Formulation Development and Evaluation of Fast Dissolving Theophylline Tablets

 

S. Palanichamy, C. Prabhu, M. Rajesh*, L. Subramanian, and A. Thanga Thirupathi.

Department of Pharmaceutics, Sankaralingam Bhuvaneswari College of Pharmacy, Anaikuttam, Sivakasi. 626130. Tamilnadu, India.

*Corresponding Author E-mail: mrajeshpharm@gmail.com  

 

ABSTRACT:

Over the past three decades, FDT has gained much attention as a preferred alternative to conventional oral dosage forms such as tablets and capsules. FDT is a solid dosage form that disintegrates and dissolves in the mouth (either on or beneath the tongue or in the buccal cavity) without water. In the present work, 10 formulations of fast dissolving tablets of theophylline (F1 to F9) using three different superdisintegrants namely crospovidone, sodium starch glycolate and pregelatinized starch with three concentrations (2%, 3% and 5%) and a control F10 (without superdisintegrant) were prepared by direct compression method. The final blend of the drug and excipients were evaluated for powder flow properties, bulk density, tapped density, compressibility index and hausner’s ratio. All the formulations were evaluated for weight variation, disintegration time, hardness, friability, wetting time and water absorption ratio. Formulation F3 showed the lowest disintegration time and more water absorption ratio. In vitro dissolution studies revealed that formulation F3 showed 97.83 % percent drug release at the end of 30 minutes. The stability studies for the formulation F3 showed no significant change in disintegration time, drug content and percentage of drug released when stored at 450C±20C/ 75% RH for a period of 90 days. These results revealed that the formulation F3 containing crospovidone (5%) as superdisintegrant was better one which satisfied all the criteria as a fast dissolving tablets.

 

KEYWORDS: Direct compression, Fast dissolving tablets, Superdisintegrant, Theophylline.

 


 

INTRODUCTION:

Theophylline, a adenosine receptor antagonist is an effective anti- asthmatic agent used in the treatment of bronchial asthma and chronic obstructive pulmonary Disease (COPD).1 Theophylline is a poorly water soluble drug. When it is administered orally it causes problems in dissolution rates and bioavailability due to its poor solubility in biological fluids. The present work was aimed at increasing the rate of dissolution of theophylline, thus providing faster rate of absorption by adding potential superdisintegrants like crospovidone, sodium starch glycolate and pregelatinized starch in tablet formulations. Mannitol was used as sweetening agent to mask the bitter taste of theophylline.2 The FDT of theophylline may overcome problems such as difficulty in swallowing, inconvenience in administration while traveling and patient’s acceptability.3

 

The bioavailability of FDT may be increased due to absorption of drugs in oral cavity and also due to pregastric absorption of saliva containing dispersed drugs that pass down into the stomach. Moreover, the amount of drug that is subjected to first pass metabolism is reduced as compared to preparation without superdisintegrant4. The main criteria for FDT is to disintegrate / dissolve rapidly in oral cavity with saliva within 15-60 seconds without the need of water and should have a pleasant mouth feel.

 

MATERIALS:

Theophylline was procured from Amaratal and Co. Chennai, India. Crospovidone, Magnesium stearate and Talc were procured from Loba Chemie., pvt. Ltd, Mumbai, India. Sodium starch glycolate, microcrystalline cellulose and Mannitol were procured from S.d fine- chem., Pvt. Ltd, Mumbai, India. Pregelatinized starch was procured from paxmy specility chemicals, Mumbai, India.

 

METHODS:

Preparation of Theophylline FDTs:

The formulations of FDTs of theophylline were prepared by direct compression method.  Total 10 formulations (F1 to F9) of fast dissolving tablets of Theophylline using three different superdisintegrants namely Crospovidone, sodium starch glycolate and pregelatinized starch with three concentrations (2%, 3% and 5%) were prepared by direct compression method. A control tablet was also prepared without any superdisintegrant (F10). All the ingredients were passed through mesh no.60 separately and collected. The drug, superdisintegrant, mannitol and microcrystalline cellulose were mixed uniformly with gentle trituration using mortar and pestle to get a uniform mixture. Finally magnesium stearate and talc were added and mixed well. The tablets were compressed using 12 mm flat- face surface punch tablet compression machine to get tablet of 400 mg weight.5,6 (Table-1). Before tablet preparation, the mixture blend of all the formulations were subjected to compatibility studies (IR) and precompression parameters like bulk density, tapped density, compressibility index and hausner’s ratio.

