Rajitha K. et al.

: Formation and Evaluation of Orally Disintegrating Tablets of Buspirone Research Paper

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Formulation and Evaluation of Orally Disintegrating Tablets of Buspirone

Rajitha K, Shravan Kumar Y, Adukondalu D, Ramesh Gannu and Madhusudan rao Y*.
Centre for Biopharmaceutics and Pharmacokinetics, University College of Pharmaceutical Sciences, Kakatiya University, Warangal 506 009, A.P. India.
ABSTRACT: Purpose: Buspirone is a classical anxiolytic agent. The present investigation deals with formulation of orodispersible tablets (ODT) of buspirone that disintegrate in the oral cavity upon contact with saliva and thereby should improve therapeutic efficacy. Methods: The ODTs were prepared by wet granulation and direct compression techniques. The optimized formulation was also prepared by freeze drying method. The influence of superdisintegrants, crospovidone, croscarmellose sodium and sodium starch glycolate at three levels on disintegration time, wetting time and water absorption ratio were studied. Tablets were evaluated for weight and thickness variation, disintegration time, drug content, in vitro dissolution, wetting time and water absorption ratio. Results: The in vitro disintegration time (DT) of the best ODTs was found to be 35 and 30 S by direct compression and by freeze drying methods, respectively. Tablets containing crospovidone exhibit quick disintegration time than tablets containing croscarmellose sodium and sodium starch glycolate. Good correlation was observed between water absorption ratio and DT. Conclusion: The directly compressible rapidly disintegrating tablets of buspirone with shorter disintegration time and sufficient hardness could be prepared using crospovidone and other excipients at optimum concentration. KEY WORDS: Buspirone, superdisintegrants; orally disintegrating tablets; mouth dissolving tablets; rapidly disintegrating tablets; wetting time

Introduction
Most pharmaceutical forms for oral administration are formulated for direct ingestion, for chewing, for prior dispersion and/or dissolution in water; some of them are absorbed in mouth (sublingual or buccal tablets). Many patients express difficulty in swallowing tablets and hard gelatin capsules, tending to non-compliance and ineffective therapy. Recent advances in novel drug delivery systems aim to enhance safety and efficacy of drug molecules by formulating a convenient dosage form for administration and to achieve better patient compliance. To obviate the problems associated with conventional dosage forms, orodispersible tablets (ODTs) that combine hardness, dosage uniformity, stability and other parameters, with extremely easy administration were developed. Advantages of ODTs include ease of administration without water, accuracy of dosage, easy portability, alternative to liquid dosage forms, ideal for pediatric and geriatric patients and rapid onset of action. *Corresponding author: Prof. Y. Madhusudan Rao Centre for Biopharmaceutics and Pharmacokinetics University College of Pharmaceutical Sciences, Kakatiya University Warangal- 506 009 (A.P) India Tel.: +91 870 2438844, Fax.: +91 870 2453508 E-mail: ymrao123@yahoo.com

Buspirone, is an anxiolytic agent and a serotonin receptor agonist belonging to the azaspirodecanedione class of compounds used in the treatment of anxiety disorder (Cohn and Rickels, 1989). It was selected as drug candidate in this study as it is not available as ODTs, which is the clinical need. ODTs are also called as mouth dissolving tablets, orodispersible tablets, quick disintegrating tablets, rapid dissolving tablets, porous tablets and rapimelts (Battu et al., 2007; Fu et al., 2004). During the last decade, ODT technology has drawn a great deal of attention (Fu et al., 2004). The European Pharmacopoeia defines the term orodisperse as a tablet that can be placed in the mouth where it disperses or disintegrates rapidly before swallowing (Pharmeuropa, 1998). The objective of present study was to develop orally disintegrating tablets of buspirone by wet granulation, direct compression and freeze drying techniques in order to achieve rapid disintegration time. It was also aimed to evaluate these buspirone formulations by in vitro methods and to select the best formulation. 327

