Pharmaceutical Development and Technology, 2009; 14(5):476–484

R E S E A R C H A R T I C L E

Understanding the mechanism for paradoxical effect of ionized and unionized chitosan: Orodispersible tablets of Ondansetron Hydrochloride

Honey Goel, Nishant Vora, Ashok K. Tiwary and Vikas Rana

Pharmaceutics Division, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India

Address for Correspondence: V. Rana, Pharmaceutics Division, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India. E-mail: vikas_pbi@rediffmail.com

(Accepted 15 January 2009)

Introduction

The development of oral solid dosage forms is a challenge, when it is specifically designed for elderly people, pediatrics and patients with swallowing difficul-ties. In addition, physiological and neurological condi-tions like, dysphagia, choking, gastrointestinal tumors, hand tremors lead to poor patient compliance in terms of self medication.[1] Developments of oral dispersible tablets (ODTs) provide a feasible means to deal with such difficulties. ODTs are solid drug delivery systems that dissolve or disintegrate rapidly in the oral/buccal cavity, resulting in a solution or suspension without the need of water or chewing.[2]

Many approaches have been investigated for manufacturing ODTs. These include vacuum drying,[3] lyophilizing, molding and compressing wet powder to construct highly porous structure,[4] crystalline transition method[5] and direct compression method.[6–8] Amongst these, the direct compression method is cheapest, most convenient and produces tablets of sufficient mech-anical integrity. However, the disintegration of ODTs is often compromised while improving the mechan-ical strength of tablets prepared by direct compression method. Superdisintegrants like croscarmellose sodium, crospovidone and sodium starch glycolate can disin-tegrate the tablets faster. However, they are of limited use when tablets are prepared with crushing strength of

ISSN 1083-7450 print/ISSN 1097-9867 online © 2009 Informa UK Ltd.DOI: 10.1080/10837450902749279

AbstractThe objective of the present investigation was to formulate and evaluate orodispersible tablets (ODTs) of ondansetron HCl possessing sufficient mechanical strength by wet granulation or direct compression method. A combination of glycine and chitosan was employed for providing a sweet tasting disintegrat-ing system. The evaluation of ODTs prepared by a wet granulation method revealed that in vitro disin-tegration time (DT) as well as wetting time (WT) increased and water absorption ratio (WAR) decreased with an increase in concentration of chitosan (as binder). However, an opposite relationship was obtained when ODTs were prepared by direct compression method. The FTIR spectra and DSC analysis indicated that the −NH3

+ moieties of chitosan interacted with COO− moieties of glycine in ODTs prepared by the wet granulation method. However, chitosan was found to be present in the unionized state in ODTs prepared by direct compression method. Furthermore, in vitro as well as in vivo disintegration tests revealed that ODTs containing the chitosan-glycine mixture were superior to those containing well known superdisinte-grants. The results suggested that the chitosan-glycine system not only improved disintegration time but also made it possible to prepare ODTs with higher crushing strength as compared to tablets containing superdisintegrants.

Keywords: Orodispersible tablets; glycine; chitosan; ondansetron HCl; direct compression method; wet granulation

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Orodispersible tablets of ondansetron HCl 477

more than 4 kg.[9] Also, microcrystalline cellulose (Avicel-PH101 and PH102) or di calcuim phosphate added in ODTs to enhance their disintegration cause unpleasant feeling of grittiness in mouth. Hence, an attempt was made to investigate a combination of glycine and chi-tosan as a sweet tasting disintegrating system for ODTs.

Ondansetron HCl is selective serotonin 5-HT3 recep-

tor antagonists indicated for the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, radiotherapy or anesthesia, and surgery. It is well absorbed form the gastrointestinal tract.[10] Ondansetron is usually admin-istered in a condition of vomiting, when the intake of even a few mililiters of water is difficult. Furthermore, persistent vomiting results in loss of hydrochloric acid, alkalosis and dehydration, which inturn may precipi-tate further vomiting. In such a condition, ODTs offers a highly acceptable method for oral drug administration.

Thus, a glycine-chitosan mixture was used as a dis-integrating system for preparing ODTs of ondansetron HCl. The tablets containing chitosan and glycine were prepared by both wet granulation and direct compres-sion methods. An attempt was made to evaluate and understand the mechanisms responsible for difference in the disintegration time of these tablets.

Material and methods

Crospovidone and Croscarmellose sodium (Panacea Biotech Ltd., Lalru, India), spray dried lactose (20–40 m, USP/NF grade, Nayan Pharmaceuticals Ltd, Patiala, India) and ondansetron HCl (99.9% Ind-Swift Labs, Parwano, India) were received as gift samples. Chitosan (Indian Sea Foods, Cochin, India), glycine (Nice Labs, Cochin, India) and potato starch (CDH, Mumbai, India) were used as supplied. All other reagents were of analytical grade.

