,

dissolution rate may affect the onset, intensity and duration of biological response.[9-10] Various techniques, such as milling or grinding of particles, solid dispersion[11-13], making liquisolid formulations, micronization[14-17] and .spherical crystallization have commonly been used to improve the dissolution and bioavailability of poorly water-soluble drugs.[18]

Risperidone (RES) is an atypical antipsychotic agent indicated for the treatment of

schizophrenia with reduced side effects especially the extra-pyramidal symptoms.

Risperidone has very low solubility in water and high permeability so that it belongs to class

limiting step for its absorption[19] and therefore, RES shows dissolution rate inadequate absorption that gives rise to difficulties in pharmaceutical formulations for oral delivery,

which may lead to variable bioavailability. This factor motivated the development of drug

delivery technologies to overcome the barrier of solubilization and it explains the rationale

for the selection of Risperidone as the model drug for this research. Very few attempts to

enhance the aqueous solubility and dissolution of RES have been reported in literature using

complexation techniques with cyclodextrin and amberlite resins.[20-23] The present work aims to increase the solubility, the dissolution rate and hence the bioavailability of RES using

quasi emulsion solvent diffusion technique as a method for spherical agglomeration with

methanol, water and chloroform as good solvent, poor solvent and bridging liquid,

respectively. Polyethylene Glycol 4000 and inutec SP1 were used as hydrophilic polymers in

the agglomeration process as to our knowledge no work was done before for the enhancement

of solubility of RES by quasi emulsion solvent diffusion technique. By performing this

approach an attempt has been made to develop dosage forms with improved oral absorption,

and increased therapeutic efficiency.

1. MATERIALS AND METHODS

Materials

Risperidone was provided as a gift sample from Delta Pharma. Pharmaceutical Co., Egypt.

Chloroform, Fisher Scientific UK Ltd., United Kingdom, Methanol, chloroform and

hydrochloric acid, Sigma-Aldrich Chemie GmbH, Germany. Polyethylene glycol 4000 (PEG

4000), Fluka GmbH, United States. Inutec SP1 (inulin lauryl carbamate) kindly supplied by

Beneo BBC, Belgium. Diazepam was generously provided as a gift sample from Amoun

Pharmaceutical Co, Egypt.

2. Preparation of RES spherical agglomerates

RES spherical agglomerates were prepared using quasi emulsion solvent diffusion technique.

RES powder was dissolved in methanol (good solvent) so as to form the saturated solution of

the drug. The solution was poured drop wise into distilled water only (poor solvent) or

distilled water containing PEG4000 or Inutec SP1 at three different concentrations (0.0125, 0.

025 and 0.05% w/v) with a stirring rate 600 rpm[24] using propeller type agitator at room temperature. When fine crystals of RES begun to precipitate (about 2 to 3 min), 5 mL of

chloroform was added and the stirring was continued for 30 min then the prepared

were washed with distilled water and left for drying in air for 24 h and then stored in desicator

over silica gel. The composition of the different prepared spherical agglomerates is shown in

Table I.

Table I: Composition of different prepared Res spherical agglomerates.

Formula code

Water to (mL)

methanol

(mL) RES (g)

Chloroform (mL) PEG 4000 (% w/v) Inutec SP1 (% w/v) F1 F2 F3 F4 F5 F6 F7 50 50 50 50 50 50 50 5 5 5 5 5 5 5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 5 5 5 5 5 5 5 - 0.0125 % 0.025 % 0.05 % - - - - - - - 0.0125 % 0.025 % 0.05 %

3. Evaluation of prepared RES spherical agglomerates

3.1.Determination of the yield of spherically agglomerated crystals[25]

The yield of spherical agglomerates was calculated by comparing the whole weight of the

agglomerates formed against the collective weight of the polymer and drug.

Percentage yield = (Weight of agglomerates obtained/Total weight of drug and polymer) ×

100.

3.2. Drug Content[26]

The assay of the weighed amount of RES spherical agglomerates was carried out to

determine the drug content. The weighed samples (about 10 mg) were dissolved in 10 mL of

0.1 N HCl and stirred by vortex mixer. The solution was subjected to serial dilution, filtered

using Whatman filter paper. The content was estimated spectrophotometrically (Shimadzu,

model UV-2450, Japan) at 237 nm.

