Research Articles

2019  |  Vol: 5(2)  |  Issue: 2(March-April)  |  https://doi.org/10.31024/ajpp.2019.5.2.9
Enhancement of solubility and dissolution rate of poorly water soluble dipyridamole using Emblica officinalis fruit powder

Syed Reshma Sulthana1, A. Anil Kumar2

1Department of Pharmaceutics, Vikas College of Pharmacy, Vissannapeta, Krishna district, Andhra Pradesh, India

2Vikas College of Pharmacy, Department of Pharmaceutics Vissannapeta, Krishna district, Andhra Pradesh, India

*Address for Corresponding Author

A. Anil Kumar (Asst. Professor),

Department of Pharmaceutics,

Vikas College of Pharmacy, Vissannapeta, Krishna District, A.P, India Pin: 521215


Abstract

Objective: The Objective of present study was to enhance the solubility of Dipyridamole and formulate Dipyridamole conventional tablets using Emblica officinalis fruit powder, Ocimum basilicum seed powder by employing Kneading technique and to carry out the Evaluation of Prepared tablets. Dipyridamole is a BCS (Biopharmaceutical classification system) class II drug which is poorly water soluble, it is freely soluble in acidic buffer pH 1.2  and shows negligible solubility in basic buffer i.e., pH 6.8  phosphate buffer. Material and methods: The technique employed for solubility enhancement is kneading technique of Solid dispersions. The formulations were prepared by direct compression and evaluated for various parameters such as disintegration time, hardness, and friability and Cumulative percent drug release. Results and Conclusion: The optimized formulation containing combination of these two natural powders has shown 98.85% of Drug release at 30 minutes which consists of 1:3 ratio of Drug and Emblica officinalis (Amla powder) fruit powder and the Ocimum basilicum (Sabja) seed powder used in the optimized formulation was 10% of the total tablet weight. The disintegration time of optimized formulation was found to be 21 seconds where as the formulation containing sodium starch glycolate as disintegrant has shown 33 sec of disintegration time. Drug interaction studies performed by using FTIR Spectroscopy shows that Ocimum basilicum and Emblica officinalis when combined with Dipyridamole there were some drug-polymer interactions seemed to be participated resulted in the improvement of solubility and dissolution characteristics. Hence, from the obtained results, it is clear that Emblica officinalis seed powder has shown Solubility Enhancement and Ocimum basilicum has shown super disintegration.

Keywords: Natural ingredient, solubility enhancement, super disintegration, Emblica officinalis, Ocimum basilicum


Introduction

There are numerous challenges in pharmaceutical formulation, but the most important is the drug solubility. Poor water solubility tops the list of critical compound properties among the five key physicochemical parameters in early compound screening, viz., dissociation constant, solubility, permeability, stability, and lipophilicity (Alsenz and Kansy, 2007). Approximately more than 40% new chemical entities (NCEs) developed in the pharmaceutical industry are practically insoluble in water. Problem of solubility is a major challenge for formulation scientist (Bonthagarala et al., 2015). Solubility is one of the important parameters to achieve desired concentration of drug in systemic circulation for showing a pharmacological response. Dipyridamole is used for controlling and treating of angina pectoris, as well as to clinically prevent recurrence of myocardial infarction and thrombosis (Gerbino and Remington, 2005). It is antiplatelet and anticoagulant drug which is a poorly water soluble, weakly basic drug which rapidly gets dissolved in stomach but in intestine it is dissolved incompletely. Dipyridamole is a drug with pH dependent solubility. Since an increase of pH in gastro-intestinal tract reduces solubility of dipyridamole hence the bioavailability of dipyridamole upon oral administration would be very low because the drug gets absorbed in the stomach but in intestine it has negligible absorbtion due to increase in pH of intestine (Tanya and Russell, 1994). So, there is need of solubility enhancement of Dipyridamole in intestinal pH. There are various Technologies for the enhancement of solubility like Micronization, Nanonization, Solid dispersions, Complexation, Crystal engineering and many other techniques (Christopher Vimalson et al., 2016).