 

EVALUATION OF POWDER BLEND:

Angle of repose: 7

The angle of repose of powder blend was determined by the funnel method. The accurately weighed powder blends were taken in funnel. The height of the funnel was adjusted in such a way that the tip of the funnel just touches the heap of the powder blend. The powder blends were allowed to flow through the funnel freely onto the surface. The diameter of the powder cone was measured and angle of repose was calculated using the following equation

θ= tan -1 (h/r)

Where ‘h’ and ‘r’ are the height and radius of the cone.

 

Bulk density: 8

Bulk density Pb is defined as the mass of the powder divided by the bulk volume and is expressed as g/cm3. Weighed quantity of powder blend from each formulation was taken in a measuring cylinder and the initial volume of the powder blend in the measuring cylinder was noted. This was calculated by using the formula

Pb = M / Vb

Where, Pb - Bulk density, M - Weight of the sample in g, Vb- Final volume of the blend in cm3.

 

Tapped density:

It is the ratio of total mass of the powder to the tapped volume of powder. The volume was measured by tapping the powder blend for 500 times. Then the tapping was done for 750 times and the tapped volume was noted. Tapped density was calculated by using the following formula

Pt  = M / Vt

Where,

Pt-Tapped density, M - Weight of the sample in g, Vt - Tapped volume of blend in cm3.

 

Compressibility index and Hausners ratio: 9

The compressibility index of the powder blend was determined by Carr’s compressibility index and the Hausners ratio is calculated by using the formula

Hausners ratio = Tapped density / Bulk density

Carr’s index (%) = [(TBD-LBD) x 100] / TBD

TBD = Total bulk density, LBD = Loose bulk density

 

IR Spectral analysis: 10

It was used to study the interactions between the drug and the excipients. The KBR disk method was used for preparation of sample and spectra were recorded over the wave number 4000 to 500 cm-I in a SHIMADZU FTIR (model- 8400) spectrophotometer. IR spectral studies of Pure Theophylline and Theophylline containing highest proportion of individual superdisintegrant were carried out. If there was no change in peaks of mixture when compared to pure drug, it indicates the absence of interactions.

 

EVALUATION OF TABLETS:

Weight variation: 6

Twenty tablets were randomly selected and individually weighed. The average weight of tablets was calculated. Then the individual weight was compared with that of average weight.

 
Hardness: 11

The tablets to be tested are held between a fixed and a moving jaw of hardness test apparatus (Monsanto) and reading of the indicator is adjusted to zero. The screw knob was moved forward until the tablet breaks and the force required breaking the tablet was noted.

 

Friability: 12

Friability test was performed using Roche friabilator. Ten tablets were weighed and placed in the friabilator, which was then operated for 25 revolutions per minute. After 100 revolutions the tablets were dusted and reweighed. The percentage friability was determined using the formula,

 

Percentage friability = Initial weight - Final weight × 100

                                                   Initial weight

 

In vitro disintegration time: 13

The test was carried out in a disintegration apparatus using distilled water (at 370 C ± 0.50 C) as disintegration medium. A tablet was placed in each of six tubes of the apparatus and one disc was added to each tube. The time taken for complete disintegration of the tablet with no mass remaining in the apparatus was measured in seconds.

 

Wetting time and water absorption ratio: 5

Wetting time is closely related to the inner structure of the tablets and hydrophilicity of the excipient. A piece of tissue paper, folded double, was placed in a Petri plate containing 6 ml of distilled water. A preweighed tablet was placed on the paper and the time for complete wetting of the tablet was measured in seconds. The wetted tablet was then weighed. Water absorption ratio was determined using the formula,

R = (Wa-Wb)/Wa X 100

Where R = Water absorption ratio

Wa= Weight of tablet after wetting.

Wb= Weight of tablet before wetting.

 

Drug content: 5

Ten tablets from each formulation were powdered. The powder equivalent to 100 mg of Theophylline was weighed and dissolved in phosphate buffer pH 7.4 in 100 ml standard flasks. From this suitable dilution was prepared to get 10 µg/ml and the solution was analyzed at 277 nm using UV-double beam spectrophotometer using phosphate buffer pH 7.4 as the blank.

