Preparation of Binary and Ternary Solid Dispersions of Nifedipine and to Compare Their Effect on Dissolution Profile

Ashish Sharma1, Anupama Kalia 1*, Deepak Malhotra1

RESEARCH ARTICLE

1:8:4, 1:8:6, 1:8:8 PVPK30:PLX407).

Abstracts: Nifedipine (NFP) is the prototype nitro-dihydropyridine calcium channel antagonist that is used to treat a variety of cardiovascular disorders. NFP is a BCS class II drug having low solubility in water which leads to low dissolution rate, slow onset of action and variable oral bioavailability. To improve the dissolution rate of NFP by preparing binary and ternary solid dispersions. Binary and ternary solid dispersions were prepared using polyvinyl pyrrolidone K30 (PVPK30) and poloxamer 407 (PLX407) in different weight ratios. The drug and the formulations were characterized by FTIR, DSC and XRD. Solubility analysis and Invitro dissolution of NFP solid dispersions (binary and ternary) were carried out and then compared. In contrast to the very slow dissolution rate of pure NFP, the solid dispersions showed enhanced dissolution rate. The solubility and dissolution were increased in the order; NFP (Pure drug) < binary solid dispersions < ternary solid dispersions. The fraction of NFP dissolved after 1 hr was approximately 70% and 90% from binary (NFP: PVPK30; 1:8) and ternary solid dispersions (NFP: PVPK30:PLX407; 1:8:2) respectively in comparison to the pure NFP, which was found to be approximately 2% in 1 hr. From this study, it was concluded that NFP showed significant improvement (statistically analyzed using ANOVA) in dissolution rate in case of ternary dispersions as compared to the binary dispersions as well as pure NFP. INTRODUCTION The solubility and dissolution of the drug are the key determinant for oral bioavailability. But more than 40% new chemical entities being produced are mostly insoluble in water [1]. Poor solubility leads to low bioavailability, high dosage and low drug plasma concentration leading to failure of new chemical entities to reach the market giving serious challenges for whole pharmaceutical fraternity for commercialization of the pharmaceutical products [2]. Various approaches can be utilized for improving the dissolution profile of the drug viz. micronization, salt formation, complexation, solubilization etc. However, solid dispersion is one of the most successful among these approaches to improve solubility, dissolution rate and thereby the bioavailability of poorly water solubility drugs [3]. Solid dispersions are the dispersions of one or more active ingredients in the inert carrier matrix at solid state prepared by fusion, hot melt, solvent and supercritical fluid method [4] [5]. In other words, solid dispersion refers to group of solid products consisting of at least two different components, generally a hydrophilic matrix and hydrophobic drug. The matrix can be either crystalline or amorphous. Solid dispersions can be prepared by solvent method [6], fusion method [5] [7] or supercritical fluid method [8]. Nifedipine (NFP; figure 1) is the prototype nitro-dihydropyridine calcium channel antagonist that is used to treat a variety of cardiovascular disorders, such as angina pectoris and hypertension [9] [10]. It is
1Lovely

Key Words: Nifedipine, solid dispersions, binary solid dispersions, ternary solid dispersions, polyvinyl pyrrolidone K30, poloxamer 407.

yellow crystalline, odorless, nonhygroscopic drug and belongs to BCS class II having low solubility in water (5-6 g/ml) [11], which may further leads to low dissolution profile. As dissolution is rate limiting step for absorption of this drug, the greater sense of dissolution and absorption behavior is required to successfully formulate it into bioavailable drug product. The present investigation is aimed to develop solid dispersions of NFP employing amorphous and combination of amorphous and hydrophilic polymers and to compare the effectiveness of dispersions in enhancing the dissolution rate of the drug. The prepared dispersions were characterized by XRD, DSC and FTIR spectroscopy.

Differential Scanning Calorimetry Thermal investigations of melting range and the peak temperature of NFP, PVPK30, PLX407, binary solid dispersions (NFP: PVPK30) and ternary solid dispersions (NFP: PVPK30:PLX407) were performed with differential scanning calorimetry (DSC; Diamond DSC Perkin, USA). Experiments were carried out in aluminium pans with a pierced lid. The nitrogen flow rate was adjusted to 50 ml/min. Samples were heated in sealed aluminum pans. Sample size ranged from 0.5 to 3.0 mg. Temperature ranged from 0 to 180 C with a heating rate of 100 C/min. Empty aluminum pan was used as reference. The slides were brought into contact with the aluminium pan by pushing it carefully onto the bottom of the pan with a glass rod thereby ensuring the contact between pan and slide over the entire lower surface of the slide. Subsequently, the samples were kept isothermally during 3 min at these end temperatures.