3.3. Solubility study[27]

Half gram of RES and its different spherical crystals were introduced separately into a series

of vials in 10 mL of distilled water. Vials were shaken in a thermostatically controlled shaker

for 48 h at 25 ± 0.5 °C at 100 rpm. The time required for equilibrium was established by

repetitive sampling. After equilibrium, the samples were centrifuged then filtered through

0.45 μm membrane filter. The drug saturation solubility in the systems under investigation

was determined spectrophotometrically after appropriate dilution of the filtrate using distilled

3.4 Particle size analysis

The particle size of RES powder and its prepared spherical agglomerates was determined by

laser scattering particle size analyzer (Horiba, model LA-920, Japan).

3.5. In vitro dissolution study[28]

In vitro dissolution tests for pure RES and its prepared spherical agglomerates equivalent to

10 mg of RES were carried out with the USP dissolution method type II using USP

dissolution testing apparatus (Pharma Test, PTW, Germany) at 37 ± 0.5 °C and rotated at 100

rpm using 900 mL of simulated gastric fluid (SGF) as dissolution medium (n=3). Samples

were withdrawn at specified time intervals, and replaced with an equivalent volume of fresh

dissolution medium to keep the volume constant. Collected samples were filtered and assayed

spectrophotometrically at λmax 237 nm using SGF as blank. The cumulative amount of drug

released was calculated and plotted versus time. The study was done in triplicate.

3. Solid state characterization[29-30]

3.1. Microscopical observation

RES powder as well as its selected agglomerated crystals was examined under the optical

microscope (model Bio-pal2-TP, Japan) and photomicrographs at appropriate magnification

were taken. Scanning electron microscopy (model JSM 840A, Jeol, Japan) was used to access

the surface morphology of the agglomerates; the crystals were splutter covered with gold

before scanning.

3.2. Differential scanning calorimetric (DSC) studies

DSC analysis was performed using differential scanning calorimeter (Shimadzu -DSC-50,

Japan). Samples of RES and its selected agglomerates were heated under nitrogen atmosphere

as carrier gas on aluminum pan at a flow rate 25 mL/min and a heating rate of 10 °C/ min over

temperature range of 20-400 °C.

3.3. Fourier Transform Infrared Spectroscopic Studies

Fourier transform infrared (FT-IR) spectroscopy was employed to further characterize the

possible interactions between the drug and the carrier in the solid state on a FT-IR

spectrophotometer (Jasco-FTIR-1700 spectrophotometer, Japan) by the conventional KBr

3.4. Powder X-ray diffraction (PXRD)

PXRD spectra of RES and the selected spherical agglomerates were traced by employing an

X-ray Diffractometer (Philips, England) for pure drug, and the selected spherical agglomerates Ni

filtered Cu K (α) radiation, a voltage of 40 kV, a current of 20 mA and receiving slit of 0.2

inch. The samples were analyzed over 2Ø range from 2◦ C -50◦C at the rate of 2º C per min at 0.02◦ at 2Ø step size.

4. In vivo Evaluation

Albino mice of 7–17 weeks of age, weighing 20 to 32 g were used. Mice were housed in

groups of two to four with free access to food and water. A 12-hr light–dark cycle was

maintained (light on from 6.00 a.m. until 6.00 p.m.) at a temperature of 22°C and a relative

humidity of 60%. All experiments were conducted in accordance with the U.S. guide for the

care and use of laboratory animals and approved by local authorities (NIH publication No.

86-23, revised 1985 and the current version of the German Law on the Protection of

Animals).

Effect of RES on Diazepam-induced Sleeping Time in Mice

The animals were divided into 3 groups (n=6). Diazepam (25 mg/ kg, i.p.) was administered

to the first (control) group. To the second and third group RES or F2 (2.5 mg / kg, p.o.) was

administered 6.0 h prior to the diazepam injection. The time interval between the loss and

regaining of righting reflex (falls asleep) was measured as sleeping time, the duration of

action of diazepam per se and in combination with RES or F2 was noted.[31]

RESULTS AND DISCUSSION

1. Evaluation of the prepared RES spherical agglomerates

The percentage yield of different spherical agglomerated crystals was in the range of 92.5 ±

1.14 to 98.6 ± 2.16. The percentage of drug content of the prepared spherical agglomerated

crystals ranged from 91.2 5 ± 1.85 to 98.45 ± 0.51. These results were very close to the

theoretical values for all of the prepared spherical agglomerated crystals. These values were

taken to calculate the amounts needed for achieving the dissolution studies under sink

conditions. Data are presented in Table II.

