Dissolution Rate Enhancement of Ramipril by Solid Dispersion Technique

 

Mr. Rohan R. Vakhariya*, S. M. Kumbhar, R. B. lade, P. S. Salunkhe, R. H. Ubale

Rajarambapu College of Pharmacy, Kasegaon, Tal.- Walwa, Dist.- Sangli, Maharashtra

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

 

ABSTRACT:

Solubility enhancement of poorly aqueous soluble drugs is an important aspect of formulation development. Dissolution of drug is rate determining step for oral absorption of poorly watersoluble drugs, which consequently affect the in-vivo absorption of drug. Ramipril is a poorly watersoluble drug and it also has poor bioavailability. Therefore, many strategies have been worked out to develop its aqueous solubility as well as its release rate from various solid dosage forms. In the present study, the solid dispersion technique was evaluated for enhancement of solubility and dissolution rate. In present study solid dispersion was prepared by using two different polymers i.e.  ß-cyclodextrin, Hydroxypropyl cellulose and there combination also with different drug-carrier ratios was evaluated for the enhancement of solubility and dissolution rate as well as flowability, compressibility of Ramipril. The solid dispersions were characterized by UV Spectroscopy, In Vitro Drug Release, etc.

 

KEYWORDS: Solubility, Ramipril, ß-cyclodextrin, Solid Dispersions.

 

 

 

1. INTRODUCTION:

Oral drug delivery is the most popular, simplest and easiest way of administering drugs. Because of the greater stability, smaller bulk, accurate dosage and easy production, solid oral dosages forms have many advantages over other types of oral dosage forms1.

 

The most demanding aspects in the pharma industry are related to strategies that improve the solubility of poorly soluble drugs, as the most of the molecules are poorly soluble. The preparation of solid dispersions (SDs) is commonly used as a method to enhance the aqueous solubility, thereby increasing the oral bioavailability of drugs with aqueous low solubility. Different approaches are being exploited to improve drug solubility as well as drug dissolution of poorly aqueous soluble drugs.

 

Solid dispersion technique has attracted significant interest as proficient means of improving the dissolution rate as well as the bioavailability of an extensive range of poorly aqueous soluble drugs2. The poor solubility and low dissolution rate of poorly watersoluble drugs in the aqueous gastro-intestinal fluids often cause insufficient bioavailability. This may be achieved by incorporating the drug in a hydrophilic carrier material obtaining products called solid dispersions3. Depending on the properties of both, drug and carrier, and depending on their ratio, a solid solution or a solid suspension of the drug in the carrier material may be formed. The mechanisms involved in solubility and dissolution rate improvement include transformation of unbalanced modifications into more steady ones or even into the amorphous state, reduction of particle size possibly to the molecular level as well as enhancement of wettability and solubility of the drug by the carrier material.

 

 

 

Table No.1: Formulation table for preparation of solid dispersion

Batch No.

Drug (mg)

Drug: Carrier ratio

ß-cyclodextrin

(mg)

Hydroxypropyl cellulose

(mg)

ß-cyclodextrin + Hydroxypropyl cellulose (mg)

R1

500

1:2

1000

-

-

R2

500

1:4

2000

-

-

R3

500

1:2

-

1000

-

R4

500

1:4

-

2000

-

R5

500

1:2

-

-

500+500

R6

500

1:4

-

-

1000+1000

 

 

Ramipril is a potent antihypertensive agent with higher lipophilic nature (log P 3.32). The major drawback of this drug is its poor aqueous solubility (BCS-II Classification) [3.5mg/L] and its oral bioavailability is 28-35%4,5. To overcome these difficulties, increase in the aqueous solubility of ramipril is an important goal. Hence, in this present study, inclusion complexation of ramipril was tried with an aim to improve its pharmaceutical properties such as aqueous solubility and dissolution properties.

 

2. MATERIALS AND METHODS:

2.1. Materials:

Ramipril was generously gifted by Sanofi Aventis, Goa and ß-cyclodextrin, Hydroxypropyl cellulose were obtained from Research-Lab Fine Chem. Industries, Mumbai. In the whole attempt AR grade chemicals were consumed.

 

2.2. Preparation of Calibration Curve:6

Standard calibration curve of Ramipril in 0.1N Hydrochloric acid at λmax 258nm:

Calibration curve of Ramipril was prepared in 0.1 N HCl at different dilutions.  Different dilutions of concentration 2, 4, 6, 8, 10, 12, 14 & 16μg/ml were prepared and their respective absorbance were taken by using double beam UV- Spectrophotometer. Using these absorbance, standard curve was prepared.

 

Y=0.0029x+c

 

R2=0.9961

 

Where,

Y is absorbance

X is concentration

R2 is coefficient of regression

 

2.3. Preparation of ramipril, ß-cyclodextrin and hydroxypropyl cellulose solid dispersion:

1.     According to formulation table drug and polymer was taken in different ratio (1:2 and 1:4) to form solid dispersions using methanol as solvent.