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Materials and Methods

Buspirone was gift sample from Dr.Reddys Laboratories, Hyderabad. Colloidal silicon dioxide, Peppermint flavor and Aspartame were gift samples from Eurodrugs Laboratories., Hyderabad, India. Pearlitol SD 200 was gift sample from Signet chemical corporation, Mumbai, India. Crospovidone (PXL), Croscaremellose sodium (ADS), Sodium starch glycolate (EXT) and Indion 204 were gift samples from Zydus Cadila, Ahmedabad, India. All chemicals and reagents used were of analytical or pharmacopoeial grade. Development of Buspirone ODTs-evaluation of granulation technique Buspirone orodispersible tablets were prepared by wet granulation, direct compression and freeze drying techniques. Wet granulation technique All the ingredients were passed through sieve # 40. The sifted Pearlitol SD 200, Avicel PH 101, disintegrant,

aspartame, peppermint flavor were mixed and granulated with drug solution. The wet mass was passed through a sieve No.16 to form the granules. The granules were dried in tray drier at 60 C for 20 min. The dried granules were passed through sieve No 20 and lubricated with aerosil and magnesium stearate. The lubricated blend was compressed into tablets using 16 station rotary tableting machine and 8 mm punches. Direct compression technique The drug, Pearlitol SD 200, Avicel PH 101, Aspartame and flavor were passed through 40 mesh. The sifted ingredients were blended for 10-15 minutes in mortar and pestle. The blend was lubricated with sifted (#80) magnesium stearate. The blend was compressed into tablets with 6 mm biconcave punches using 16 station rotary tabletting machine (Riddhi, Ahmedabad, India). The composition was given in Table 1 and 2.

Table 1. Tablet Formulations for Buspirone ODTs by wet granulation and direct compression
Ingredients Super disintegrants concentration (%) of PXLa / ADSb/EXTc 4% 10.00 53.35 23.15 4.00 5.00 3.00 1.00 0.50 6% 10.00 52.15 22.35 6.00 5.00 3.00 1.00 0.50
c

Buspirone Pearlitol SD 200 Avicel pH 101/102d Super disintegrantse Aspartame (5%) Pipppermint flavour (3%) Aerosil (1%) Mg. stearate (0.5%)
a b

8% 10.00 51.25 21.25 8.00 5.00 3.00 1.00 0.50

All the amounts given in above table are in milligrams. PXL -Cross povidone; ADS- Crosscaremellose sodium; EXT- Sodium starch glycolate Avicel PH101/102d- Avicel PH101 and Avicel PH102 were used in wet granulation and direct compression techniques, respectively. Superdisintegrantse- Cross povidone, crosscaremellose sodium and sodium starch glycollate

Table 2. Tablet formulation for buspirone ODT by freeze drying

Ingredients Buspirone Pearlitol SD 200 Indion 204 PVP (2.5%) Aspartame Peppermint flavor Aerosil Magnesium stereate Water Quantity (mg)/Tablet 10.0 63.0 15.0 2.5 5.0 3.0 1.0 0.5 q.s

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Freeze drying method Freeze drying was carried using a lyophilizer (LYODEL, India) using blisters. Slurry was prepared by dissolving or dispersing drug, Pearlitol, poly vinyl pyrrolidone and Indion 204 in water. Required quantity of prepared slurry was accurately filled in the cavities (8 mm) of blister. The slurry was frozen within the cavities by using deep freezer (- 20 C). The frozen units are placed on to the shelves of the freeze dryer and dried at 50 C. The tablets are produced within the cavities which are very porous.

In vitro disintegration time

In vitro disintegration time (DT) of the ODTs was determined following the procedure described by Gohel et al (2004). Briefly, 10 mL of water at 25 C was placed in a petri dish of 10 cm diameter. The tablet was then carefully positioned in the center of the petri dish and the time required for the tablet to completely disintegrate into fine particles was noted. Measurements were carried out in replicates (n=6) and mean SD values were recorded.