The technique employed in the present study is Kneading technique. In some cases like pH dependent soluble drugs, using pH modifiers the solubility enhancement will be achieved effectively. There are various pH modifiers like citric acid, tartaric acid, succinic acid, Fumaric acid and some other organic acids. The present work is for focussing on the importance of natural excipients. So here naturally obtained Emblica officinalis fruit powder commonly called as amla powder was selected as pH modifier as it consists of various kinds of minerals, Vitamins like ascorbic acid and B-Complex and different kinds of amino acids and it also contains Phenolic compounds like Gallic acid and ellagic acid and organic acids like citric acid (Zhang et al., 2003). Indian gooseberry or amla (Emblica officinalis) is a euphorbiaceous plant, which is widely distributed in subtropical and tropical areas of India, China and Indonesia. Amla fruit is mainly used in many traditional medicinal systems (Khan, 2009). The pulpy portion of present around the seed of Emblica officinalis was used for the solubility enhancement of the drug Dipyridamole in the present work.

The main aim of the present work is investigation of natural ingredients on solubilisation and improvement of dissolution characteristics of Dipyridamole. So the ingredients used in the present work are mostly natural ingredients. Keeping into consideration of natural products here in the present study another natural ingredient used was Ocimum basilicum seed powder which is investigated for disintegration and super disintegration purpose. There are various superdisintegrants like Sodium starch glycolate, Cross caramellose sodium, Cross povidone which are already available and readily used in the Pharmaceutical industry. As the present study was focussed on to investigate natural powders, Ocimum basilicum seed powder was selected for investigation of disintegration and super disintegration effect. Ocimum basilicum is commonly called as Sabja and basil obtained from the herb basil plant which is having a wide variety of medicinal uses .The formulations were designed using the combination of Emblica officinalis fruit powder and Ocimum basilicum seed powder were carried out by direct compression method. The super disintegration property Ocimum basilicum seed powder was compared with Sodium starch glycolate.

Materials and methods

Materials

Dipyridamole was obtained from Pharmaceutics laboratory (Department of Pharmaceutics at Vikas college of Pharmacy (Vissannapeta) which was received as gift sample from Ra Chem Pharma (Hyderabad , India).The very fine Amla powder of food grade and Sabja seeds were  purchased from Sree anjaneya ayurvedic pharmacy (Vijayawada, India) Magnesium stearate and Talc and all the other chemicals were used from the chemicals present in the pharmaceutics laboratory at Vikas college of Pharmacy which were of high analytical grade.

Solubility studies and Dissolution studies of Pure drug Dipyridamole

Solubility of Dipyridamole was determined in methanol, water, chloroform, pH 1.2 and pH 6.8 Phosphate buffer. Solubility studies were performed by taking excess amount of Dipyridamole in different beakers containing solvent. The mixtures were shaken for 24 hrs at regular intervals. The solutions were then filtered by using whatmann’s filter paper. The filtered solutions are analyzed by double beam UV Visible Spectrophotometer. Pure drug Dipyridamole was compressed into tablets using all other excipients and dissolution was carried out by USP Type II dissolution apparatus using acidic buffer and basic buffers. Samples were collected upto 3 hours and analyzed by double beam UV visible spectrophotometer.

Preparation of Ocimum basilicum (Sabja seed) powder

Ocimum basilicum seeds were powdered and passed through sieve No.80. The powdered material was collected and packed and stored under good conditions.

Preparation of kneading mixture of Drug and Emblica officinalis (Amla powder) fruit powder

Drug and natural powder i.e., amla powder were taken in different ratios i.e., upto 1:4 ratios into a clean mortar and pestle and triturated with small quantity (few drops) of Propanol. Constant triturating was done up to 30 minutes, and then air dried at room temperature. The obtained powder was made finer using mortar and pestle, passed through sieve no.100 and stored in desiccators over fused calcium chloride. Common names of Emblica officinalis i.e., Amla powder (A) and Ocimum basilicum i.e., Sabja powder(S) are also used in the further sections of present study.

Drug content studies of Kneaded mixtures of Drug and Emblica officinalis fruit powder (Amla powder)

Required quantity of kneaded mixture was weighed accurately which is equivalent to 25mg of drug Dipyridamole and transferred to 25 ml volumetric flask. The volume was made up to the mark by using 0.1 N HCl and 6.8 pH phosphate buffer in separate flasks and kept aside for 1-2 hours with occasional shaking and then filtered. The drug content was analyzed spectrophotometrically at wavelength of 283 nm for 0.1 N HCl and 293 nm for 6.8 pH Phosphate buffer using UV -Vis spectrophotometer.

