Design Development of Liquisolid Compacts of Atorvastatin Calcium

 

A. Navya Krishna*, Y. Deepthi, S. Aruna, T E G K Murthy

Department of Pharmaceutics, Bapatla College of Pharmacy, Bapatla, Guntur (Dt), A.P.-522101 India, *Corresponding Author E-mail: bcpbtl@sancharnet.in

 

 

ABSTRACT:

The present work is to formulate and evaluate liquisolid compacts of Atorvastatin calcium. Atorvastatin calcium is an anti hyperlipedmic drug belongs to class of statins. The bioavailability is 14% due to dissolution rate limitation and its biological half life is 14 hours. The solubility of Atorvastatin was enhanced by liquid solid compact technology. So the aim of this work is to increase the solubility and in-vitro dissolution of practically insoluble drug Atorvastatin, liquisolid tablet consists of lactose (flowlac), cab-o-sill and PG as liquid vehicle. The prepared formulations were evaluated for drug content, weight variation, hardness, friability, disintegration, dissolution. The better drug release was observed from the F8 formulation (1:5) containing (flowlac) Atorvastatin 20 mg, carrier 505.65 mg, coating material 10mg, and super disintegrating and lubricants 11.64, 23.45 were added. The selected formulation was evaluated for stability studies.

 

KEY WORDS- Atorvastatin calcium, liquisolid compacts, carrier, coating material, in-vitro dissolution, bioavailability

 

 


INTRODUCTION:

The poor dissolution of water insoluble drugs is still a substantial problem confronting the pharmaceutical industry. A great number of new and possibly, beneficial chemical entities do not reach the public merely because of their poor oral bioavailability due to inadequate dissolution. Over the years various solid dosage formulation techniques, to enhance the dissolution of poorly soluble substances, have been introduced with different degrees of success. The technique of “liquisolid compacts” is a new and promising addition towards such a novel aim. The active ingredient in a solid dosage form must undergo dissolution before it is available for absorption from gastrointestinal tract. The poor dissolution characteristics of water soluble drugs are a major challenge for pharmaceutical scientists.

The absorption rate of poorly water soluble drug, formulated as an orally administrated solid dosage form, is controlled by its dissolution rate in fluid present at the absorption site, i.e the dissolution step is often rate determining step in drug absorption. Several researches have shown that the liquisolid techniques are the most promising method for promoting dissolution rate of poorly water soluble drugs1, 2. 

 

The immediate or sustained release tablets or capsules that prepared by liquisolid system combined with inclusion of appropriate adjutants required for tabletting or encapsulation such as lubricants and disintegrants or binders. Liquisolid compacts prepared by different solvents which dissolves the poorly soluble drugs and gives better bioavailability3, 4. It has been observed that the drug release superiority of liquisolid tablets is inversely proportional to the aqueous solubility of the contained drug5.

 

Atorvastatin calcium is an anti-hyperlipidemic agent belong to class to statins. Liver is the main site of action of Atorvastatin. It acts by inhibiting HMG-COA reductase inhibitor, the enzyme involved in the conversion of HMG-COA to mevolanate in the cholesterol biosynthesis. The intestinal permeability of Atorvastatin was high at physiological intestinal pH of 6-6.5. Its oral bioavailability is 14% and is primarily metabolised through hepatic CYP3A4. The oral bioavailability of drug depends on factors such as solubility, dissolution and membrane permeability and as Atorvastatin is a class-II drug. The solubility and dissolution rate are critical factors in its oral bioavailability. The present study was aimed to develop an immediate release formulation for Atorvastatin with different formulations. Variables to achieve the require dissolution rate and comparative in-vitro dissolution profiles with the marketed formulation6, 7.

 

EXPERIMENTAL METHODS:8-10

Materials used:

Atorvastatin calcium- Natco Pvt Ltd., Hyderabad; Lactose- Qualigens, Mumbai; MCC- Yarrow-Chemproducts; SSG-S. Dfine Chem, Mumbai; PG - Qualigens, Mumbai; Magnesium Stearate- S.Dfine Chem, Mumbai; Talc- S.Dfine Chem, Mumbai.

 

Solubility studies:

Solubility studies of atorvastatin calcium were carried out in methanol, 6.8 phosphate buffer, PG, PEG400 and PEG200. Saturated solutions were prepared by adding excess amount of atorvastatin ca to the vehicles and subjected to shaking on the shaker for 24 hr at 25°C under constant vibration. Filtered samples were diluted appropriately with 6.8 phosphate buffer and Atorvastatin was determined spectrophotometrically at 246nm.