FTIR Spectroscopy FTIR spectra were obtained by using a FTIR spectrophotometer (Shimadzu-4800S, Japan) in the region of 500-4000 cm-1 using a resolution of 2 cm-1. The samples (NFP, polymers and solid dispersions) were ground and mixed thoroughly with potassium bromide (KBr) in the ratio of 1:5 (sample: KBr). KBr discs were prepared by compressing the powders under force of 6 tons for 5 min in hydraulic press. The FTIR spectra were compared to check the interaction between drug and carriers.

and

1:8:10

(NFP:

H3C H3C O O

H N

CH3 O O NO2 CH3

MATERIALS AND METHODS Materials NFP was provided as a gift sample by Medicamen Biotech limited, Bhiwadi. Poloxamer 407 (PLX407) and Polyvinylpyrrolidine K30 (PVPK30) were provided by Central drug house Pvt. Ltd. New Delhi. All the reagents were of analytical grade. Triple distilled water was used wherever required. Formulation of Solid Dispersions Binary and ternary solid dispersions were prepared by solvent evaporation method. In binary solid dispersions, different weight ratios of NFP and PVPK30 (1:1, 1:2, 1:4, 1:6, 1:8 and 1:10) were dissolved in 20 ml chloroform and the solvent was removed. The residues were dried in an oven at 50 C for 24 hours, ground in a mortar and passed through sieve no. 60. The resultant granules were stored in desiccator. In ternary solid dispersions, PLX407 was incorporated into binary dispersions exhibiting best dissolution behavior to obtain the dispersions with weight ratios of 1:8:1, 1:8:2,

Figure 1: Nifedipine (NFP)

School of Pharmaceutical sciences, Lovely Professional University, Phagwara, Punjab, India. E-mail: anukalia@ymail.com *Corresponding author

X-Ray Diffractometry The X-ray diffraction (XRD) studies were carried out to determine the physical state of the drug, polymers and drug in binary and ternary solid dispersions. The XRD was investigated by scanning powder samples using X Pert PRO instrument (Philips, The Netherland), equipped with X Pert PRO Data Collector software. The diffraction pattern was measured with a voltage of 32 kV. The Monochromatic radiation used was generated by a CuK ( = 1.54184A). Samples were analyzed in the 2 angles ranging from 5-45, at a scanning rate of 10/min. The peak intensities of diffractograms of powdered samples of NFP,
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Table 1: Solubility of NFP and its solid dispersion system at 37 0.5 C Medium Type of NFP pH 1.2 HCl buffer Pure NFP pH 1.2 HCl buffer Binary solid dispersion (NFP:PVPK30; 1:8) pH 1.2 HCl buffer Ternary solid dispersion (NFP:PVPK30:PLX407; 1:8:2)
7 5 % T 6 .5 7 6 0 5 .5 2 4 5

RESEARCH ARTICLE

Solubility (mg/ml) 0.0043 14.9 24.7

3 .5 7

a)

3 0

1645.17

2 .5 2

3330.84

1226.64

7 .5

1689.53 1679.88

1529.45

1350.08

1120.56

1 5

4 0 0 0 3 5 7 0 Nf e i i dpn i e

3 0 5 0

3 5 2 0

3 0 0 0

2 5 7 0

2 0 5 0

2 5 2 0

2 0 0 0

1 5 7 0

1 0 5 0

1 5 2 0

1 0 0 0

7 0 5

5 0 0 1 /c m

7 5 % T 7 0

3103.25

2952.81

6 5

6 0

5 5

5 0

b)

4 0

3 5

2359.02

7.26

1458.23

1288.49

4 5

1494.73 1433.01

1309.58

4 0 0 0 P D V K V 3

3 0 6 0

3 0 2 0

2 0 8 0

2 0 4 0

2 0 0 0

1 0 8 0

1 0 6 0

1 0 4 0

1 0 2 0

1 0 0 0

8 0 0

6 0 0

4 0 0 1 /c m

5 0 % T 4 5

4 0

3 5

3 0

2 5

c.)

2 0

1 5

1 0

2694.65

2360.95

1467.88

1242.20

962.51

1342.50

0 3 0 6 0 4 0 0 0 P l oo a x m r 4 7 e 0 3 0 2 0

2970.48

1280.78

842.92

2 0 8 0

2 0 4 0

2 0 0 0

1 0 8 0

1 0 6 0

1 0 4 0

1 0 2 0

1 0 0 0

8 0 0

6 0 0

4 0 0 1 /c m

6 0 % T 5 .5 7

5 5

5 .5 2

5 0

4 .5 7

4 5

4 .5 2

d)

2359.02

4 0

3 .5 7

2953.12

1531.53 1494.88 1462.09

3 5

3 .5 2

3 0 4 0 0 0 N :P b 3 0 6 0 3 0 2 0 2 0 8 0 2 0 4 0 2 0 0 0 1 0 8 0 1 0 6 0 1 0 4 0 1 0 2 0 1 0 0 0 8 0 0 6 0 0 4 0 0 1 /c m