2.     Drug and polymer wetted with a mixture of methanol and water (1:2) in mortar and pestle.

3.     Triturate this mixture thoroughly for 45 min in a mortar by kneading method.

4.     The formed dried powder was scrapped, crushed, pulverized, and passed through sieve no 100 (ASTM-100, 150 µm).

 

Prepared solid dispersion was packed and stored in screw cap bottles in dessicator for further studies7.

 

3. Evaluation of Solid Dispersions of Ramipril:

The solid dispersions were evaluated by their micrometrics properties, such as bulk density, tapped density, Carr’s compressibility index, Hausner’s ratio and flow property. 

 

3.1. Bulk density:8,9 

The bulk density was obtained by dividing the mass of a solid dispersion by the bulk volume in cm3. The sample of about 5 gm solid dispersion was carefully introduced into a 25ml cylinder. The cylinder was dropped at 2 second intervals onto a hard wood surface three times from a height of 1 inch. The bulk density of each formulation was then calculated by using equation given below

 

Where, 

ρo = bulk density 

M = weight of samples in grams 

Vo = final volumes of solid dispersion in cm3

 

3.2. Tapped density:8,9 

The tapped density was obtained by dividing the mass of a solid dispersion by the tapped volume in cm3. The sample of about 5 gm of solid dispersion is carefully introduced into a 25ml cylinder. The cylinder was dropped at 2 second intervals onto a hard wood surface 100 times from a height of one inch. The tapped density of each formulation was then calculated by using equation given below

 

Where, 

ρt = tapped density 

M = weight of samples in grams 

Vf = final tapped volume of solid dispersion in cm3

 

3.3. Carr’s index: 8, 9 

The percentage compressibility of solid dispersion was calculated according to equation given below

 

Where,

ρo = bulk density

ρt = tapped density 

 

3.4. Hausner’s ratio: 8, 9 

The Hausner’s ratio of a solid dispersion was calculated according to equation given below

Where,

ρt= Tapped density 

ρo = Bulk density

Hausner’s ratio between1 to 1.2 shows good Flowability.

 

3.5. Angle of repose:8, 9 

The Angle of repose (θ) i.e. flow property of the solid dispersion, which measures the resistance to particle flow, was calculated as

Tan θ = 2H / D

Hence, θ = tan-1 h/r

Where, 

2H / D is the surface area of the freestanding height of the solid dispersion heap that is formed after making the solid dispersion flow from the glass funnel.

 

3.6. Determination of drug content: 10, 11 

Weigh accurately solid dispersion equivalent to 5 mg of Ramipril and transferred to 25 ml volumetric flask and volume was made up to the mark with 0.1N HCl. From this 1ml was taken in 10ml volumetric flask and the volume is adjusted up to the mark with 0.1N HCl. The absorbance of the solution was measured at 258nm using appropriate blank. The drug content of Ramipril was calculated using calibration curve.

 

3.7. Solubility Study: 6

The solubility of the drug, physical mixtures, and solid dispersions were determined in distil water. Excess of samples were transferred to flask before adding distil water. The mixtures then placed in mechanical shaker maintained at 37°C for 48hr. The samples were filtered through 0.45µm filter and assayed by UV- spectrophotometry after suitable dilution.

 

3.8. In-vitro dissolution studies: 12

In-vitro dissolution of Ramipril solid dispersion was studied in USP XXIII dissolution apparatus employing a paddle stirrer. The dissolution medium was 0.1N HCl (pH 1.2) maintained at a temperature of 37±0.5°C with a paddle speed of 75rpm. The temperature of dissolution media was previously warmed to 37±0.5ºC and was maintained throughout the experiment. The powdered samples (sieved through a 355µm sieve) of pure drug, physical mixtures and solid dispersion mixtures equivalent to 25 mg of Ramipril were fill in to the capsule and this capsule add to the dissolution vessels while stirring. 5ml of sample of dissolution medium were withdrawn at 0, 5, 10, 15, 20, 25, 30, 35, 40 and 45 min. The volume withdrawn at each time interval was replaced with fresh quantity of dissolution medium. These samples were immediately filtered through 0.45µm filters and analyzed for drug release by measuring the absorbance at 258nm after suitable dilution with 0.1N HCl. Percentage amount of Ramipril released was calculated and plotted against time.

 

Table No. 2: Parameters of in-vitro dissolution test for solid dispersions

Sr. No.

Parameters

Detail

1

Apparatus

USP Type II

2

Volume of medium

900 ml

3

Temperature

37 ± 0.50C

4

Paddle speed

75 rpm

5

Dissolution medium

0.1 N HCl (pH 1.2)

6

Aliquot withdrawn

5 ml

 

4. RESULT AND DISCUSSION: 

4.1. Preparation of Calibration Curve:

Standard calibration curve of Ramipril in 0.1N Hydrochloric acid at λmax 258nm:

 

Table No. 3: Calibration curve for Ramipril in 0.1 N HCl

Concentration (mg/ml)

Absorbance

0

0

2

0.005

4

0.010

6

0.016

8

0.022

10

0.03

12

0.034

14

0.040

16

0.047

 

 

Figure No. 1: Standard calibration curve of Ramipril in0.1N HCl

 

4.2. Evaluation of Solid Dispersions of Ramipril:

4.2.1. Micromeritic properties:

The results of micromeritic properties of solid dispersion formulations were as below

 

 

Table No. 4: Micromeritic studies of solid dispersion formulations

Sr. No.