Preparation of ondansetron HCl ODTs by wet granulation

Lactose-chitosan granules were prepared by using 1–3% w/v chitosan solution prepared in 2% v/v acetic acid. The wet mass was prepared with 10 g of spray dried lac-tose using 5 mL of binder solution and passed through 22-mesh sieve. The granules which were retained on 44-mesh sieve were drier at 50°C for 2 h in a drier (151, Narayan Scientific Works, New Delhi, India). The Lactose-chitosan granules were then mixed with glycine and ondansetron HCl by gentle tumbling. This solid mixture was finally compressed using multipunch, sin-gle station tableting machine (Cadmach, Ahmedabad, India) operated at a speed of 15 strokes per min. The compositions of different batches are summarized in Table 1. The weight of the compressed tablets was

100 ± 5 mg and their diameter was 6 ± 0. 5 mm. The batch size was fixed to 100 tablets per batch.

Preparation of ondansetron ODTs by direct compression

Glycine and chitosan were mixed in dry state. To this mixture potato starch (q.s. to 100 mg) and ondansetron HCl were mixed for 10 min to obtain a uniform blend. The resulting blend was compressed into tablets with a multipunch single station tableting machine (Cadmach, Ahmedabad, India). The average weight and diameter of ODT was 100 ± 5 mg and 6 ± 0. 5 mm, respectively.

Preparation of ondansetron HCl ODTs using superdisintegrants

Crospovidone or croscarmellose and ondansetron HCl were mixed for 10 min to obtain a uniform blend. The resulting blend was compressed into tablets with a multipunch single station tableting machine (Cadmach, Ahmedabad, India). The average weight and diameter of ODT was 100 ± 5 mg and 6 ± 0. 5 mm, respectively.

Evaluation of ondansetron HCl ODTs

Tablet crushing strengthPfizer hardness tester was used to measure the tablet crushing strength. The data reported is the mean of six individual determinations.

Wetting time (WT)Five circular pieces of tissue paper ( 10 cm diameter) were placed in a Petri dish; 10 mL of 0.05% w/v eosin dye

Table 1. Compositions of ODTs containing 8 mg of ondansetron HCl and prepared by wet granulation method.

Concentration of chitosan solution* (% w/v) Glycine (% w/w)

Colloidal silica (% w/w)

Spray dried lactose (q.s to)

1–7WG

1.0 60,55,50,45,40, 35 and 30

1 100 mg

8WG-14WG 1

1.5 60,55,50,45,40,35 and 30

100 mg

15WG-21WG 1

2.0 60,55,50,45,40,35 and 30

100 mg

22WG-28WG 1

2.5 60,55,50,45,40,35 and 30

100 mg

29WG-35WG 1

3.0 60,55,50,45,40,35 and 30

100 mg

*Chitosan solution prepared by dissolving chitosan in 2% v/v acetic acid.

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solution in water was added to the Petri dish. A tablet was carefully placed on the surface of the tissue paper. The time required for the dye solution to appear on the upper surface of tablet was noted as wetting time.[3]

Water absorption ratio (WAR)Tablet was weighed and carefully placed on the surface of the filter paper and the whole procedure discussed above was repeated using distilled water alone in place of the dye solution. After complete wetting of the tablet it was weighed again and the water absorption ratio was calculated using following Equation (1):

WAR W W /Wb a a= −( ) (1)

where Wa and W

b are the tablet weights before and after

water absorption, respectively.

Weight variationThe weight variation test was performed on 20 tablets col-lected randomly from a batch. The procedure described in USP30NF25 was followed for this test.

FriabilityTwenty tablets were weighed and placed in a Roche fria-bilator. The friabilator was rotated at 25 rpm for 4 min. The tablets were then reweighed after removal of fines (using 60 mesh sieve) and the percentage of weight loss was calculated.

Content uniformityFor estimation of ondansetron HCl content in prepared tablets, 30 tablets were randomly selected from each batch and 10 tablets were analyzed individually. The amount of ondansetron HCl in ODTs was determined spectrophotometrically in 0.1 N HCl by measuring the first derivative reading at 310 nm using Beckman DU-640B UV/VIS spectrophotometer.