 

In-vitro drug release studies: 5.13

In vitro dissolution studies of theophylline FDTs were carried out using USP II paddle method at 50 rpm in 900 ml of pH 7.4 buffer solution as a dissolution medium. The dissolution medium was maintained at 37 ± 0.50C. 10ml sample was withdrawn at 10 minutes intervals of time. 10 ml of buffer solution (pH 7.4) was replaced to maintain the constant volume throughout the experiment. The samples were suitably diluted and the percentage of theophylline released from each formulation was measured at 277 nm using UV-visible spectrophotometer.

 

Stability Studies: 14

The stability test was carried out to evaluate the stability of Theophylline in formulations (F3, F6 and F9). The prepared tablets were kept at 450C ± 2 0C 75% RH for 90 days. Every 30 days interval, the tablets were evaluated for drug content, disintegration time and in-vitro drug release studies.

 

RESULTS AND DISCUSSION:

In the present study, ten batches (F1-F9) of theophylline FDTs were prepared with three superdisintegrants such as crospovidone, sodium starch glycolate and pregelatinized starch at various concentrations (2%, 3% and 5%) by direct compression method. Also one control batch (F10) was prepared without any superdisintegrant (Table-1).The final blend of the drug and excipients were evaluated for powder flow properties, Bulk density, Tapped density, Compressibility index and Hausner’s ratio. The values of pre-compression parameters evaluated were found to be within the prescribed limits and indicated good free flowing property (Table-2). Infra-red (IR) spectroscopy was used as means of studying drug – excipient compatibility and confirmed by comparing undisturbed structure of IR spectra of Pure theophylline  with theophylline containing highest proportion of superdisintegrants. It showed that IR spectrum of pure theophylline and theophylline containing highest proportion of superdisintegrants were similar fundamental peaks and patterns which indicated no drug excipient interaction (Figure-1 and 2).

 

The data obtained of post-compression parameters such as hardness, friability, weight variation, amount of drug content, disintegration time, wetting time and water absorption ratio are shown in table-3. The hardness was found to be in the range of 3.84 ± 0.49 to 4.24± 0.62 kg/cm2 in all the formulations indicating good mechanical strength with an ability to withstand physical and mechanical stress conditions, while handling. In all the formulations, the friability values were less than 1% and meet the United States pharmacopoeia (U.S.P) limits. All the tablets passed weight variation test as the percentage weight variation was within the U.S.P limits. (Table-3).


 

 

 

Table 1: Formulation Design of Theophylline Fast Dissolving Tablets

S .No

INGREDIENTS (mg)

F1

F2

F3

F4

F5

F6

F7

F8

F9

F10

1.

Theophylline

100

100

100

100

100

100

100

100

100

100

2.

Crospovidone

8

12

20

_

_

_

_

_

_

_

3.

Sodium starch glycolate

_

_

_

8

12

20

_

_

_

_

4.

Pregelatinized starch

_

_

_

_

_

_

8

12

20

_

5.

Mannitol

10

10

10

10

10

10

10

10

10

10

6.

Microcrystalline cellulose

266

262

254

266

262

254

266

262

254

274

7.

Talc

8

8

8

8

8

8

8

8

8

8

8.

Magnesium stearate

8

8

8

8

8

8

8

8

8

8

Formulations Fl, F2 and F3 contains crospovidone as superdisintegrant in 2%, 3% and 5% concentrations.

Formulations F4, F5 and F6 contains sodium starch glycolate as superdisintegrant in 2%, 3% and 5% concentrations.

Formulations F7, F8 and F9 contains pregelatinized starch as superdisintegrant in 2%, 3% and 5% concentrations.

Formulation F10 is control tablets (without superdisintegrant).

