Formulation and Evaluation of Pioglitazone HCl Fast Dissolving Tablet using Solid Dispersion

 

Pinky Yadav*, Pankaj Patel, Prabhat Das, Nitin Deshmukh, Dr. Sujit Pillai

Dept. of Pharmaceutics, GRY Institute of Pharmacy, Borawan, Khargone (M.P)

*Corresponding Author E-mail: kumar_prabhat3027@yahoo.com

 

ABSTRACT:

Pioglitazone HCL is a BCS class-II (poorly water soluble) drug and its absorption is dissolution rate limited. The solubility and the dissolution rate of the drug was enhanced by using the solid dispersion technique. The main purpose of this investigation was to increase the solubility and dissolution rate of pioglitazone HCL by the preparation of its solid dispersion with PEG-6000 using solvent evaporation methods. FT-IR spectra revealed no chemical incompatibility between drug and PEG-6000. The result obtained show that the dissolution profile of pioglitazone HCL solid dispersion was considerably improved. The dissolution profile solid dispersion formulation SD1 contains (1:1) (drug: polymer) formulation SD2 (1:2) & formulation SD3 (1:3) was found to be 97.83±0.09, 94.03±0.09, 91.26±0.03 respectively. Based on the above dissolution data SD1 is found to be best as a solid dispersion for fast dissolving tablet. Based on the result solid dispersion technique can be an acceptable method for improving the dissolution profile of poorly aqueous soluble drug.

 

KEYWORDS: Pioglitazone HCL, Fast dissolving tablet, Solid dispersion, PEG-6000, Solvent Evaporation Method.

 

 


INTRODUCTION:

Pioglitazone hydrochloride is an oral hypoglycemic agent, which is a commonly prescribed drug for the treatment of patients with type II diabetes mellitus. Pioglitazone hydrochloride is a basic (pKa = 12.06) which is practically insoluble in water and alkaline buffer solutions, but as per the Biopharmaceutical Classification System (BCS) Pioglitazone categorized as class II drug. The oral absorption is uniform, rapid and complete with a bioavailability of nearly 100% and an elimination half-life of 3-7 hrs. Delivery Systems (NDDS) aim for the same by formulating a dosage form, convenient to be administered so as to achieve better patient compliance. One such approach is oral dispersible tablet. Solid dosage forms are popular because of ease of administration, accurate dosage, selfmedication, pain avoidance and most importantly the patient compliance.

 

 

Mouth dissolving tablets are also called as fast dissolving tablets, melt-in mouth tablets, Orodispersible tablets, rapid melts, porous tablets, quick dissolving etc. Mouth dissolving tablets are those when put on tongue disintegrate instantaneously releasing the drug which dissolves or disperses in the saliva the faster the drug into solution, quicker the absorption and onset of clinical effect. Some drugs are absorbed from the mouth, pharynx and esophagus as the saliva passes down into the stomach. In such cases, bioavailability of drug is significantly greater than those observed from conventional tablets dosage form. Diabetes Mellitus (DM) is a group of syndromes and chronic metabolic disorder characterized by hyperglycemia, altered metabolism of lipids, carbohydrates and proteins because of a lack of or ineffective use of the hormone insulin and associated with reduced life expectancy, significant morbidity due to specific diabetes related micro vascular complications and diminished quality of life. A fasting blood glucose level of 126 mg/dl and 200 mg/dl post prandial (oral Glucose load) is considered as indication of  DM. In present work, an investigation was made to use crospovidone and sodium starch glycolate, Croscarmellose sodium as superdisintegrants in the design of mouth dissolving tablets.

Oral bioavailability of drugs depends on its dissolution rate, therefore major problems associated with these drugs was its very low aqueous solubility, which results into poor bioavailability after oral administration. Many methods are available to improve dissolution rate, solubility characteristics, including salt formation, micronization, and addition of solvent or surface active agents1.