In vitro disintegration time (DT)The in-vitro DT of ondansetron HCl ODTs was estimated using texture analyzer (TAXT-Plus, Stable Microsystems, UK). The ondansetron HCl ODTs were adhered (one at a time) to the bottom of a probe with a double-sided adhesive tape. The probe was in turn attached to the load cells. The texture analyzer was set at compression mode with pretest speed of 0.5 g/s and forced target mode of 50 g. The hold time and trigger force were 60 s and 50 g, respectively. With constant force, the ODT was intro-duced to a reservoir containing 6 mL of simulated saliva. When tablet started to disintegrate, the rate of move-ment of the probe traveled showed a sudden increase. This increase rate continued until the tablet disinte-grated. The point where the increased rate of movement

stopped was taken as the disintegration time. The data reported is the average of six individual determinations.

In vivo disintegration timeThe time required by ondansetron HCl ODT for com-plete disintegration in the oral cavity was measured in six healthy, trained male volunteers in the age group of 18–25 years. The end point of disintegration in the oral cavity was measured as the time when the tablet placed on the tongue disintegrated without leaving any lumps. The volunteers were given strict instructions not to chew or swallow the tablets, although, licking was allowed. All the volunteers were instructed to rinse their mouth after completion of test. The data reported is the mean ± stand-ard deviation (SD) of six individual determinations.

In vitro release studiesOndansetron HCl released from ODTs was evaluated by using USP dissolution apparatus II – paddle (Tab-Machines, Mumbai, India). 0.1 N HCl (500 mL) main-tained at 37 ± 0.5°C and stirred at 50 rpm was employed as dissolution media with stirring speed of 50 rpm. Aliquots (5 mL) withdrawn at various time intervals were imme-diately filtered through Whatman filter paper (28 µm), diluted suitably and analyzed for ondansetron HCl spec-trophotometrically (Beckman DU 640B UV/VIS spec-trophotometer) at 310 nm. The absorbance values were transformed to concentration by reference to a standard calibration curve obtained experimentally (r2 = 0.9997).

Similarity and dissimilarity factorsA model independent approach was used to estimate dis-similarity factor (f

1) and similarity factor (f

2) to compare

dissolution profile of ODTs containing chitosan and gly-cine, with ODTs containing superdisintegrant.[8] The FDA and SUPAC-IR guidance define difference factor (f

1) as

the calculated percent difference between the reference and test curve at each time point and is a measurement of the relative error between the two curves. The follow-ing equations were used for calculating f

1 and f

2.

It is given by following Equation (2):

f R T R 1001t 1

n

t tt 1

n

t= − ×Σ Σ− −( )

é

ëêê

ù

ûúúé

ëêê

ù

ûúú

ìíïïîïï

üýïïþïï

/

(2)

The similarity factor (f2) is given according to

Equation (3):

f n R T2 t tt 1

n

= × − ×=

−

50 1 1 10020 5

log /.

+ ( )é

ëêêê

ù

ûúúú

ìíïïï

îïïï

üýïïå ïï

þïïï

(3)

where n is the number of pull points, Rt is the reference

batch profile at time point t and Tt is the test batch

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Orodispersible tablets of ondansetron HCl 479

profile at the same time point t. For in vitro dissolution curves to be considered similar f

1 values should be in

the range of 0–15 while values of f2 should lie within

50–100.

Physicochemical characteristics of ondansetron HCl ODTs

Infrared absorption spectroscopic analysisA sample of chitosan powder, glycine, spray dried lactose powder, chitosan-lactose granules, dried chitosan-glycine complex, crushed and powdered optimized ODTs prepared by wet granulation or by direct compression method, disintegrated (in artificial saliva pH 6.8) and dried optimized ODT samples pre-pared either by wet granulation or direct compression method, chitosan-glycine physical mixture, chitosan-glycine-ondansetron physical mixture or ondansetron HCl was subjected to FTIR spectral analysis. A sample of chitosan-glycine complex was prepared by adding 10 mL of chitosan solution (3% w/v in 2% acetic acid) into glycine solution (0.5% w/v prepared in distilled water). The precipitates formed were washed with dis-tilled water, dried and subjected to FTIR analysis. The spectra of each KBr disc were recorded on IR spectro-photometer (Perkin Elmer RXI, USA) in the spectral region of 500– 4000 cm−1.

Differential scanning calorimetric (DSC) analysisEach sample as prepared for FTIR spectral analysis was also subjected to Differential scanning calorimetry (Mettler Toledo Star System, 821E, Switzerland) at a heating rate of 10°C/min and in a temperature range of 40–400°C.