7 0 % T 6 5

6 0

5 5

5 0

e) Figure 2: FTIR spectra of a) NFP b) PVPK30 c) PLX407 d) Binary solid dispersions (NFP:PVPK30; 1:8) e) Ternary solid dispersions (NFP:PVPK30:PLX407; 1:8:2)
4 5 3 0

2359.02

1112.96

3 5

1286.56

4 0

2889.46

1464.02

1288.49

N :P :P b -

3 0 6 0

3 0 2 0

2 0 8 0

2 0 4 0

2 0 0 0

1 0 8 0

1 0 6 0

1 0 4 0

1 0 2 0

1 0 0 0

8 0 0

6 0 0

4 0 0 1 /c m

In-vitro Dissolution Studies Dissolution study was conducted in triplicate on the pure drug and prepared dispersions (binary and ternary) using USP dissolution apparatus-I (Labindia DS 8000). To simulate the dissolution of the compound in stomach, 900 ml of pH 1.2 HCl buffer was used as dissolution media at a temperature of 370.5C with basket speed of 100 rpm.
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Solubility Study Solubility of NFP and solid dispersions was determined by adding excess amount of NFP or equivalent to 20 mg of NFP (in case of solid dispersions) into pH 1.2 HCl buffer at 370.5C. This was agitated for 48 hr in mechanical shaker up to saturation and then saturated solution was withdrawn, filtered to obtain clear solution and analyzed by using Double beam spectrophotometer (Shimadzu, model no. 1800, India) at 239.8nm.

PVPK30, PLX407 and solid dispersions were compared.

RESULT AND DISCUSSION FTIR Spectroscopy FTIR spectra of NFP, polymers (PVPK30, PLX407) and solid dispersion systems are shown in Fig. 2. The IR spectrum of NFP (Fig. 2a) is characterized by principal absorption peaks at 3330.84 cm-1 (N-H stretch), 3103.25 cm-1 (C=O stretch), 1689.53 cm-1 (C-H stretch), 1529 cm-1 (N-O stretch). The IR spectrum of binary system (Fig. 2d) showed

Amount of powdered samples, equivalent to 20 mg NFP were added to the dissolution medium. 10 ml samples were taken and immediately replaced with fresh dissolution medium. At predetermined intervals (0, 15, 30, 45, 60, 90, 120, 180 min), 10 ml samples were withdrawn from each vessel, filtered with whatman filter paper and analyzed for NFP content by using Double beam spectrophotometer (Shimadzu, model no. 1800, India) at 239.8nm. The results of dissolution studies were statistically analyzed using ANOVA.

Differential Scanning Calorimetry (DSC) The DSC curves for pure NFP, polymers (PVPK 30 and PLX407) and solid dispersions are shown in Figure 3. NFP exhibited sharp
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disappearance of peaks at 3330.84 cm-1 and the presence of all other peaks corresponding to NFP with decreased intensity. However, the spectrum of ternary system (Figure 2e) showed disappearance of peaks at 3330.84 cm-1 while the peaks at 3103.25 cm-1 and 1689.53 cm-1 were shifted to 3023.19 cm-1 and 1660.77 cm-1 respectively. The peak at 3103.25 cm-1 of C-H appeared consistently but slightly shifted in binary and ternary solid dispersions. All other NFP peaks were smoothened indicating a strong physical interaction of NFP with polymers and drug-polymers are compatible to each other. However, no additional peak was observed in any binary and ternary system indicating absence of any chemical interaction between NFP and polymers (PVPK30 and PLX407).

RESEARCH ARTICLE

a)

b)

c)

d)

Figure 3: DSC thermograms of a) NFP b) PVPK30 c) PLX407 d) binary solid dispersions (NFP: PVPK30; 1:8) e) ternary solid dispersions (NFP: PVPK30:PLX407; 1:8:2)

e)

a)

b) c)

d)

e) Figure 4: XRD spectra of a) NFP b) PVPK30 c) binary solid dispersions (NFP: PVPK30; 1:8) d) PLX 407 e) ternary solid dispersions (NFP: PVPK30:PLX407; 1:8:2)
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RESEARCH ARTICLE

Figure 5: Release profile of NFP, binary solid dispersions consisting of NFP and PVPK30 (1:1; 1.2; 1:4; 1:6; 1:8: 1:10) (n=3; error bars indicate SD; BSD: Binary solid dispersions)