 

 

Table 2: Evaluation of powder blend

FORMULATION CODE

ANGLE OF

REPOSE*

BULK DENSITY* (g/cm3)

TAPPED  DENSITY* (g/cm3)

COMPRESSIBILITY INDEX* (%)

HAUSNER’S RATIO*

F1

32.42 ± 0.65

0.23 ± 0.01

0.23  ± 0.05

14.02  ±  0.47

1.16  ± 0.03

F2

33. 59 ± 0.79

0.19 ± 0.02

0.22 ± 0.04

15.20  ±  0.52

1.15 ± 0.06

F3

33. 77 ± 0.92

0.18 ± 0.03

0.20 ±  0.02

11.30 ±  0.73

1.12  ± 0.08

F4

33.95 ± 0.62

0.19 ± 0.03

0.22  ± 0.04

14.23  ± 0.62

1.16  ± 0.02

F5

33. 51± 0.56

0.19 ± 0.01

0.22 ±  0.02

13.66 ±  0.71

1.15 ±  0.06

F6

32. 98 ± 1.27

0.18 ± 0.02

0.21  ±  0.04

11.60 ±  0.28

1.12  ±  0.04

F7

32.93 ± 1.12

0.19 ± 0.03

0.21 ±   0.04

11.20  ±  0.64

1.12   ±  0.07

F8

32. 47 ± 0.95

0.19 ± 0.02

0.21  ±  0.02

11.52  ±  0.36

1.13  ±  0.05

F9

33. 57 ± 0.67

0.19 ± 0.02

0.21  ±  0.02

11.36   ± 0.98

1.12   ± 0.03

F10

32. 44 ± 0.59

0.19  ± 0.02

0.21  ±  0.03

12.28 ±    0.67

1.13  ±   0.07

*All values are expressed as mean ± standard deviation, n=3

 

 

Table 3: Evaluation of Theophylline fast dissolving tablets

FORMULATION

CODE

WEIGHT VARIATION*

(mg)

HARDNESS*

(kg/cm2)

FRIABILITY*

(%)

DRUG CONTENT* (%)

DISINTEGRATION

TIME* (SEC)

WETTING TIME*  (SEC)

WATER ABSORPTION RATIO* (%)

F1

0.398±0.004

4.04±0.37

0.90±0.33

98.66±0.23

44 ± 1.34

9±2.80

53.27±1.78

F2

0.399±0.003

4.04±0.42

0.92±0.39

99.03±0.77

36 ± 1.50

7±2.30

59.34±3.90

F3

0.398±0.005

4.04±0.37

0.92±0.32

99.37±0.24

29 ± 1.89

6±1.80

64.84±6.75

F4

0.398±0.006

3.88±0.24

0.90±0.35

9 7.96±0.12

48 ± 1.21

11±1.90

55.01±4.65

F5

0.398±0.002

4.16±0.83

0.95±0.31

98.32±0.84

38 ± 0.85

9±2.70

59.67±2.57

F6

0.399±0.002

3.84±0.49

0.97±0.37

98.36±0.67

32 ± 1.12

7±1.50

63.70±4.80

F7

0.398±0.006

3.96±0.31

0.85±0.34

98.42±0.68

49 ± 1.25

9±0.75

55.19±5.97

F8

0.399±0.003

4.00±0.32

0.90±0.35

97.40±0.71

39 ± 0.91

7±1.20

59.73±7.21

F9

0.398±0.002

4.24±0.62

0.97±0.38

98.60±0.61

36 ± 1.45

6±2.10

59.53±2.70

F10

0.398±0.001

4.04±0.56

0.82 ±0.32

98.90±0.63

42 ±  1.53

14±1.67

50.80±3.92

*All values are expressed as mean ± standard deviation, (n=3)   

A                                                                                                                     B

Figure-1   A - IR Spectrum of Pure Theophylline;   B -   IR Spectrum of Pure Theophylline + Crospovidone

 

C                                                                                                                            D

Figure-2 C - IR Spectrum of Pure Theophylline + Sodium starch glycolate; D - IR Spectrum of Pure Theophylline + Pregelatinized starch

 


Table 4: Percentage of drug release from formulations F3, F6and F9 after stored at 450C± 20C 75% RH for 90 days

Time (Min)

Percentage of drug release*

F3

F6

F9

30 days

60 days

90 days

30 days

60 days

90 days

30 days

60 days

90 days

10

37.26±0.95

38.62±0.32

37.42±0.25

34.18±0.27

33.53±0.44

33.80±0.52

29.20±0.40

30.09±0.39

29.60±0.39

20

63.65±0.45

64.12±0.24

63.86±0.42

58.65±0.22

56.83±0.42

57.10±0.91

56.20±0.64

57.63±0.04

56.30±0.46

30

96.12±0.33

96.80±0.26

94.92±0.31

95.12±1.64

95.13±0.39

94.35±0.82

94.19±0.22

93.90±0.08

93.86±0.75

*All the values are expressed as mean ± standard deviation (n=3)