Results and discussion

Orally disintegrating dosage forms dissolve or disinte-grate in the patient’s mouth within less than a minute without the intake of water. Therefore, these tablets are easily swallowed. This is the reason that these tablets have high patient compliance. Moreover, most of the researchers are looking for new, safe and effective dis-integrating agents that can rapidly disintegrate tablets prepared even high tablet crushing strength greater than 3.5 kg. The water insoluble diluents such as Avicel (PH 102) and di-calcium phosphate were previously highly preferred for orally disintegrating tablets. However, nowadays, these agents are seldom used because they cause an unacceptable feeling of grittiness in the mouth. Therefore, water soluble diluents such as spray dried lactose and biodegradable polymers were selected as model excipients in the present investigation.

Wet granulation technique

Chitosan is a biodegradable polymer and has a good binding property.[12] However, chitosan is insoluble in water. Therefore, it is solubilized in water as chitosan acetate, which is prepared by adding chitosan in 2% (v/v) acetic acid solution. Glycine, an amino acid is sweet in taste. It has less polar surface free energy and exhibits with low WT.[10] Therefore, a combination of glycine (wetting enhancer) and chitosan (a swellable biodegradable polymer) was used to prepared ODTs of ondansetron HCl.

The weight variation, % friability and content uni-formity of all the ondansetron HCl ODTs prepared by wet granulation method were, respectively, 2.98%, 1.19% and 98.5 ± 1.3%. The results revealed that an increase in concentration of chitosan increased the DT as well as WT (Figure 1). The WT indicates water absorbing capacity of a tablet.[10] Therefore, an increase in WT suggested a decrease in water absorbing capac-ity possible due to reduced swellability of acetylated Chitosan (Chitosan is solubilized in acetic acid). Furthermore, Figure 2 indicated that decrease in the concentration of glycine, decreased the WT as well as DT. This observation seems to be due to reduced wick-ing property of glycine, which could be attributed to its interaction with Chitosan during disintegration proc-ess. However, tablets prepared with higher crushing strength showed greater DT as well as WT as shown in Figure 1.

Overall, the DT tablets possessing crushing strength greater than 3.0 kg ranged between 45– 60 s (some-times exceeding 60 s). This is near the upper limit of 60 s required of orodispersible tablets.[13,14] Therefore, orodispersible tablets containing chitosan (as binder), glycine and prepared by wet granulation method could

0

10

20

30 40

50

60

70

80

1 1.5 2 2.5 3 concentration of chitosan(%w/w)

In v

itro

DT/

WT

(in s

ec)

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2

WA

R (%

)

in vitro DT4 In vitro DT3 In vitro DT2 WT4 WT3 WT2 WAR4 WAR3 WAR2

Figure 1. Effect of concentration of chitosan on in vitro disintegration time (DT), wetting time (WT) and Water absorption ratio (WAR) at tablet crushing strengths of 2, 3 and 4 kg in ODTs prepared by wet granulation method.

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not be considered as a better disintegrating system for ondansetron HCl.

Direct compression technique

The evaluation of ondansetron HCl ODTs prepared by direct compression method revealed that these ODTs satisfied the official limit of DT for ODTs. Further, an increase in concentration of chitosan in these ODTs sig-nificantly (P < 0.05) decreased the in vitro DT (Figure 3). The decrease in in vitro DT was due to decrease in WT and increase in the WAR. This suggested that chitosan

reduced the WT and increased the water absorbing capacity of ODTs in presence of glycine. This is the reason that a combination of chitosan and glycine was capable of disintegrating ODTs in less than 40 s even when the tablets prepared possessed crushing strength greater than 4.0 kg.

Croscarmellose sodium and Crospovidone are well known superdisintegrants used in ODTs. They have excellent disintegrating ability. Croscarmellose sodium swells to a large extent after coming in contact with water, to disintegrate tablets. Also, it has fibrous nature that allows intraparticulate as well as extraparticulate

0

10

20

30

40

50

60

70

80

90

30 35 40 45 50 55 60Concentration of glycine (%w/w)

In v

itro

DT(

sec)

/WT(

sec)

0

0.2

0.4

0.6

0.8

1

1.2

WA

R(%

)

in vitro DT4 WT4 WAR4

Figure 2. Effect of concentration of glycine on in vitro disintegration time (DT), wetting time (WT) and water absorption ratio (WAR) at a tablet crushing strength of 4.0 kg and 1% (w/w) concentration of chi-tosan in ODTs prepared by wet granulation method.

0

5

10

15

20

25

30

35

40

45

2.5 5 7.5 10 12.5 15Concentration of chitosan (% w/w)

In v

itro

DT

(sec

)/WT

(sec

)

0

0.5

1

1.5

2

2.5

3

WA

R (%

)

in vitro DT4 in vitro DT3 in vitro DT2WT4 WT3 WT2WAR4 WAR3 WAR2

Figure 3. Effect of concentration of chitosan (% w/w) on in vitro disintegration time (DT), wetting time (WT), water absorption ratio (WAR) at tablet crushing strength of 2, 3 and 4 kg in ODTs prepared by direct compression method.