Table 1. Formulation composition of designed formulations

Ingredients (mg)/Tablet

                    Formulation code

AS1

AS2

AS3

AS4

AS5

AS6

AS7

AS8

AS9

ASSG

R

DEOM

75

100

125

75

100

125

75

100

125

125

-

Dipyridamole

-

-

-

-

-

-

-

-

-

-

25

OBS Powder

10

10

10

20

20

20

30

30

30

-

20

SSG

-

-

-

-

-

-

-

-

-

20

-

Avicel pH 101

107

82

57

97

72

47

87

62

37

47

147

Mg Stearate

4

4

4

4

4

4

4

4

4

4

4

Talc

4

4

4

4

4

4

4

4

4

4

4

Total weight (mg)

200

200

200

200

200

200

200

200

200

200

200

*DEOM= Drug and Emblica officinalis powder kneaded mixture; OBS Powder=Ocimum basilicum seed powder; SSG=Sodium Starch Glycolate; *Common names of natural powders A=Amla powder, S=Sabja powder are used as formulation codes

Determination of Flow Properties of Powders of Designed Formulations

Angle of Repose

Angle of repose (θ) was determined by using a funnel whose tip was fixed at a constant height (h) of 2.0 cm from the horizontal surface. The powder was passed separately through the funnel until the tip of the conical pile touches the tip of the funnel (Lachman and Lieberman, 2009; Marshall et al., 1987). The radius of the base of the conical pile is measured as r (cm). It was caluculated by formula as follows:

                                                                  θ = tan-1 (h/r)                        

Bulk density (Db)

It is the ratio of total mass of powder to the bulk volume of powder. It was measured by pouring the weighed powder (passed through standard sieve # 20) into a measuring cylinder and initial weight was noted (Lachman and Lieberman, 2009; Marshall et al., 1987).

It can be calculated as follows:

This initial volume was called the bulk volume. It is expressed as

                                                  Bulk density = M/ Vo     

M = Powder mass; Vo = apparent unstirred vol

Tapped density

The power sample under test was screened through sieve no.18 and the weight of sample equivalent to 25 gm filled in 100 ml graduated measuring cylinder. The minimum volume (Vt) occupied in the cylinder and the weight (M) of the blend were measured. The tapped (pt) was calculated using formula:

                                           Tapped density (pt) = M/Vt

                                   M = weight of sample power taken, Vt = tapped volume

Compressibility index

The bulk density, tapped density was measured and compressibility index was calculated using form

                                                 C.I. = (Pt ‐Po)/ (Pt) x 100

                                     Pt = tapped density; Po = bulk density

Hausner’s ratio

Hausner’s ratio is the indirect index of ease of powder flow. Hausner’s ratio of the blend was calculated using the following formula (Lachman and Lieberman, 2009; Marshall et al., 1987):

                       Hausner’s ratio = Pt/Po     Pt = tapped density, Po = bulk density

Evaluation of tablets

Weight Variation

Ten tablets were selected randomly from each formulation batch and weighed individually for checking the weight variation as per Pharmacopoeia standards (Lachman and Lieberman, 2009).

Thickness

The thickness of the tablets was measured using a micrometer screw gauge (Lachman and Lieberman, 2009).

Friability

Friability test was carried out using Veego friability testing apparatus by taking Five tablets, weighed and revolved at 25 rpm and 100 revolutions and again the tablets were weighed (Lachman and Lieberman, 2009).

Hardness

Hardness of the tablets was measured using Pfizer hardness tester.

Drug content

Estimation of drug content was carried out by taking two tablets from a batch then crushed into fine powder in the mortar using pestle. The obtained fine powder equivalent to 25 mg of Dipyridamole was extracted in pH 6.8 phosphate buffer. This solution was filtered through a Millipore filter of 0.45 μm pore size. After suitable dilutions, drug content was spectrophotometrically determined at a wavelength of 293 nm (Lachman and Lieberman, 2009; United States Pharmacopoeia, 1980).