 

Binding capacity:

Binding capacity is defined as capacity of powder excipients to hold liquid without change in their flow properties. It was determined by the following simple method. A constant weight of 5g of different powder excipients (lactose, MCC, manitol and starch) were put into a mortar and PG was added in increment of 0.01ml. The mixture was triturated after each addition to help distribution of the liquid throughout the powder particles. The volume of the binder required to produce damp mass was noted.

 

Preformulation studies:

The preformulation studies like flow properties, solubility, drug excipient compatibility studies were determined.

 

Flow Properties of Atorvastatin Calcium:

The following flow properties were of granules was determined.

 

Bulk density and tapped density:

The previously weighed pure drug and or granules (w) were placed separately into a graduated measuring cylinder and the initial bulk volume (VB) was noted. It was placed in tapped density tester USP and subjected to constant tapping at a rate of 200drops/min until a difference between the initial and final volume was less than 2%. It was recorded as the final (tapped) volume and various flow properties were recorded with following formulae.

 

Bulk density = 

 

 

Tapped density =

 

 

Compressibility index:

It was calculated by using following formula:

 

Carr’s index = tapped density-bulk density/tapped density ×100

 

The ci value below 15% indicates good flow of the powder and above 30% indicates poor flow of powder.

 

Hausner’s ratio:

It was calculated by following formula:

Hausner’s ratio = tapped density / bulk density

 

Angle of repose (θ):

It was determined by using a funnel whose tip was fixed at a constant height (H) of 2.5 cm from horizontal surface. The granules and powder were passed separately through the funnel until the tip of the conical pile touches to the tip of funnel. The radius of the base of the conical pile is measured as R (cm). It was determined by following formula;

 

Angle of repose (θ) = Tan -1(height/ radius)

 

Formulation studies:

Liquisolid compacts were prepared by dispersing atorvastatin in 2 ml of the liquid vehicle and to this carrier: coating material (1:1) was added in increasing amounts till lumps were formed. These amounts of carrier and coating materials were enough to maintain acceptable flow and compression properties. Finally 5% (W/W) of sodium starch glycolate was added as the disintigrant and 1% (W/W) magnesium stearate and talc were mixed with liquisolid compact. The final mixture was compressed using the manual tableting machine to achieve tablet hardness of 6-7kp.

 

Preparation of liquisolid compacts:

Several liquisolid compacts were prepared as follows. Atorvastatin was dispersed in PG with different ratios ranging from 1:1, 1:3, 1:5, 1:7 (drug: PG). The binary mixture contains lactose (flowlac)-cabosil. Lactose as the carrier powder and cabosil as the coating material was added to the mixture containing the drug and PG under continuous mixing in a mortar. Depending on the ratio of drug: PG in formulation, different liquid load factors were employed in our liquisolid preparations. These amounts of the carrier and coating materials are enough to maintain acceptable flow and compression properties. Finally 5% (W/W) of sodium starch glycolate was used as the disintigrant and 1% (W/W) magnesium stearate and talc were mixed with liquisolid compact. The final mixture was compressed using the manual tableting machine to achieve tablet hardness of 6-7kp. The Composition of atorvastatin tablets is given in table1.

 

Evaluation of liquisolid compacts

The post compressional parameters like hardness, thickness, friability, disintegration time, drug content and dissolution studies were conducted or all prepared liquisolid compacts.

 

Weight variation:

Twenty tablets were collected randomly and the average weight and individual weight was calculated with the following formula

 

%Weight variation = average weight-individual weight/ individual weight × 100

 

Thickness:

The thickness of a tablet was measured in mm by using Vernier callipers.

 

Hardness:

The hardness of the ten tablets was measured by using Varian VK200 Tablet Hardness Tester and is given in units of KP.

 

Friability:

Ten Tablets were carefully de dusted prior to testing and weighed accurately (W0). The tablets were placed in   Friabilator (USP) EF-2. The drum was rotated for 100 times at a speed of 25rpm. The tablets were collected, de-dusted and accurately weighed (W1). It is calculated from the fallowing formula.

 

%Friability =

 

Disintegration Test:

The disintegration study was performed for atorvastatin compacts by sing disintegration apparatus Electrolab DT tester (USP). For this water was used as the disintegration medium. 6 tablets were placed in 6 tubes of the disintegration apparatus. The time (min) taken for the compacts to disintegrate was noted.