In vitro release studies

Release studies of buspirone from different formulations were performed using USP XXX apparatus II, paddle method utilizing a dissolution system (Disso 2000, Lab India, Thane, India) equipped with an auto sampler and fraction collector. Paddle speed was maintained at 50 rpm and 900 mL of phosphate buffer (pH 6.6) was used as the dissolution medium. Samples of 5 mL were collected from the vessels at predetermined time intervals (1, 2, 3, 5 and 7 min) and replenished with same volume of the fresh buffer. The samples were filtered through 0.22 filter and analyzed for drug content using UVVis spectrophotometer at 235 nm.

Physicochemical Evaluation
Weight and thickness variation The weights of buspirone ODTs were measured using digital balance (Denver, Germany). The average values, standard deviation and relative standard deviation were calculated. The thickness was measured using a digital screw gauge (Mitutoyo, Japan). Assay of the tablets Twenty tablets were taken and powdered; powder equivalent to one tablet was taken and was allowed to dissolve in 100 mL of phosphate buffer (pH 6.6) on a rotary shaker overnight. The solution was centrifuged and the supernatant was filtered through 0.22 membrane filter. The absorbance of filtrate was measured using a UVVis spectrophotometer (Elico, India) at 235 nm against pH 6.4 phosphate buffer as blank.

Results and Discussion

An objective of a directly compressible rapidly disintegrating tablet is that it disintegrates or disperses in the saliva within seconds. To achieve such a formulation most of the excipients selected are inherently required to be water-soluble. Pearlitol SD 200 utilized in the formulation is a directly compressible grade of mannitol with good flow properties and provides a refreshing or cooling mouth feel due to its negative heat of solution (Rowe et al., 2003). Pearlitol SD 200 was thus used as a bulking agent to achieve the desired tablet weight. Avicel PH 102 was included in the formulation as a disintegrant and a diluent. This grade of microcrystalline cellulose is granular in nature and thus displays excellent flow properties. To impart pleasant taste and improve mouth feel, aspartame and peppermint flavor were included as sweetening and flavoring agents, magnesium stearate was employed as a lubricant. Colloidal silicon dioxide (Aerosil), which acts both as a glidant and lubricant, also helps in appreciably decreasing tablet friability. This may be due to Aerosil helping in restoring the bonding properties of the excipients.

Wetting time and water absorption ratio (R)

Five circular tissue papers were placed in a petri dish with a 10-cm diameter. Ten milliliters of water containing eosin, a water-soluble dye, was added to the petri dish. The dye solution is used to identify the complete wetting of the tablet surface. A tablet was carefully placed on the surface of tissue paper in the petri dish at room temperature. The time required for water to reach the upper surface and wet the tablets completely wet was noted as the wetting time (Bi et al., 1996). The measurements were carried out in replicates (n=6). The weight of the tablet prior to placement in the petri dish was noted (wb) utilizing a Shimadzu digital balance. The wetted tablet was removed and reweighed (wa). Water absorption ratio, R, was then determined according to the following equation. R = 100 (Wa - Wb) / Wb Where Wb and Wa are the weight before and after water absorption, respectively.

Weight, thickness and drug uniformity

The result of weights, thickness and drug content of formulations are given in Table 3 and 4. The weights and thicknesses of tablets prepared by wet granulation and direct compression techniques were within the limits of uniformity. The weights of the tablets prepared by wet

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granulation technique ranged from 99.3 to 101.6 mg with RSD values 2.71 - 2.99 % and thicknesses ranged between 3.61 and 3.87 mm with RSD of 0.51 to 2.21 %. The weights of tablets prepared by direct compression technique ranged from 99.5 to 101.8 mg with RSD values 1.23-4.43 % and thicknesses ranged between 3.62 and 3.81 mm with RSD of 0.26 to 0.28 %. The drug content of tablets ranged from 90.1 (EXT4) to 96.9 (PXL8) and 96.0 (EXT4) to 104.4 (PXL8) prepared by wet granulation and direct compression techniques respectively. A good content uniformity was observed among all the formulations of buspirone by using direct compression and freeze drying.