Table 2. Formulations of directly compressed ondansetron HCl ODTs containing crospovidone (CP), croscarmellose sodium (CS) or chitosan-glycine mixture (DS) with their in vitro disintegration time.

Formulation no. CP1

CP2

CP3

CP4

CS1

CS2

CS3

CS4

DS1

DS2

DS3

DS4

Spray dried lactose (mg)

88.5 86 83.5 81.0 88.5 86.0 83.5 81.0 - - - -

Croscarmellose sodium (mg)

- - - - 2.5 5 7.5 10 - - - -

Crospovidone (mg)

2.5 5 7.5 10 - - - - - - - -

Ondansetron HCl (mg)

8 8 8 8 8 8 8 8 8 8 8 8

Chitosan (mg) - - - - - - - - 2.5 5.0 7.5 10

Glycine (mg) - - - - - - - - 60 60 60 60

Colloidal silica (mg)

1 1 1 1 1 1 1 1 1 1 1 1

Potato starch (mg)

- - - - - - - - 28.5 26.5 23.5 21.5

Total weight (mg) 100 100 100 100 100 100 100 100 100 100 100 100

Tablet crushing strength (kg)

3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 4.0 4.0 4.0 4.0

In vitro disintegration time* (s)

47 ± 4 37 ± 3 32 ± 3 29 ± 2 51 ± 4 42 ± 3 36 ± 3 32 ± 2 34 ± 3 28 ± 2 25 ± 2 21 ± 2

*Values represent mean ± standard deviation (SD); (n = 6).

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Orodispersible tablets of ondansetron HCl 481

wicking of water even at low concentration level.[6] Crospovidone has excellent wicking nature though it swells only to a small extent.[15] The ODTs containing Croscarmellose sodium or Crospovidone are reported to disintegrate within 30 s at tablet crushing strength of 3 kg. However, in tablets having crushing strength greater than 3 kg, the DT exceeds 60 s.[9] Hence, the max-imum value of tablet crushing strength of ODTs pre-pared using Croscarmellose sodium or Crospovidone was fixed at 3 kg (Table 2). The results indicated that DT of ODTs containing Croscarmellose sodium (CS

1–CS

4)

or Crospovidone (CP1–CP

4) decreased with an increase

in concentration of either of the superdisintegrants.The batches CS

4, and CP

4 were selected as they

showed lowest in vitro DT. Also, DS4 was found to be

the best formulation of ondansetron HCl ODTs con-taining chitosan and glycine and prepared by direct compression method. Therefore, formulations CS

4 and

CP4 were taken for comparison with DS

4 formulations.

The results of in vitro DT and WT revealed that both parameters followed the order CS

4 > CP

4 > DS

4 in tablets

possessing more than 3 kg crushing strength (Figure 4). Similar results were observed when DT was observed in the oral cavity (Figure 5). This indicates that DS

4

batch showed most quick wetting as well as disinte-gration in the oral cavity even when at tablet crushing strength greater than 3 kg. On the other hand, CS

4 and

CP4 batches did not exhibit this property. Hence, tab-

lets of DS4 batch could be suggested to be better than

those of CS4 and CP

4 batches with respect to friability

and DT.The dissolution studies of tablets of CS

4, CP

4 and DS

4

batches in 0.1 N HCl revealed that 89% of ondansetron HCl was released within five min. as shown in Figure 6. Further, a comparison of dissolution data of CS

4, CP

4 and

DS4 ODTs was conducted using f

1 and f

2 statistics. An f

1

of 1.9 and 1.852 was obtained for CS4 vs. DS

1 and CP

4 vs.

DS4, respectively. Also, an f

2 of 67.4 for CS

4 vs. DS

4 and

67.82 for CP4 vs. DS

4 was obtained. This indicated that

the release profiles of CS4, CP

4 and DS

4 ODT batches in

0.1N HCl were comparable and in good agreement with each other. Therefore, in the light of the above evaluation results it can be hypothesized that glycine and chitosan combination could be used as superdisintegrant for preparing ODTs of ondansetron HCl having comparable drug release and better in vitro as well as in vivo DT as compared to ODTs containing Croscarmellose sodium or Crospovidone.