1.1. Solubility study

The solubility of all RES agglomerated crystals was improved, it was found to be in the

2.16 ± 0.12 µg/mL (Table II). Agglomerated RES containing polymers showed highest

solubility than those without polymers. This expected result was due to wetting effect of the

hydrophilic polymers.[32] An increase in polymer concentration was accompanied by a decrease in RES solubility. According to phase solubility method of Higuchi and Connors this

type of solubility can be classified as AN subtype (negatively deviating isotherms) because at

higher polymer concentrations a negative deviation from linearity exists, meaning that they

are less effective at higher concentrations.[33] The highest improvement in solubility was observed with polyethylene glycol 4000 at 0.0125% w/v concentration level.

1.2. Particle size determination

The pure drug exhibited a small particle size, 174 ± 6.7 µm, whereas the size of the prepared

agglomerates ranged from 312 ± 5.1 to 412 ± 8.1 µm; this indicates agglomeration of crystals

(Table II).

Table II: Percentage yield, Drug content, Solubility and Particle Size of different

spherical agglomerated crystals.

Formula Percentage yield

± SD

Drug content ± SD

Solubility (µg/mL ± SD)

Particle size (µm ± SD) RES F1 F2 F3 F4 F5 F6 F7 --- 93.4 ± 2.11 98.6 ± 2.16 96.1 ± 3.15 92.5 ± 1.14 97.88 ± 2.17

96.9 ± 2.21 95.25 ± 1.31

--- 96.73 ± 1.5 97.45 ± 1.14

95.94 ± 1.15 98.45 ± 0.51 95.55 ± 1.34 97.24 ± 1.25 91.2 5 ± 1.85

2.16± 0.12 15.6 ± 0.27 188.2 ± 0.2 172.5 ± 0.28 162.4 ± 0.49 176.3 ± 0.15 155.5 ± 0.37 75.4 ± 0.72

174 ± 6.7 372 ± 9.4 348 ± 4.6 412 ± 8.1 351 ± 14.6

340 ± 7.1 312 ± 5.1 366 ± 9.4

1.3. Dissolution study

Dissolution profiles of RES and different prepared agglomerates are illustrated in Figure 1

Recrystallization of RES into spherical agglomerates successfully improved dissolution rate

comparing to RES powder in SGF. The enhancement in the rate of dissolution in comparison

to the pure drug was a result of improved porosity resulting from diffusion of solvents during

solidification process.[34] Data of dissolution study were consistent with that of solubility study where RES agglomerates containing polymers showed higher dissolution rate than

those without polymers (F1). Also, highest dissolution rate enhancement was associated with

agglomerates containing polymers at low concentration levels. In SGF: RES spherical

agglomerates showed 3.45 - 6.16 times improvement in the dissolution compared to RES

while the pure drug gave only 57.4% release after 60 min. the results indicated that, there was

a dramatic improvement in the rate of dissolution in comparison with pure RES. However,

the increase in dissolution rate was in order of F2 > F5> F3> F4> F6> F7 > F1 as shown in

Figure 1.

Figure 1: Dissolution profiles of RES from its agglomerates in SGF.

2. Solid state characterization of RES spherical agglomerates

Light microscopy photographs of RES powder and its prepared agglomerates, Figure 2

showed that the agglomerated crystals are nearly spherical in shape while the crystals of pure

RES were irregular shaped. SEM (Figure 3) showed that particles of unprocessed RES were

smaller in size than processed ones. Unprocessed RES particles were flat shaped while the

processed ones were spherical agglomerates. It was apparent that degree of surface roughness

of spherical agglomerates crystallized in the presence of polymers was higher compared to

agglomerates with no polymer due to adhesion of polymers to the surface of the agglomerates

which is supported by DSC and XRD analysis.