 

Solid dispersion prepared by solvent evaporation is one of these methods, which was most widely and successfully applied to improve the solubility, dissolution rates and consequently the bioavailability of poorly soluble drugs2,3. Several water soluble carriers such as mannitol, urea, lactose, citric acid, polyvinyl pyrrolidone, β-cyclodextrin and polyethylene glycols like PEG 6000 are used as carriers for enhancement of aqueous solubilty 4-6.Pioglitazone hydrochloride is a thiazolidinedione antidiabetic agent that decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output 7. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma 8. The solid dispersions of pioglitazone solve the problems like gastro-intestinal disturbances, headache, dizziness, fatigue and insomnia 9. Pioglitazone is practically insoluble in water; this prompted us to investigate the possibility of improving the dissolution rate of drug by preparing solid dispersion of pioglitazone, prepared by solvent evaporation with water-soluble carrier PEG 6000.

 

 

 

Pioglitazone contains not less than 90.0 per cent and not more than 110.0 per cent of C19H2ON2O3S.HCl, calculated on anhydrous basis. It is a Thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. PG is a potent and highly selective agonist for peroxisome proliferators-activated receptor-gamma (PPARg). The drug decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Thus the mouth dissolving tablets of Pioglitazone may be prepared with Croscarmellose, crospovidone and sodium starch glycolate, the well proven and acceptable polymers having least limitations.

 

 

MATERIAL AND METHOD:

Pioglitazone HCl was obtained as sample from Yarrow Chem. Ltd., Mumbai, India. PEG 6000 was procured from SD Fine Chemical Pvt. Ltd., Mumbai, India.Crosspovidone was procured from Yarrow Chem, Mumbai. All other chemicals and reagents used were of analytical grade and procured from authorized dealer.

 

METHODS OF PREPARATION:

Development of standard calibration curve:

100 mg of pioglitazone hydrochloride was accurately weighed and transferred to a clean and dry 100 ml into volumetric flask. Sufficient quantity of Phosphate buffer pH 6.8 (about 70 ml)was added and the flask was gently shaken by circular motion till all the powder dissolved . The volume was made up to 100ml with 6.8 phosphate buffer then 10ml solution was taken from the above solution and in 100 ml volumetric flask and volume make up to 100ml with 6.8 Phosphate buffer.Aliquot of 1.0 ml,2 ml,3ml, 4 ml,5 ml, 6ml were transferred to clean and dry 10 ml volumetric flask and volume was made up to 10 ml with 6.8 Phosphate buffer in each flask. Taken absorbance in UV visible spectrophotometric (Shimadzu 1700) at 268 nm.

 

Preparation of solid dispersion by solvent evaporation:

The solid dispersions were prepared by solvent evaporation method using pioglitazone HCl as drug and PEG 6000 as carrier in the ratios of 1:1, 1:2, 1:3 respectively10. The pure drug of pioglitazone HCl was considered as formulation F0. The required quantity of carrier (PEG 6000) was weighed in electronic digital balance, taken in a china dish and it was dissolved completely in methanol. Accurately weighed quantity of drug was then added to polymer solution. The solvent was then allowed to be evaporated at 40°C over water bath. The solid dispersion thus obtained was dried properly using Hot air oven (Rolex Pvt. Ltd., Calcutta, West Bangle, India) at 45°C for 1 h. The dried solid dispersion was stored in a desiccator for further study.