Direct compression vs. wet granulation: Reasons for paradoxical behavior of chitosan and glycine

A comparison of the DT of ODTs revealed that tablet crushing strength significantly (P < 0.05) influenced the DT of ODTs prepared with various concentrations of chitosan, irrespective of type of method used to prepare

0

20

40

60

80

2 2.5 3 3.5 4Tablet crushing strength (kg)

In v

itro

disi

nteg

ratio

n tim

e(s

ec)

0

20

40

60

80

Wet

ting

time

(sec

)

DT of CS4 WT of CS4 DT of CP4WT of CP4 DT of DS4 WT of DS4

Figure 4. Relationship between in vitro disintegration time and wet-ting time with tablet crushing strength of directly compressed ODTs prepared using croscarmellose sodium (CS

4) or crospovidone (CP

4)

or chitosan-glycine (DS4) mixture.

0

20

40

60

80

2 2.5 3 3.5 4Tablet crushing strength (kg)

In v

itro

disi

nteg

ratio

n tim

e (s

ec)

0

20

40

60

80

Wet

ting

time

(sec

)

DT of CS4 WT of CS4 DT of CP4WT of CP4 DT of DS4 WT of DS4

Figure 5. Relationship between in vivo disintegration time and wet-ting time with tablet crushing strength of directly compressed ODTs prepared using croscarmellose sodium (CS

4), crospovidone (CP

4) or

chitosan-glycine mixture (DS4).

0

20

40

60

80

100

0 5 10 15 20 25 30 35Time (min)

% C

umul

ativ

e am

ount

rele

ased

DS4CS4CP4

Figure 6. In vitro dissolution of ondansetron ODTs batches contain-ing croscarmellose sodium (CS

4), crospovidone (CP

4) or chitosan-

glycine mixture (DS4) and prepared by direct compression method.

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them. The DT increased in tablets prepared by wet granulation but decreased in tablets prepared by direct compression method with an increase in the concentra-tion of chitosan as shown in Figure 7. The IR spectra of chitosan powder showed band characteristics of OH groups (3450– 3100 cm−1), -C-H stretching between ( 2990 cm−1 and 2850 cm−1 ), free primary −NH

2 group

( 1220 cm−1 and 1020 cm−1) and at 1610cm−1 represent-ing acetylated amino groups (Figure 8A). For glycine, absorption bands at 1130 cm−1 and 1040 cm−1(free-NH

2

group) and at 1332 cm−1(−COOH group) were observed (Figure 8B). The IR spectrum of lactose granules pre-pared using chitosan (solution dissolved in acetic acid) as binder (Figure 8D) showed symmetric and antisym-metric stretch corresponding to 1412 cm−1 and 1501 cm−1, respectively. Absorption band at 1610 cm−1 indicated presence of chitosan in ionized state (because of pres-ence of −NH

3+ moieties). The IR spectra of chitosan-

glycine complex gave prominent peaks at 1595 cm−1, 1515 cm−1, 1407 cm−1, 1330 cm−1 indicating the presence of ammonium ion (−NH

3+), antisymmetric stretch of car-

boxylate ion (−COO−), symmetric stretch of carboxylate ion and carboxylic acid (Figure 8E). Similarly, peaks at 1597 cm−1 (for ammonium ion), 1520 cm−1 and 1410 cm−1 (for carboxylate ion) and 1350 cm−1 (for carboxylic acid) are seen in IR spectra of disintegrated and dried ODTs containing chitosan- glycine and prepared by wet granu-lation method (Figure 8F). Hence, the ionized chitosan can be expected to have interacted with chitosan dur-ing disintegration. This would have reduced the wicking efficiency of glycine as well as water absorption and swelling property of chitosan. Therefore, the DT of ODTs prepared using wet granulation method decreased with an increase in concentration of chitosan. However, peaks at 1595 cm−1 representing ammonium ion as well as at 1515 cm−1 and 1407 cm−1 representing carboxylate ions were absent in physical mixture of chitosan, glycine

and ondansetron HCl (Figure 8G and 8H). This indicated that there was no interaction between chitosan, glycine and ondansetron HCl in ODTs prepared by direct com-pression method. Hence, the −NH

2 groups of glycine

and chitosan were free to interact with water molecules resulting in efficient wicking as well as swelling thereby, resulting in a decrease in DT with increase in concentra-tion of chitosan.

All the DSC thermograms showed an endothermic transition below 100°C. This could be attributed to the moisture present in the samples or due to presence of acetic acid. The thermogram of chitosan powder revealed one exothermic transition at 311.5°C along

0

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2 3 4Tablet crushing strength (kg)

In v

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n tim

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ec)

0

20

40

60

80

Wet

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)

DT DC WT DC DT WG WT WG

Figure 7. Effect of tablet crushing strength on in vitro disintegration time (DT) and Wetting time (WT) of ondansetron HCl ODT batches prepared by either wet granulation (WG) or direct compression (DC) method.