Batch Code

Bulk density

Tapped density

% Compressibility index

Hausner’s ratio

Angle of repose

1

R1

0.270±0.06

0.310±0.05

11.09

1.10

28°45'

2

R2

0.241±0.05

0.272±0.03

12.05

1.12

25°75'

3

R3

0.298±0.02

0.350±0.06

15.25

1.17

27°23'

4

R4

0.258±0.03

0.298±0.04

15.47

1.19

28°82'

5

R5

0.278±0.05

0.316±0.05

12.84

1.16

29°76'

6

R6

0.26±0.08

0.305±0.08

14.73

1.15

27°87'

*mean ± standard deviation (n=3)

 

 

4.2.2. Determination of Drug Content:

The results of drug content of solid dispersion formulations were as below

 

Table No. 5: Percent drug content of solid dispersion formulations

Sr. No.

Batch Code

% Drug Content

1

R1

65.7%

2

R2

92.6%

3

R3

87.3%

4

R4

70.4%

5

R5

97.6%

6

R6

96.6%

 

 

4.2.3. Solubility Studies:

The results of solubility study of solid dispersion formulations were as below

 

Table No. 6: Solubility (µg/ml) of solid dispersion formulations

Sr. No.

Batch Code

Solubility (µg/ml)

1

R1

27.46±0.37

2

R2

29.25±0.58

3

R3

29.30±0.69

4

R4

30.87±0.26

5

R5

33.72±0.43

6

R6

31.27±0.36

*mean ± standard deviation (n=3)

 

4.2.4. In-vitro Dissolution Studies: 

The solid dispersions of Ramipril were prepared and the results of their in-vitro dissolution profile were observed.

 

 

 

Table No. 7: Cumulative percentage drug release of solid dispersions

Sr.

no.

Time (min)

% Cumulative drug release

Batch R1

Batch R2

Batch R3

Batch R4

Batch R5

Batch R6

1

0

0

0

0

0

0

0

2

5

24.48

31.68

26.31

33.85

35.95

34.50

3

10

54.67

62.21

56.89

58.28

59.70

58.28

4

15

64.73

71.62

66.52

62.75

66.35

64.57

5

20

71.02

79.19

72.80

69.21

72.57

70.19

6

25

79.27

83.37

79.97

75.30

79.81

77.28

7

30

88.59

89.55

89.78

84.62

87.19

86.61

8

35

92.61

93.73

92.95

90.58

91.27

90.91

9

40

94.10

95.68

95.78

93.47

94.82

93.87

10

45

96.58

97.20

96.88

97.38

98.40

97.53

 

 

 

Figure No.2: In-vitro dissolution profile of solid dispersion formulations

 

5. CONCLUSION:

This research showed that when ramipril was dispersed in suitable water-soluble carriers such as ß-cyclodextrin, hydroxypropyl cellulose and combination of both polymers, its dissolution was improved compared with pure drugs. In comparison to this, all water soluble carriers combination of ß-cyclodextrin, hydroxypropyl cellulose gave the best result from solid dispersion in 1:2 (drug: polymer) ratio. By in-vitro study, it was obviously proved that preparation of solid dispersion of ramipril with combination of ß-cyclodextrin, hydroxypropyl cellulose enhanced the dissolution rate of ramipril. Ramipril solid dispersions with combination of ß-cyclodextrin, hydroxypropyl cellulose provide a promising way to enhance solubility and dissolution rate of ramipril. Thus the problem of the dissolution and drug release from poorly soluble drug can be improved with solid dispersions of the drug with polymers and combination of polymers in different ratios. It is concluded that the solid dispersion of ramipril increased the solubility and dissolution rate of drug, suggesting a possible enhancement of its oral bioavailability.

 

6. REFERENCES:

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7.      Aftab Modi, Pralhad Tayade, Enhancement of dissolution profile of solid dispersion (kneading technique), AAPS Pharm Scitech, 7(3), 2006.

8.      Aulton M. E., Pharmaceutics “The Science of Dosage Form Design”, 2nd Edition Published by Livingstone C. Elsevier science Ltd., 2002, 200-208.

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10.   Sandrien Janssens, Hector Novoa de Armas, Ward D’Autry, Ann Van Schepdael, Guy Van den Mooter, Characterization of ternary solid dispersions of Itraconazole in polyethylene glycol 6000/polyvidone-vinylacetate 64 blends, European Journal of Pharmaceutics and Biopharmaceutics, 69, 2008, 1114–1120.

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Received on 29.11.2019            Modified on 31.12.2019

Accepted on 28.01.2020      ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Res. 2020; 10(1):08-12.

DOI: 10.5958/2231-5691.2020.00002.7