 

DRUG CONTENT:

Dispersions and physical mixtures equivalent to 25 mg drug were taken and dissolved in 6.8 Phosphate Buffer. The solution was suitably diluted with 6.8 Phosphate buffer volume was made up to 100 ml. The solution was assayed for drug content using spectrophotometry (Shimadzu 1700) method by measuring the absorbance at 268 nm.11

 

IN VITRO DRUG RELEASE:

In vitro release studies of Pioglitazone, physical mixtures and SDs (equivalent to 30 mg Pioglitazone) were performed using USP XXII tablet dissolution test apparatus at the basket rotation speed of 50 rpm in 900 ml 6.8 Phosphate Buffer at 37±5°C.An aliquotsample (5 ml) was withdrawn at an interval of 2 min with replacement of fresh medium and each drug solution was analyzed for pioglitazone content by spectrophotometer at 268 nm.11

 


 

Table no. 1: Composition of fast dissolving Tablet of Pioglitazone HCl

Ingredients (in mg/tablet)

Formulation code

1:1

1:2

1:3

F1

F2

F3

F4

F5

F6

Solid dispersion (equivalent to30 mg of drug )

30

30

30

30

30

30

Microcrystalline cellulose

86.42

81.42

61.05

56.05

36.42

31.42

Starch

1.25

1.25

1.25

1.25

1.25

1.25

Magnesium stearate

3.75

3.75

3.75

3.75

3.75

3.75

Talc

5

5

5

5

5

5

Crospovidone

5

10

5

10

5

10

Sodium saccharin

1.25

1.25

1.25

1.25

1.25

1.25

Total weight of tablet

150

150

150

150

150

150

 


EVALUATION OF POWDER MIXTURE:

Determination of pre-compression characteristics :

Angle of Repose:

It is determined by allowing a powder to flow through a funnel and fall freely on to a surface. Further addition of powder is stopped as soon as the pile touches the tip of the funnel. A circle is drawn around the pile without disturbing it. The height and diameter of the resulting cone are measured. The same procedure is repeated three times and the average value is taken. Angle of repose is calculated by using the following equation: Tan θ = h/r Where, h = height of the powder cone; r = radius of the powder.

 

Bulk Density:

The bulk density of the formulated powder was evaluated using a bulk density apparatus. It is expressed in gm/ml and is calculated by formula, Bulk density (ρb) = Mass of the powder (M)/Volume of the bulk powder (Vb).

 

Tapped Density:

The tapped density was obtained by dividing the mass of a powder by the tapped volume in cm3 . The sample of about 10 cm3 of powder is carefully introduced into a 25 ml graduated cylinder. The cylinder was dropped at 2-second intervals onto a hard wood surface 100 times from a height of 1 inch. The tapped density of each formulation was then obtained by dividing the weight of sample in grams by the final tapped volume in cm3 of the sample contained in the cylinder. It was calculated by using equation given below:

 

Do = M / Vp

 

Where, Do = bulk density

M = weight of samples in grams

Vp = final tapped volumes of granules in cm3

 

Carr’s Index:

The percentage compressibility of microspheres was calculated according to equation given below:

 

% Compressibility = Tapped density - Bulk density ×  100

                                          Tapped density

 

Hausner Ratio:

The Hausner ratio can be determined using the following formula:

Hausnerratio(%) = Tapped density/Pour density × 100

 

Determination of Post-Compression:

Thickness:

Thickness of tablets was measured with Verniar caliper.

 

Hardness:

The Hardness of the tablet was determined using a Monsanto Hardness tester. It is expressed in kg / cm2 .

 

Friability:

Friability of the tablets was determined using Roche friabilator at 25 rpm/min for 4 min. Ten tablets were weighed and loss in weight (%) was calculated.

 

Weight variation:

Twenty randomly selected tablets were weighed individually and all together. The average weight and the percentage deviation were calculated. The percentage difference in the weight variation should be within the permissible limits (±7.5%). The percentage deviation was calculated using the following formula:

 

Percentage Deviation = Individual weight – Average weight x 100 Average weight

 

As per Indian Pharmacopoeia (IP), permissible limit of weight variation is 7.5% for tablet weight of 150 mg (Table).

 

Disintegration:

The disintegration time was measured using disintegration test apparatus. One tablet was placed in each tube of the basket. The time required for complete disintegration of the tablet in each tube was determined using a stop watch. To be complied with the pharmacopoeia standards, fast dissolving tablets must disintegrate within few min when examined by the disintegration test for tablets.