Wetting time
The wetting time of ODTs prepared by wet granulation method were found to be higher than the tablets prepared by direct compression method (Fig 1). The wetting times were found to be ranging from 120-390 (PXL); 240-420 (ADS); 300-420 (EXT) and 47-68 (PXL); 81-92 (ADS); 171-202 (EXT) for the ODTs prepared by wet granulation and direct compression method respectively. The results reveal that ODTs prepared by direct compression showed quicker disintegration than the tablets prepared by wet granulation method.

Table 3. Mean weights, thicknesses and assay of BUSP ODT prepared by wet granulation method
Formulation code PXL4 PXL6 PXL8 ADS4 ADS6 ADS8 EXT4 EXT6 EXT8 Weighta (mg) 99.3 2.88 99.8 4.07 100.4 2.51 101.6 2.76 100.0 1.74 100.0 4.11 99.5 3.84 101.1 2.79 100.8 3.02 Thicknessb (m) 3.87 0.02 3.80 0.03 3.77 0.02 3.74 0.04 3.84 0.01 3.70 0.06 3.73 0.03 3.70 0.03 3.61 0.08
a

DTc (Sec) 189.0 8.26 147.5 7.23 250.0 8.87 578.3 10.21 413.3 9.63 250.0 6.41 886.2 7.63 755.8 5.34 660.8 4.68
b

Drug content (%)a 94.7 1.74 94.9 2.80 96.9 1.95 95.8 2.32 96.1 2.27 96.4 2.82 90.1 1.05 95.5 2.28 96.1 2.54
c

Q5 (%)c 23.1 1.21 25.6 0.82 30.3 0.16 13.5 0.15 16.7 0.26 23.6 1.41 10.4 0.13 13.9 0.21 15.2 1.16

The results are mean SD of 20 tablets; 10 tablets and 6 tablets

Table 4. Mean weights, thicknesses, assay and drug release (Q5) of BUSP ODT prepared by direct compression and freeze drying
Formulation Code PXL4 PXL6 PXL8 ADS4 ADS6 ADS8 EXT4 EXT6 EXT8 Freeze drying

Weight a (mg) 99.4 1.23 99.6 1.14 100.1 4.14 99.6 4.13 101.8 4.51 99.7 1.52 100.3 2.86 100.1 1.37 100.5 1.39 100.5 1.70

Thickness b (m) 3.72 0.02 3.81 0.01 3.76 0.05 3.69 0.03 3.68 0.03 3.62 0.01 3.71 0.06 3.64 0.03 3.65 0.05 3.69 0.02
a

DTc (Sec) 44.5 1.04 41.8 2.13 35.2 2.56 58.7 1.21 55.5 3.39 46.7 4.13 460.0 6.58 340.8 5.26 226.6 2.86 30.3 0.82
b

Drug content (%) a 100.7 0.21 98.8 1.17 104.4 0.77 98.8 2.83 100.3 1.25 97.1 2.81 96.0 3.07 96.1 5.41 96.9 1.17 98.3 1.56
c

Q5 (%)c 98.7 1.25 99.0 1.46 99.7 1.16 97.3 2.01 97.3 1.38 98.4 1.65 45.4 0.86 46.8 1.29 55.8 1.37 99.1 1.64

The results presented are mean SD of

20 tablets; 10 tablets and 6 tablets

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500 450 400 350 Wetting time (Sec) 300 250 200 150 100 50 0 PXL4 PXL6 PXL8 ADS4 ADS6 ADS8 EXT4 EXT6 EXT8 Wet granulation Direct compression Freeze drying

Formulation code
Fig 1. Wetting time of different buspirone ODT, values represented are mean SD (n=3) PXL-Polyplasdone XL; ADS- Ac-di-sol; EXT- Explotab; 4, 6 and 8 are the concentration of disintegrant.