Figure 2: Microscopic photographs of RES, F2 and F5.

Figure 3: SEM images of RES, F2 and F5.

2.1. Differential scanning calorimetery studies

DSC thermograms of RES, and selected agglomerates are illustrated in figure 4. A sharp

endothermic peak appeared in pure RES thermogram with the following peak parameters:

onset at 166.69°C, peak at 175.20°C, with an area of 150.06m J and Delta H value of 50.020

which is indicative of its high crystalline nature.[35-37] A broad single endothermic peak was observed at 155°C and 195°C (for PEG4000 and Inutec SP1 respectively) which indicated the

nature of the polymers. The peaks of the prepared agglomerated crystals using PEG4000 and

Inutec SP1 were 178.65°C and 180.2°C respectively. The non-appreciable change in RES

endotherms in all of the tested samples indicates that no interaction has occurred between

RES and polymers during crystallization of particles.

Figure 4: DSC patterns of RES, polymers and selected agglomerates prepared using

different polymers at 0.0125% w/v concentration.

2.2. Fourier Transform infrared spectroscopy

The FT-IR spectra of pure RES, F2 and F5 are shown in figure 5. The following

stretching); 820 cm-1 (C-Cl stretching). The FT-IR spectrum of all selected agglomerates shows the characteristic bands of RES. Also, there was no great difference in the fingerprint

region (almost unique for every organic compound) between FT-IR spectrum of the drug and

that of its selected spherical agglomerated crystals.[38] These findings indicated that there was no remarkable interaction occurred between drug and different polymers used during

crystallization process confirming DSC study data.

Figure 5: FT-IR spectra of pure RES, F2 and F5.

2.3. Powder X-ray diffraction studies

X-ray diffractograms of RES powder, and the selected crystal agglomerates are represented

in Figure 6. The diffraction pattern of RES showed that the drug has high crystallinity

because of the presence of numerous distinct peaks. The most characteristic peaks in

ascending order of intensity are at 2θ diffraction angles of 6, 9.5, 11, 12.5, and 16.5°. The

results of PXRD of the spherical agglomerates showed presence of several distinct peaks

characteristic for RES which revealed that the agglomerates are in a crystalline form.

Although the agglomerates showed crystalline pattern in PXRD diffractograms, but the

intensity of the peaks have been reduced in comparison to the pure RES suggesting the

conversion of crystalline RES to partially disordered molecules (decreased crystallinity or

Figure 6: PXRD spectra of pure RES, F2 and F5.

3. In vivo Evaluation

Both RES and F2 enhanced the diazepam-induced sleeping time in mice. The average

sleeping time due to diazepam (25 mg / kg, i.p.) per se was found to be 82.6 ± 3.5 min., while

the average sleeping time due to diazepam and RES was increased to 92.2± 5.5 min and the

average sleeping time due to diazepam and F2 was increased significantly to 160.5 ± 6.5

min. The data were subjected to one way analysis of variance (ANOVA) followed by post hoc

analysis (LSD). The results demonstrated that RES powder and F2 significantly (p < 0.05)

enhanced the diazepam-induced sleeping time in mice as compared to the control. F2

significantly increased the diazepam-induced sleeping time in mice in comparison to the RES

powder (p < 0.05), indicating that there is a significant improvement in the bioavailability of

RES demonstrated by the significant enhancement of RES activity.[41–44]

CONCLUSIONS

The spherically agglomerates crystals of RES were successfully prepared by quasi emulsion

solvent diffusion technique and the incorporation of hydrophilic polymers as polyethylene

glycol 4000 and Inutec SP1 to such systems resulted in an improvement in the quality of the

produced spherical agglomerates. Our result revealed that the F2 formula significantly

improved RES activity (manipulated by a significant increase in the diazepam-induced

sleeping time in mice) in comparison to the RES powder. From these results we can conclude

that this technique may be applied fruitfully to enhance the bioavailability of RES powder

ACKNOWLEDGEMENTS

Our deepest thanks and appreciation to Dr. Rola Bayram, Assistant prof. of analytical

chemistry for her continuous help during our research.

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