 

Drug Content:

An accurately weighed 100 mg equivalent amount of Pioglitazone HCl taking from crushing of 20 tablet. Extracted with 6.8 Phosphate buffer and the solution was filter. The absorbance was measured at 268 nm after suitable dilution.

 

Dissolution Study:

Drug Release of Pioglitazone HCl from the fast dissolving tablets was studied in 6.8 Phosphate Buffer (900 ml) for 10 min. using USP single station dissolution rate test apparatus with a rotating paddle stirrer at 50 rpm and 37° ± 0.5°C. A Samples of dissolution fluid were withdrawn through a pipette at different time intervals and were assayed at 268 nm for Pioglitazone HCl in6.8 Phosphate buffer content using spectrophotometer (Shimadzu 1700).

 

 

 

 

 

RESULT AND DISSCUSION:

Standard calibration curve in 6.8 Phosphate Buffer at λmax 268 nm:

 

 

FIGURE NO: 1

 

Drug polymer Compatibility studies:

The IR spectrum of pure drug were studied. The characteristic absorption peaks of PGTZN like N-H str, C-H str , C=Ostr, C=Cstr, C-Nstr, C-S str, C-O str and C-O-C aliphatic bond were obtained at wave number 3082.35, 2929.27, 2876.96, 1745.64, 1612.14, 1465.95, 1240.27, 1084 cm-1 respectively.


 

 

Figure No.2: FTIR spectrum of  Pioglitazone Hydrochloride

 

 

Figure No.3: FTIR spectrum of mixture (drug+ PEG 6000)

Table no.2: Evaluation of powder mixture:

Formulation Code

Angle of Repose(θ)

Loose Bulk Density

Tapped Density

Hausner’s Ratio

Carr’s Index

F1

29.89±0.03

0.612±0.01

0.694±0.01

1.13±0.03

11.83±0.05

F2

28.05±0.01

0.617±0.02

0.668±0.02

1.08±0.04

7.63±0.04

F3

29.74±0.02

0.612±0.01

0.700±0.03

1.14±0.05

12.65±0.05

F4

28.74±0.01

0.609±0.03

0.694±0.02

1.13±0.05

12.19±0.04

F5

24.70±0.01

0.548±0.01

0.581±0.02

1.074±0.05

6.80±0.05

F6

23.74±0.01

0.541±0.02

0.560±0.01

1.037±0.04

3.57±0.05

 

Table no.3: Evaluation of Tablet:

Formulation Code

F1

F2

F3

F4

F5

F6

Uniformity of Weight(mg)

148±0.01

149±0.03

147±0.03

147±0.02

145±0.05

145±0.04

Thickness(mm)

4±0.03

4±0.01

4.1±0.02

4±0.01

4±0.05

4.1±0.01

Hardness(kg/cm2)

3.4±0.09

3.5±0.01

3.1±0.06

3.1±0.06

3.0±0.03

3.2±0.01

Friability (%)

0.53±0.04

0.54±0.01

0.52±0.08

0.53±0.01

0.46±0.04

0.47±0.03

Disintegration Time(sec.)

18±0.01

14±0.02

25±0.08

24±0.06

28±0.13

28±0.12

Drug Content

99.33±0.01

99.33±0.01

97.84±0.01

97.52±0.01

97.51±0.01

98.06±0.01

 


Table no.4: %CDR Cumulative Percentage Drug Release of Solid dispersion:

Time

SD1

SD2

SD3

0

0

0

0

2

51.01±0.08

47.21±0.04

44.26±0.03

4

70.56±0.03

68.70±0.03

64.32±0.01

6

84.26±0.04

78.80±0.06

71.40±0.02

8

93.42±0.03

90.23±0.03

80.34±0.03

10

97.83±0.09

94.03±0.09

91.26±0.03


 


In-vitro Dissolution studies of tablet:

Table no.5: Cumulative % drug release of tablet formulation:

Time (min.)