200 180 160

W ater absorption ratio

Wet granulation Direct compression Freeze drying

140 120 100 80 60 40 20 0 PXL4 PXL6 PXL8 ADS4 ADS6 ADS8 EXT4 EXT6 EXT8 Formulation code

Fig 2. Water absorption ratio of different buspirone ODT, values represented are mean SD (n=6) PXL-Polyplasdone XL; ADS-Ac-di-sol; EXT-Explotab; 4, 6 and 8 are the concentration of disintegrant.

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Water absorption ratio

The water absorption ratio (R) ranged from 84-136 (PXL); 92-122 (ADS); 122-152 (EXT) and 99-112 (PXL); 98-115 (ADS); 129-160 (EXT) for the ODTs prepared by wet granulation and direct compression techniques, respectively. The R value increased with increasing in the superdisintegrant concentration from 4-8 %. There existed a direct relationship for each of buspirone ODT

formulation. This increase was due to the water up taking ability of the superdisintegrants. More the superdisintegrant concentration greater was the water up take and there by increase in the R value was observed. This pattern was observed in all the 3 superdisintegrants used in wet granulation method and direct compression method, an increased value was observed for the freeze dried formulations (Fig 3).

100 Cumulative % drug released

80

60

Wet granulation Direct compression Freeze drying

40

20

0 0 5 10 15 20 Time (Min) 25 30

Fig 3. Dissolution profiles of Buspirone ODT containing Polyplasdone 8 %, values represented are mean SD (n=6).

Disintegration of ODTs
Disintegration time was given the major importance in selection of the best ODT formulation among all the formulations. For all the formulations, with increase in the superdisintegrant concentration from 4-8 %, the disintegration time was found to be decreased accordingly (Table 3 & 4). An increase in superdisintegrant concentration from 4 to 8 % showed a decrease in DT. The DT of formulations containing PXL was lower than those containing ADS and EXT at similar concentration which might be attributed to its rapid water absorbing nature involving both capillary and swelling mechanisms (Kornblum SS, Stoopak, 1973), building up the pressure internally leading to the faster disintegration. The tablets prepared with EXT as a superdisintegrant took more time to disintegrate than the ODTs prepared using other superdisintegrants. The probable reason for delayed disintegration and wetting of the tablets might be slow water uptake or more gelling tendency of the Ac-di-sol (ADS) and Explotab (EXT). From the above results PXL8 was selected as the best ODT formulation among all the

buspirone formulations for direct compression. The time for an ODT to disintegrate in the oral cavity also varies by product and the method of manufacturing. Buspirone ODT formulations prepared by wet granulation method took more time to disintegrate than the tablets prepared by direct compression method and freeze drying method. The tablets prepared from blister packs using freeze drying method took less time compared to wet granulation and direct compression. Compressed tablets will typically take slightly longer time to disintegrate than freeze-dried wafers due to a different bonding mechanism and differences in porosity between the two dosage forms. The buspirone ODTs prepared by direct and wet granulation techniques showed bitter ness. To mask the bitter taste and improve acceptability, the drug was complexed with an ion exchange resin, Indion 204.

Correlation between R and DT

An inverse relationship was observed between the two parameters R and DT, when R values of the different RDT formulations were plotted against their respective

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DTs as a function of the concentrations of different superdisintegrants (Fig 4a-b). As the superdisintegrant concentration was increased, R value increased and DT was decreased. The more the amount of superdisintegrant in the formulation, the greater the volume of water being

absorbed (increased R value), which is an inherent property of each superdisintegrant. Also, this volume expansion of each formulation led to faster disintegration of the same due to increased hydrostatic pressure inside the tablet (ISP, 2006).

Fig 4. Correlation between water absorption ratio and disintegration time of buspirone ODT prepared by (a) wet granulation technique and (b) direct compression method. Values represented are mean SD (n=6).