% T

rans

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A

B

C

D

E

F

G

H

I

J

4000 3000 2000

Wave number (cm−1)

1500 1000 500

Figure 8. FTIR spectra of chitosan powder (A), glycine (B), lactose (C), lactose granules prepared by using chitosan (D), chitosan- glycine complex (E), disintegrated (in artificial saliva pH 6.8) and dried ODTs prepared by wet granulation (F), chitosan-glycine physical mixture (G), chitosan-glycine-ondansetron HCl physical mixture (H), dis-integrated (in artificial saliva pH 6.8) and dried ODTs prepared by direct compression (I) and ondansetron HCl (J).

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A

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Figure 9. DSC thermogram of chitosan powder (A), glycine (B), lac-tose (C), lactose granules prepared by using chitosan (D), chitosan-glycine complex (E), disintegrated (in artificial saliva pH 6.8) and dried ODTs prepared by wet granulation (F), chitosan-glycine physi-cal mixture (G), chitosan-glycine-ondansetron HCl physical mixture (H), disintegrated (in artificial saliva pH 6.8) and dried ODTs pre-pared by direct compression (I) and ondansetron HCl (J).

with one endothermic transition below 100°C. The exotherm is attributed to degradation of chitosan at 311.5°C (Figure 9A). Glycine produced one endo-thermic transition at 261°C because of its melting (Figure 9B). The DSC thermogram of lactose pow-der produced one endothermic transition at 220°C (Figure 9C). The DSC thermogram of lactose granules prepared by using chitosan solution as binder indi-cated two endothermic transitions, one below 100°C and other at 219°C, along with one exothermic transi-tion at 280°C (Figure 9D). The H of first endothermic transition in these granules was 246.1 J/g, which was higher than the H of first endothermic transition of chitosan powder as shown in Table 3. This may be due to presence of acetic acid as well as moisture in lactose granules.

The chitosan-glycine complex produced two endothermic transitions each at 96.57°C and 232°C (Figure 9E). The first endotherm could be attributed to the presence of moisture or acetic acid in the complex. The second endothermic transition seems to arise due to interaction of chitosan with glycine. The DSC ther-mogram of disintegrated (in artificial saliva pH 6.8) and dried ODTs prepared by wet granulation showed a similar peak at 234.6°C (Figure 9F). The occurrence of this endotherm in chitosan-glycine complex as well as in disintegrated tablets strongly suggested that chi-tosan had interacted with glycine in ODTs prepared by wet granulation method (Figure 9F). However, this second endothermic transition at 234.6°C was absent in physical mixtures containing chitosan and glycine (Figure 9G and 9H) as used in direct compression

Table 3. DSC analysis of chitosan or its combinations with glycine used in wet granulation or direct compression method.

Sr. No. Samples

Endotherms Exotherms

First Second Third Fourth First Second

Tm

(°C) H (J/g) Tm

(°C) H (°C) Tm

(J/g) H (J/g) Tm

(J/g) H (J/g) Tm

(°C) H (J/g) Tm

(°C) H (J/g)

1 Chitosan 70.2 173.3 - - - - - - 311.5 116.46 - -

2 Glycine - - - - - - 261 825 - - - -

3 Lactose - - - - 220 232 - - - - - -

4 Lactose granules 80.64 246.1 - - 219 230 - - 280 101.9 - -

5 Chitosan-glycine complex 96.57 256 - - - - 232 282 - - - -

6 Disintegrated (at pH 6.8) and dried ODTs prepared by wet granulation

97 259 - - 219 230 234.6 279 - - - -

7 Chitosan-glycine Physical mixture

70 168 - - - - 262.4 804 310 114 - -

8 Chitosan-glycine-ondansetron HCl physical mixture

72 169 105 192 184 84 264 810 309 114 335.2 122

9 Disintegrated (at pH 6.8) and dried.ODTs prepared by direct compression

73.2 171.3 104.1 190 180 82 264 813 312 118 337.2 126

10 Ondansetron HCl - - 105.3 192 186 86 - - - - 331.2 120

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method and even in disintegrated and dried ODTs prepared by direct compression method (Figure 9I). Moreover, physical mixtures between chitosan, glycine and ondansetron HCl gave similar peaks as seen in their individual thermogram (Table 3). Therefore, the interaction of ionized chitosan with glycine made wet granulation method less efficient in decreasing the DT of ODTs as compared to direct compression method.