 

 

Determination of drug content of atorvastatin calcium compacts:

Ten AT compacts were weighed accurately and then crushed well in a clean mortar and pestle. The powder equivalent to25 mg of the drug was weighed and then transferred to a 100ml volumetric flask. 50ml methanol was added and sonicated for 5min at 27°C. Then the volume was made up to 100ml using methanol. The sample was suitably diluted with pH 6.8 phosphate buffers and analysed for drug content at 246nm using UV spectrophotometer. The drug content was calculated using the following formula.

 

Drug content = =

 

In vitro drug release studies of atorvastatin compacts:

In vitro drug release studies of atorvastatin tablets were carried out using electrlab, US apparatus-II paddle type apparatus with 6.8 pH buffer as dissolution media(900ml) the paddle speed was set at 50 rpm and replaced with 5ml of fresh buffer at the sampling intervals of 5,10,15,20, 30 mins. The collected samples were analysed at 246nm using UV spectrophotometer.

 

Stability studies

An ideal dosage form apart from other requirements, it should provide consistency in drug release throughout its shelf life. The stability of drug release from tablets developed in this investigation was studied by keeping the selected formulation under following storage conditions.

 

1.25±20c/60±5%RH

2.40±20c/75±5%RH

 

All the products were stored for 2 months. Samples were taken at 30, 60, and 90 days and subjected to in-vitro dissolution studies and the observed dissolution data of atorvastatin from the stored product was presented in the following table.

 

RESULTS AND DISCUSSIONS:

Solubility:

Different non-volatile solvents such as PEG400, PEG200, PG, were screened based on their solubility and solubility data was represented in table 2. High solubility was observed from the solvent PG so it was selected for further studies.

 

Selection of carriers:

To select the better carrier among the mannitol, starch, lactose, MCC they were tested for wet point and flow point. Lactose was selected, as it offered less flow and wet points. The blend containing carrier and adsorbent was accessed for Binding capacity and observed Binding capacity was shown in the following table 3.

 

Micromeritic properties:

The micromeritic properties of all carriers were within the limits and results were shown in the table no. the material exhibited desired flow property it was compressed to form a tablet. The tablets were subjected to various quality control tests and the results were given in a table no4.

 

Average weight:

Prepared formulations are subjected to weight variation test as per I.P acceptance criteria for weight variation test is as follows. The results are given in table. The observed weight variation was found to be within the acceptance range78-1239 and thus all the tablets were satisfied the weight variation test. The results are shown in table no-5.

 

Hardness:

The hardness of all formulations was tested using Varian VK200 Tablet Hardness Tester. The data was given in table no 5.

 

% Friability:

% Friability for all the formulations was carried out in Roche’s friabilator. The % friability range for all formulations was in between 0.019±0.24- 0.248±0.45 and thus all formulations were satisfied the friability test. The results are shown in table no-5.

 

Drug content:

The content of active ingredient test was determined as per I.P requirement. The results are in between 95.23±0.35-98.89±0.18. The observed data indicated that tablets are satisfying the drug content requirement. The results are shown in table no-5.

 

Disintegration test:

The disintegration test determines for tablets disintegrate with in a prescribed time when placed in a liquid medium under the prescribed experimental conditions. According to IP disintegration time for tablets was 30 mins. Disintegration time for all the formulations was varied from 11.07±0.24-13.36±0.16. The results are shown in table no-5.

 

Dissolution:

The in-vitro dissolution was carried out for all the formulations under the prescribed experimental conditions. The time vs %drug release plot was shown in figure 1. The dissolution data follows 1st order rate kinetics.

 

The highest drug release was observed for the formulation F8 containing ATORVASTATIN 20 mg, carrier 505.6 mg, coating material 10 mg, PG 2.5 mg; super disintigrating agent and lubricants of 11.64, 23.45, and 11.64 were added. The selected formulation was selected to stability studies. The stability studies data was given in table 6.


 

Table 1: Composition of Atorvastatin tablets

Formulation

Drug dose

Carrier

Amount of PG (ml)

Amount of carrier (mg)

Amount of coating material (mg)

 Mg. Stearate

  SSG

Talc

Total dose (mg)

F1

20

Lactose

0.5

320

16

8.32

20.8

8.32

394

F2

20

Lactose

2.0

546

27

15.74

33.3

15.78

660

F3

20

Lactose

2.3

586

29

16.58

35.45

16.45

706

F4

20

Tabletose100

3.1

435

43.5

12.66

31.65

11.6

558.5

F5

20

Microlac

0.42

200

80

6.9

17.25

6.9

331.4

F6(1:1)