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In vitro dissolution
The results of in vitro study are shown in Table 3, 4 and Fig 3. The cumulative % of drug release increased in 5 min with increase in the concentration of superdisintegrant. Formulation PXL and ADS prepared by direct compression method showed a release of 99 % of drug in 5 min. But formulation EXT released the drug very slowly and 99 % of drug was released in 30 min (Fig 3). The rapid drug dissolution was observed for direct compression and freeze drying techniques; it may be due to easy breakdown of particles and rapid dissolution of drug into the dissolution medium. Buspirone is a highly water soluble drug and hence rapid disintegration by super disintegrants promotes rapid dissolution also. The tablets prepared with wet granulation were found to take more time to release the drug than the tablets prepared by direct compression and freeze drying technique. The taste of the tablets was found to be improved with the inclusion of resin. Freeze drying process is one of the first generation techniques of preparing ODT, in which water sublimes from the product after freezing (Bi et., al 1996). The product obtained by freeze drying process dissolves more rapidly than other available solid products. Primary problems associated with water soluble drugs are formation of eutectic mixture, resulting in freezing point depression and formation of glassy solid on freezing which might collapse during sublimation. The addition of cryoprotectants like poly vinyl pyrrolidone imparts rigidity to amorphous material and can prevent collapse of structure (Kuchekar et al., 2003).

These results demonstrate that the formulations afford high utility as oral drug delivery systems.

Acknowledgement
We acknowledge generous help of Dr Reddys Laboratories, Hyderabad, India and Zydus Cadila, Ahmedabad, India for providing gift samples of Buspirone hydrochloride and superdisintegrents, respectively.

References
Battu S, Repka M.A, Majumdar S and Madhusudan Rao. Y. Formulation and evaluation of rapid disintegrating fenoverine tablets: effect of superdisintigrants. Drug Dev. Ind. Pharm. 33: 1225-1232 (2007). Bi Y, Sunada H, Yonezawa Y, Danjo K, Otsuka A and Iida K. Preparation and evaluation of a compressed tablet rapidly disintegrating in the oral cavity. Chem. Pharm Bull. 44(11): 21212127 (1996) Cohn JB and Rickels K. A pooled, double-blind comparison of the effects of buspirone, diazepam and placebo in women with chronic anxiety. Curr Med Res Opin. 11 (5): 304320 (1989). Fu Y, Yang S, Jeong SH, Kimura S and Park K. Orally fast disintegrating tablets: Development Technologies, TasteMasking and Clinical Studies. Crit Rev Ther Drug Carrier Sys 21(6): 433-475 (2004) Gohel M, Patel M, Amin A, Agrawal R, Dave R and Bariya N Formulation design and optimization of mouth dissolve tablets of nimesulide using vacuum drying technique. AAPS Pharm Sci Tech. 3:36 (2004) ISPCrospovidone-International http://www.ispcorp.com/ (2006) specialty products.

Conclusion
The orodispersible tablets of buspirone with sufficient mechanical strength and smaller disintegration time were achieved employing suitable superdisintegrants and other excepients at optimum concentration. Among three superdisintegrants PXL (crospovidone) showed better performance in disintegration time when compared to ADS (croscaremellose sodium) and EXT (sodium starch glycolate) as it exhibited the lowest disintegration time and a better dissolution profile. Based on the disintegration results freeze drying technique and direct compression techniques were more efficient than wet granulation technique. The formulations of Polyplasdone XL8 was found to be the best among buspirone formulations which were prepared by wet granulation, direct compression and freeze drying technique because it has exhibited faster disintegration time when compared to other formulations.

Kornblum SS and Stoopak SB. A new tablet disintegrating agent: Cross-linked polyvinylpyrrolidone. J. Pharm. Sci, 62(1): 43 49 (1973) Kuchekar BS, Badhan AC and Mahajan HS, Mouth Dissolving Tablets: A Novel Drug Delivery System, Pharma Times. 35: 7-9 (2003) Pharmeuropa, European directorate for the quality of medicines. 10(1): 547 (1998) Rowe RC, Sheskey PJ and Weller P.J. Handbook of pharmaceutical excipients 4th ed, London: Pharmaceutical Press, pp. 373377 (2003)