Disintegration

For carrying out determination of disintegration time the apparatus used was Disintegration testing apparatus (Electro Lab (ED-2L) Mumbai) The USP device to test the disintegration time has 6 glass tubes that 3 inches long open at the top and 10 mesh screen at bottom end. To test disintegration time one tablet is placed in each tube and the basket rack is positioned in the 1 litre capacity of buffer which is filled with the buffer we need and temperature maintained is 37±2°C.The basket is moved up and down through a distance of 5-6 cms from 28-32 cycles. According to USP standard the tablets must disintegrate and all particles must pass through 10 mesh screen. If any residue remains it must have soft mass with no hard core. There are certain limits of disintegration time mentioned in IP and USP and other standard books (Lachman and Lieberman, 2009; United States Pharmacopoeia, 1980; Wagner, 1971).

In -vitro dissolution studies

The In-vitro drug release study was conducted using USP Type-II, rotating paddle apparatus (Veego Instruments Corporation, Mumbai, India). The operating speed was at 50 rpm and carried out for 30 minutes according to USP. The dissolution medium used was 6.8 pH Phosphate buffer. The temperature was maintained at 37 ± 0.5°C. Samples were withdrawn at pre-determined time intervals, filtered, and analyzed using UV-Visible spectrophotometer (Elico SL-210) at 293 nm (Lachman and Lieberman, 2009; United States Pharmacopoeia, 1980).

FT-IR Spectroscopy Studies

The Fourier transform infrared spectroscopy is carried out in order to identify the drug and polymer interactions. FT-IR studies were carried out for drug, natural powders and mixture of drug and natural powders. Spectrum was integrated in transmittance mode at the wave number range 400-4000 cm-1.

Statistical Analysis

Considering the evaluation data obtained from dissolution profile, Zero order and first order plots were plotted and the regression values were found to be 0.9852 and 0.9172 respectively. To know the drug release mechanism of the formulated tablets,the release data was fitted into mathematical models Higuchi and Korse-meyer peppas plots. The R2 values are 0.9729 & 0.99 respectively.

Results and discussion

Preformulation Studies

The Dipyridamole pure drug was observed as yellow in colour and found to be pure crystalline powder and bitter in taste which is odourless and having solubility in chloroform, methanol, acidic buffers, ethanol and Di methyl Sulfoxide, and it was found to be practically insoluble in Water and basic buffers. Its melting point was found to be 168±0.5°C.

Table 2. Flow Properties of Dipyridamole

S. No.

Parameters

Observed Value

1

Angle of repose

330.52ʹ

2

Bulk density

0.48 gm/cc

3

Tapped density

0.6 gm/cc

4

Cars index %

25%

5

Hausner’s ratio

1.25

Dissolution studies of Pure drug Dipyridamole

When dissolution was carried out for pure drug using other excipients and without addition of any solubility enhancer the values tabulated clearly shows that it is having a good solubility in the acidic buffer and a insoluble nature in case of basic buffer, dissolution values of pure drug dipyridamole are tabulated in (Table 3). In order to make it soluble in basic buffer Emblica officinalis fruit powder is added in different concentrations.

Table 3. Dissolution studies of Pure drug Dipyridamole

S. No

Time

0.1 N HCl

6.8 pH buffer

1

10 min

101.1

1.11

2

20 min

100.8

2.34

3

30 min

99.8

5.14

4

45 min

96.5

7.18

5

60 min

-

10.88

6

2 hr

-

14.94

7

3 hr

-

17.97

Drug content studies of kneaded mixtures of Drug and Emblica officinalis fruit powder

After estimation of drug content of the kneaded mixtures of Drug and Emblica officinalis fruit powder (Amla powder) in different ratios the drug content values are increased from 1:2 ratio of Drug: Emblica officinalis fruit powder. So, the formulations were designed using 1:2, 1:3, 1:4 ratios of Kneaded mixture (Table 4).

Table 4. Drug content values of Kneaded mixtures

Ratio of Drug : Amla powder

Drug Content (%)

1:1

41.27

1:2

76.83

1:3

95.47

1:4

96.58

Determination of flow properties of powders of designed formulations

The flow properties of the designed formulations are found to be better when compared with the flow properties of the pure drug Dipyridamole (Table 5).