 

Table 5: Drug content and disintegration time of formulation F3, F6 and F9 after stored at 450 C ± 20 C 75% RH for 90 days

Formulation

Code

Percentage of drug content *

Disintegration time (sec) *

30 days

60 days

90 days

30 days

60 days

90 days

F3

99.17±0.64

99.96±0.31

99.06±0.64

29.52±0.13

30.32±0.21

29.76±0.36

F6

98.26±0.95

98.82±0.27

97.60±1.55

32.20±0.27

33.01±0.40

32.62±0.28

F9

97.60±0.23

97.95±0.64

96.08±1.42

36.08±0.85

36.86±0.51

35.20±0.52

*All the values are expressed as mean ± standard deviation (n=3)


The weight of all the tablets was found to be uniform with low standard deviation (S.D) values indicating efficient mixing of drug, disintegrants and excipients. The percentage drugs content of all the tablets were found in the range of 97.40± 0.71 to 99.37± 0.24 of theophylline, which was within the acceptable limits. The results of in-vitro disintegration time and wetting time of all the formulations were found to be within the prescribed limits and satisfied the criteria of fast dissolving tablets. The values were found to be in the range of 29 ± 1.89 to 49 ± 1.25 sec and 6.0 ± 1.80 sec to 14.0 ± 1.67 seconds, respectively. The water absorption ratio for all formulations was found to be in the range of 50.80 ± 3.92 to 64.84 ± 2.70 % (Table-3).It was observed that when crospovidone was used as disintegrant, the tablets disintegrated rapidly within less time due to easy swelling ability of crospovidone when compared to that of other tablets prepared by using sodium starch glycolate, pregelatinized starch as superdisintegrants and control (without superdisintegrant). Among the formulations, F3 containing crospovidone 5% was found to be the best as it showed good hardness, least weight variation, optimum friability, least wetting time,  least disintegration time and more water absorption  ratio which  is  an ideal characteristic of  a fast dissolving type tablet (Table-3).

 

Figure-3 Comparative Invitro release profiles of formulations F3, F6, F9 and F10

 

The cumulative percentage of the drug released for formulation F3 showed better drug release of 97.83 ± 0.21% than F6 (96.33 ± 0.23), F9 (95.90 ± 0.33) and F10 ( control ) 72.63 ± 0.41 at the end of 30 minutes (Figure-3). The drug release was rapid in formulations containing crospovidone as superdisintegrant followed by sodium starch glycolate and pregelatinized starch. This may be due to easy swelling ability and more water penetration capacity. Crospovidone, when comes in contact with water, gets inflated immediately and burst out there by releasing the drug in the short duration of time. Further formulations F3, F6 and F9 were subjected to stability studies for the period of three months at 450C ±20C / 75% RH and was analyzed after specific time period of 30 days interval. No significant changes were seen in drug content, disintegration time and in vitro drug release after three months. (Table-4 and Table-5) Overall results indicated that formulation F3 was better, which satisfied all the criteria as a fast dissolving tablet.

 

CONCLUSION:

The present investigation thus indicated that FDTs of theophylline can be prepared by direct compression method using three superdisintegrants crospovidone, sodium starch glycolate and pregelatinized starch. The formulations prepared with superdisintegrants showed a rapid drug release than control (without superdisintegrant). The formulation F3 containing 5% crospovidone as superdisintegrant showed a better percentage of drug release when compared with formulations F6 and F9 which contains 5% sodium starch glycolate and 5% pregelatinized starch as superdisintegrant. Hence crospovidone was found to be a better superdisintegrant for the formulation of theophylline FDTs.

 

ACKNOWLEDGEMENTS:

The authors are thankful to Mr. S. Sriram Ashok, Correspondent, Sankaralingam Bhuvaneswari College of Pharmacy, Anaikuttam, Sivakasi, for providing excellent facilities to carry out this work.

 

ABBREVIATIONS:

FDTs = Fast Dissolving Tablets.

UV    =  Ultra Violet.

USP = United States Pharmacopoeia.

RH   = Relative Humidity.

 

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Received on 10.01.2011          Modified on 28.01.2011

Accepted on 06.02.2011         © RJPT All right reserved

Research J. Pharm. and Tech. 4(5): May 2011; Page 793-797