Conclusion

The present investigation revealed overwhelming influ-ence of chitosan, when present in ionized or union-ized state in influencing the disintegration of ODTs. The −NH

3+ moieties of chitosan interacted with COO−

moieties of glycine in ondansetron HCl ODTs prepared by wet granulation method. This interaction reduced the wicking efficiency of glycine and decreased the swelling property of chitosan. Therefore, an increased WT as well as DT (in vivo and in vitro) with increase in concentration of chitosan was observed ODTs pre-pared by wet granulation method. On the other hand, in direct compression method, chitosan was present in unionized state. Increase in concentration of chitosan, decreased the DT (in vitro and in vivo) in the tablets prepared by direct compression. This was correlated with decrease in WT and increase in WAR. Further, the ODTs formulated with chitosan and glycine even at higher crushing strength exhibited significantly lower DT as compared to those formulated with well known superdisintegrants Croscarmellose and Crospovidone. It is noteworthy to envisage that this novel combina-tion of chitosan and glycine could be considered as a superdisintegrating system in the future for formulat-ing ODTs.

Acknowledgements

We gratefully acknowledge Panacea Biotech Ltd. (Lalru, India), and Ind-Swift Labs, (Parwanoo, India) for providing gift samples to complete this work. We are highly thankful to Mr G.S. Saxena for providing the instrumentation facilities of texture analyser in his company.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

References

1. Chang RK, Guo X, Burnside BA, Couch RA. Fast dissolving tab-lets. Pharm Technol 2000;24(6):52–59.

2. Ghosh TK, Pfister WR. Quick dissolving oral dosage forms: Scientific and regulatory considerations from a clinical phar-macology and biopharmaceuticals perspective. In: Ghosh TK, Pfister WR, editors. Drug delivery to the oral cavity: Molecules to market. New York: CRC Press: 2005:337–356.

3. Gohel M, Patel M, Amin A, Agrawal R, Dave R, Bariya N. Formulation design and optimization of mouth dissolve tablets of nimesulide using vacuum drying technique. AAPS Pharm Sci Tech 2004;5(3):E1–6.

4. Virely P, Yarwood R. Zydis – a novel, fast dissolving dosage form. Manufac Chem 1990;36–37.

5. Sugimoto M, Narisawa S, Matsubara K, Yoshino H, Nakano M, Handa T. Effect of formulation ingredients on rapidly disinte-grating oral tablets prepared by crystalline transition method. Chem Pharm Bull 2006;54(2):175–180.

6. Bi Y, Sunada H, Yonezawa Y, Danjo K. Evaluation of rapidly disintegrating tablets prepared by direct compression method. Drug Dev Ind Pharm 1999;25(5):571–581.

7. Zhao N, Augsburger LL. Functionality comparison of 3 classes of superdisintegrants in promoting aspirin tablet disintegration and dissolution. AAPS Pharm Sci Tech 2005;6(4):E634–640.

8. Sutaryia VB, Mashru RC, Sankalia MG, Sankalia JM. Preparation of rapidly disintegrating tablets of ondansetron hydrochloride by direct compression method. Ars Pharm 2006;47(3):293–311.

9. Fukami J, Yonemochi B, Yoshihashi Y, Terada KS. Evaluation of rapidly disintegrating tablets containing glycine and car-boxymethylcellulose. Int J Pharm 2006;310:101–109.

10. Fukami J, Ozawa A, Yonemochi B, Yoshihashi Y, Terada K. Development of fast disintegrating compressed tablets using amino acid as disintegration accelerator: Evaluation of wetting and disintegration of tablet on the basis of surface free energy. Chem Pharm Bull 2005;53(12):1536–1539.

11. Salem II, Lopez JMR, Galan AC. Ondansetron hydrochloride. In: Brittain HG, editor. Analytical profiles of drug substances and excipients. Vol. 27. California: Academic Press; 2001:301–308.

12. Nunthanid J, Laungtana-anan M, Sriaornsak P, Limmatvapirat S, Puttipatkhachorn S, Lim Y, Khor E. Characterisation of chitosan acetate as a binder for sustained release tablets. J Cont Rel 2004;99(1):15–26.

13. Morita Y, Tsuslma Y, Yasui M, Termoz R, Ajoika, J, Takayama K. Evaluation of disintegration time of rapidly disintegrating tab-lets via novel method utilizing a CCD camera. Chem Pharm Bull 2002;50(9):1181–1186.

14. Schiemeir S, Schmidt PC. Fast dispersible ibuprofen tablets. Eur J Pharm Sci 2002;15:295–305.

15. Sakr A, Bose M, Menon A. Comparative effectiveness of super-disintegrants on the characterstics of directly compressed tri-amterene hydrochlorethiazide. Pharm Ind 1993;55(10):953–957.

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