Table 5. Flow properties of the designed formulations

Formulations

AOR (θ)(°)

BD(g/cc)

TD(g/cc)

Carr’s index (%)

Hausner's Ratio

AS1

26.23

0.47

0.55

17.02

1.17

AS2

27.51

0.46

0.53

15.21

1.15

AS3

27.45

0.45

0.53

17.77

1.17

AS4

28.32

0.41

0.50

21.95

0.2

AS5

27.54

0.42

0.51

21.42

1.2

AS6

29.12

0.50

0.55

10

1.1

AS7

28.32

0.37

0.41

10.8

1.10

AS8

29.40

0.36

0.42

16.66

1.16

AS9

28.34

0.37

0.45

21.62

1.21

ASSG

28.52

0.49

0.54

11.1

1.1

FT-IR Spectroscopy Studies

The drug polymer interaction study results has shown that there is some difference in the peaks shown by pure drug Dipyridamole and the combination of drug and the natural powder. Few drug polymer interactions were participated due to which the peaks were changed, which resulted in the improvement of the solubility and dissolution characteristics.

Figure 1. FTIR spectra of pure drug Dipyridamole

 

Figure 2. FTIR spectra of drug + Amla powder

 

Figure 3. FTIR spectra of drug + Sabja Powder

 

Figure 4. FTIR spectra of optimized formulation AS6

 

Evaluation of formulated tablets

Table 6. Post Compression parameters of designed formulations

Formulations

Weight Variation (%)

Hardness (kg/cm2)

Friability (%)

% Drug content (%)

AS1

1.95 ± 0.01

5.1± 0.03

0.239 ± 0.02

85.92± 0.02

AS2

1.95± 0.02

5.0± 0.04

0.118± 0.02

87.03± 0.02

AS3

1.28± 0.03

5.1± 0.03

0.301 ± 0.02

89.56± 0.01

AS4

1.2± 0.02

4.8± 0.05

0.199± 0.01

93.95± 0.01

AS5

1.16± 0.03

4.7± 0.04

0.865± 0.02

94.29± 0.02

AS6

1.36± 0.02

4.5± 0.03

0.421± 0.01

99.83± 0.02

AS7

1.51 ± 0.01

4.7± 0.04

0.317± 0.02

90.25± 0.01

AS8

1.83± 0.02

4.8± 0.05

0.210± 0.01

91.81± 0.03

AS9

1.65 ± 0.01

4.7± 0.03

0.382± 0.02

89.75± 0.02

ASSG

1.37± 0.02

5.0± 0.04

0.210± 0.01

82.16± 0.02

R

1.22± 0.01

4.1± 0.04

0.303 ± 0.02

13.47± 0.03

Disintegration time

The disintegration of AS6 formulation which contains 10% Sabja powder was quick when compared with the synthetic super disintegrant Sodium starch glycolate, all the other formulations other than optimized also shown a quick disintegration, Hence (Sabja powder) Ocimum basilicum seed powder can be considered as a super disintegrant according to the present study (Table 7).

Table 7. Table representing Disintegration time of designed formulations

S. No.

Formulation code

Disintegration time(sec)

1

AS1

32±3

2

AS2

35±2

3

AS3

37±3

4

AS4

23±4

5

AS5

24±3

6

AS6

21±2

7

AS7

26±3

8

AS8

29±2

9

AS9

27±3

10

ASSG

33±2

11

R

22±3

In-vitro drug release of the formulations

The Dissolution was carried out using 6.8 pH Phosphate buffer. The poorly water soluble Dipyridamole has a great extent of drug release by the usage of the naturally obtained Emblica officinalis fruit powder at different ratios, The highest drug release of 98.85% was observed for the formulation AS6 which contains 1:3 ratio of Drug and Amla powder was noted at 30 minutes of dissolution. In case of ASSG formulation the super disintegrant used was Sodium starch glycolate 10% concentration which has shown 33±2 disintegration time which is greater when compared to optimized formulation AS6 which consists of Sabja powder of 10% Concentration. The R formulation has shown Disintegration time of 22±3 which consists of Sabja powder used as Super disintegrant but in this formulation the drug release was 16.89% at 30 minutes because here in this formulation R, no solubility enhancer was used, this formulation was designed for comparison purpose. Hence it is clear that the formulations containing Natural powders Emblica officinalis fruit powder and Ocimum basilicum seed powder has shown good results when compared to the formulations which do not contain these natural powders in the present study (Table 8).