20

Flowlac

0.5

0.8

40

1.58

3.85

1.58

68.4

F7(1:3)

20

Flowlac

1.5

8

400

8.9

22..2

8.9

469.5

F8(1:5)

20

Flowlac

2.5

10

505.65

11.64

23.4

11.64

584.8

F9(1:7)

20

Flowlac

3.5

26

1040

24.82

62.05

24.82

1201

 


 

Table 2: Solubility of drug in different solvents

S.No

Solvent

Solubility(mg/ml)

1

PEG400

5.53

2

PEG200

10.01

3

PG

12.03

 

 

Table 3: Binding capacity of carriers

carrier

Amount of carrier (mg)

Amount of coating material(mg)

Amount of PG(ml)

Lactose

5

572

0.8

Mannitol

5

480

1

MCC

5

600

2.2

starch

5

743

3.1

Table 4: Flow properties of carriers

Carrier

Bulk density

Tapped density

Carr’s index

Hausner’s ratio

Lactose

0.475

0.558

14.874

1.174

Mannitol

0.476

0.526

9.505

1.105

MCC

0.454

0.555

18.198

1.222

Starch

0.5

0.633

21.01

1.266

 

Table 5: Evaluation parameters of liquisolid compacts

Formulation

Avg. Wt.

Hardness

%Friability

Disintegration Time(mn.)

Drug Content

F1

415±0.15

3.4±0.73

0.048±0.31

13.06±0.19

95.23±0.35

F2

785±0.28

2.6±0.67

0.019±0.24

13.15±0.17

96.54±.26

F3

831±0.11

3.5±0.34

0.248±0.36

11.07±0.24

96.78±0.14

F4

629±0.12

2.3±0.46

0.133±0.51

13.09±0.11

97.84±0.31

F5

345±0.26

2.9±0.32

0.248±0.45

12.35±0.32

95.93±0.26

F6

78±0.11

2.5±0.72

0.145±0.11

11.15±0.24

97.35±0.35

F7

447±0.24

2.3±0.12

0.213±0.16

12.2±0.12

98.12±0.14

F8

580±0.18

2.2±0.55

0.155±0.28

13.36±0.16

97.32±0.25

F9

1239±0.23

3.1±0.69

0.213±0.33

12.24±0.22

98.89±0.18

 

 

Figure 1: In- vitro drug release profiles of liquisolid compacts

 


Table 6: Stability Studies:

Dissolution Data of Atorvastatin Stored at Various Temperatures:

Time

% Drug release data

Initial Temp

1 Month

2 Month

3 Month

5

25.43

25.43

24.43

23.43

10

43.99

45.11

44.99

43.99

15

60.93

59.93

58.93

57.93

20

73.3

72.3

71.3

70.30

25

86.91

85.51

85.91

83.91

30

96.45

95.45

94.45

93.45

 

CONCLUSION:

The solubility of drug is dependent on the non-volatile liquid employed. The liquid holding capacity is influenced by carrier, adsorbent and the composition of carrier: adsorbent. The liquisolid compacts exhibited good flow properties. The formulations satisfied the quality control requirements. The dissolution profiles are dependent on the composition of liquisolid compact and the formulations are quite stable.

 

REFERENCES:

1.       Kapsi, SG, Aters, JW. Processing factors in development of solid solution formulation of itraconazole for enhancement of drug dissolution and bioavailability. Int.J.Pharm:2001:229:193-203.

2.       Venkat. B. Yadav, Adhikrao, V. Yadav. Enhancement of solubility and dissolution rate of BCS class II pharmaceuticals by non-aqueous granulation technique.IJPRD2010:1:1-12.

3.       Spireas S, Bolton M. Liquisolid systems and methods preparing same. U.S. Patent, 1999; 5968550

4.       Spireas S Liquisolid systems and methods preparing same. U.S. Patent; 2002; 6,423,339.

5.       D.M. Brahmankar Sunil. B. Jaiswal, methods for enhancement of Bioavilability Biopharmaceutics and Pharmacokinetics Vallabh Prakashan Delhi, 297-301.

6.       www.drugbank.com/atorvastatin/html

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8.       Pharmacopeia specification of powders and tablets: http://www.uspbpep.com/search.asp

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Received on 15.11.2014       Modified on 25.11.2014

Accepted on 02.12.2014     ©A&V Publications All right reserved

Res. J. Pharm. Dosage Form. & Tech. 7(2): April-June, 2015; Page 93-97

DOI: 10.5958/0975-4377.2015.00013.0