F1

F2

F3

F4

F5

F6

0

0

0

0

0

0

0

2

53.03±2.34

54.08±0.03

43.67±0.03

48.13±0.42

38.46±0.3

41.48±0.6

4

63.87±1.12

64.37±0.9

56.23±0.03

58.67±1.3

52.08±0.3

53.94±2.5

6

71.08±0.32

74.81±0.03

63.54±1.32

69.62±2.1

62.87±0.5

67.28±0.7

8

88.53±1.3

93.82±1.8

89.61±2.34

89.03±1.6

84.49±1.3

89.07±0.8

10

95.67±2.1

97.43±0.03

92.47±0.03

93.64±2.8

90.03±1.2

91.62±0.6


 

 

Figure no.4

 

 

 

Figure no.5:

 

CONCLUSION:

The parameters of fast dissolving tablets were within acceptable official IP limits. Pre-compressional parameters of fast dissolving tablets (angle of repose, % compressibility and hausner’s ratio are in the range of given in official standard,. The post-compressional parameters of fast dissolving tablet’s (hardness, friability, weight variation, thickness and drug content) were within the acceptable official limits.

 

The present study revealed that solid dispersion of pioglitazone HCl enhances the solubility & drug release. From the dissolution study, it was concluded that Solid dispersion enhance solubility of drug of tablet.

 

The release of drug from fast dissolving tablet formulation F1,F2,F3,F4,F5 and F6 was found to be 95.67,97.43,92.47,93.64,90.03 &91.62.Cumulative release within 10 min. We conclude that F2 was found to be best because of better drug release.

 

REFERENCE:

1.     Refere Sekiguchi K and Obi N: Studies on absorption of eutectic mixture I.A. comparison of the behavior of eutectic mixture of sulfathiazole and that of ordinary sulfathiazole in man. ChemPharma Bull 1961; 9: 866-872.

2.     Chiou WL and Riegelman S: Pharmaceutical applications of solid dispersion systems. Journal Pharmaceutical Sciences 1971; 60: 1281-1302.

3.     Modi A and Tayade P: Enhancement of dissolution profile by solid dispersion (kneading) technique. AAPS Pharm Sci Tech 2006: 7(3): 68-73.

4.     Baylan S: Encycolpedia of pharmaceutical technology, 2nd (Ed), Vol. 1, Marcel Dekker Inc., New York, 2002: 641-647.

5.     Leunner C and Dressman J: Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm 2000; 50: 47-60.

6.     Brahmankar DM and Jaiswal SB: Biopharmaceutics and Pharmacokinetics A Treatise, 1st (Ed), VallabhPrakashan, New Delhi, 1995: 171-172.

7.     Crum CP: Diabetes. In: Cotran RS, Kumar V and Collins T (Eds.): Robbins, Pathologic Basis of Disease, 6th (Ed), Published by Harcourt (India) Private Limited, New Delhi, 1999: 934-946.

8.     Rang and Dales Pharmacology, Antidiabetic drugs. Churchill Living Stone, Elsevier, Philadelphia, 2007, 48: 696-678.

9.     Tripathi KD: Antidiabetic drugs. In: Essentials of Medical Pharmacology, 5th (Ed), Jaypee Brothers Ltd., New Delhi, 2003: 345-352.

10.   Modi A and Tayade P: Enhancement of dissolution profile by solid dispersion (kneading) technique. AAPS Pharm Sci Tech 2006: 7(3): 68-73.

11.   Jani BR*, Shah KV.Development and Validation of Analytical Method for Simultaneous Estimation of Valsartan and Pioglitazone Hydrochloride by Simultaneous Equation Method ,IJPRS,research article,2014 V-3, I-3.

 

 

 

 

Received on 13.06.2018          Modified on 28.07.2018

Accepted on 30.08.2018        © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(12): 5313-5318.

DOI: 10.5958/0974-360X.2018.00967.8