Table 8. In vitro drug release values of designed formulations

Time

Formulation code

AS1

AS2

AS3

AS4

AS5

AS6

AS7

AS8

AS9

ASSG

R

0

0

0

0

0

0

0

0

0

0

0

0

5

20.26±1.5

31.45 ±1.4

30.59 ±0.8

24.74  ±0.3

32.76±0.1

18.97±0.8

24.65 ±0.2

25.67±0.6

28.22±0.5

24.61±0.6

2.9 ±0.9

10

31.35±1.1

42.91±0.3

41.87±0.6

37.56±0.8

44.98±0.1

34.76±0.6

39.36 ±0.6

39.30±0.4

32.12 ±0.8

36.58 ±0.3

5.1 ±0.7

15

42.29±0.9

53.87±0.3

52.90±0.9

49.80±0.1

56.51±0.6

56.84 ±0.7

52.11±0.8

52.91±0.2

58.23 ±0.2

41.02 ±0.8

9.20 ±0.1

20

53.72±0.6

65.55±0.5

63.24 ±0.3

61.45±0.9

68.35±0.6

61.32±0.1

66.23±0.9

68.50±0.6

71.62 ±1

54.70 ±0.5

11.21±0.6

25

74.41±0.5

76.3±0.5

73.88 ±0.3

74.21±1.1

79.07±0.5

83.12±0.1

78.30±0.2

82.13±0.6

84.20±0.9

68.90 ±0.9

14.60 ±0.2

30

81.92 ±1.5

84.0±0.4

89.56±0.5

91.95±0.5

93.29±0.6

98.85±1

91.25±0.3

92.8 ±0.9

90.16±0.8

84.57±4

16.89±0.4

Figure 5. Plot representing Cumulative drug release data Vs Time of AS6, ASSG, R Formulations

 

Drug release kinetics

The results of release kinetics were shown in table 9 and figure 6-9.

Table 9. Model fitting for In vitro drug release kinetics of the optimized formulation

Formulation Code

            Kinetic Models

Zero order R2

First order R2

Peppas R2

Higuchi R2

AS6

0.9852

0.9172

0.99

0.9729

Figure 6. Zero order plot of optimized formulation

 

Figure 7. First order plot of optimized formulation

 

Figure 8. Higuchi plot of optimized formulation

 

Figure 9. Korsemeyer–Peppas plot of optimized formulation

 

Conclusion

The present work was carried out for the design and development of Dipyridamole conventional tablets using naturally obtained powders. From the above study it may be concluded that the natural powders such as Emblica officinalis fruit powder (Amla powder) investigated for solubility enhancement activity is found to be a natural solubility enhancer of poorly water soluble drug Dipyridamole  and Ocimum basilicum seed powder (Sabja powder) was investigated for Disintegration, super disintegration and found to be super disintegrant, the Kneading technique employed was proved best for the solubility enhancement of poorly soluble drug Dipyridamole. Solubility of Dipyridamole was increased  and optimized at 1:3 ratio of (Drug : Emblica officinalis fruit Powder) hence it can be concluded that the concept of effect of Natural ingredients on Dipyridamole is best, it is safe and cost effective for enhancing the solubility, bioavailability of poorly water soluble drugs.

Acknowledgement

First author is thankful to Mr. A. Anil Kumar (Ph. D), HOD of Department of Pharmaceutics, Vikas College of Pharmacy, for his guidance. The authors are thankful to the management of Vikas College of Pharmacy, Vissannapeta, Andhra Pradesh for providing good laboratory facilities, Chemicals and Principal of Vikas College of Pharmacy Dr. N. Srinivasa Rao, for his Moral support and Encouragement. This work is a part of M. Pharmacy Project Thesis Submitted to JNTUK, A.P.

Conflicts of interest: Not declared.

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