Figure 6: Release profile of NFP and ternary solid dispersions of NFP, PVPK30 and PLX407 (1:8:1; 1:8:2: 1:8:4: 1:8:6: 1:8:8: 1:8:10) (n=3; error bars indicate SD; TSD: Ternary solid dispersions) melting endotherm at 174.21 C (Fig. 3a). PVPK30 indicates broad melting endotherm ranging from 55 to 125 C (Fig. 3b). PLX407 exhibited a sharp endothermic peak at 58.3 C (Fig 3c). The binary solid dispersions (NFP: PVPK30; 1:8) showed no endothermic peak corresponding to NFP suggesting complete amorphization of NFP (Fig. 3d). However, thermogram of ternary solid dispersions (NFP: PVPK30:PLX407; 1:8:2) exhibited sharp endotherm at 58.3 C corresponding to PLX407, while complete absence of endothermic peak corresponding to NFP indicating complete transformation of the crystalline NFP into amorphous form (Fig. 3e). X-Ray Diffraction The XRD spectrum of pure NFP, polymers (PVPK30 and PLX407) and solid dispersions
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(binary and tertiary) are shown in Fig. 4. The XRD pattern of NFP displayed sharp peaks at 7.35, 8.22, 10.49, 11.89, 13.05, 14.78 and 16.31 (2) with relative intensities of 0.16, 79.39, 1.82, 53.80, 0.65, 1.58 and 100.00 respectively, indicating that NFP is present in the highly crystalline state. Relative decrease in crystallinity was determined by comparing some representative peak heights in the diffraction patterns of the binary and ternary systems with those of a reference (pure NFP). As is very clear from the diffractograms, in both types of dispersion systems (binary and ternary solid dispersions), the intensity of the crystalline peaks has reduced to the greater extent, suggesting the loss of crystallinity and transformation of drug into amorphous form.

In-vitro Dissolution of Solid Dispersions Solid dispersion systems of NFP with PVPK30 and PLX407 showed significant improvement in the drug dissolution rate (p< 0.05 for SD) as analyzed using ANOVA. The percentage of pure NFP dissolved was 0.99% in 30 min and only 2.82% in 3 hour. In comparison to the pure NFP, the percentage drug released in case of binary solid dispersions showed a hike as the concentration of PVPK30 increases from 1:1 to 1:8 (NFP: PVPK30) up to 50.76% in 30 min, then decreases if more amount of polymer is incorporated (1: 10 ratio of NFP: PVPK30) as shown in fig. 5. The probable reason behind this behavior may be due to increase in drug wettability, dispersibility with PVPK30 and reduction in the crystallinity of the drug with increase in the concentration of the polymer as the polymer exhibits a matrix type of system and entangles the drug into it. On the other hand, the reason behind decrease in the dissolution rate on further addition of polymer may be attributed to leaching behavior of the polymer during dissolution. Leached polymer could form a concentrated layer of solution around the particles, therefore the migration of the released drug particles to the bulk of the dissolution medium was slowed down [12] [13]. However, in case of ternary solid dispersions, the percentage drug released was found to be 77.55% in 30 min (Figure 6). The rapid dissolution of NFP from ternary solid dispersions may be attributed to the decrease in the drug crystallinity and formation of molecular colloidal dispersion in the hydrophilic carrier matrix. The wetting properties are also greatly increased due to the surfactant property of the PLX407, resulting in decreased interfacial tension between the medium and the drug [14]. It was observed that the higher ratios of PLX407 (1:8:4, 1:8:6, 1:8:8, 1:8:10) retarded the drug release system even though the drug crystallinity was reduced to greater extent in the solid dispersions. This might be due to the gelling property of the PLX at higher concentration [15]. Higher hydrophilicity and surfactant
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Solubility Study The solubility of NFP from prepared dispersion systems in pH 1.2 HCl buffer at 37 0.5C was found to be significantly greater than pure NFP as shown in table 1. The solubility of pure NFP was observed to be 4.3g/ml whereas, solubility of binary (1:8) and ternary solid dispersions (1:8:2) was found to be 14.9g/ml and 24.7g/ml respectively. More improvement in the solubility of ternary dispersion systems in comparison to binary dispersion systems may be attributed to micellar solubilization or reduction in the activity coefficient of the drug due to reduction in hydrophobic interaction or by both processes. In addition, improved wetting of the hydrophobic NFP crystals may also lead to improved solubility[11].

property of the PLX407 results in greater wetting and increase the surface available to dissolution by reducing the interfacial tension between the hydrophobic drug and dissolution medium. Thus, the combination of PVPK30 and PLX407 (ternary solid dispersions) has improved significantly the dissolution rate of the NFP in comparison to PVPK30 alone (binary solid dispersions).

RESEARCH ARTICLE

CONCLUSION In the present investigation, combination of PLX407 and PVPK30 (ternary solid dispersions) has improved significantly the dissolution rate of the NFP in comparison to PVPK30 alone (binary solid dispersions). Among the ratios used, 1:8:2 ratio of solid dispersion was found to be optimal for its superior performance in dissolution

enhancement. This indicated that an increase in the mass fraction of polymer could not offer any advantage for dissolution enhancement. Based on these results, it can be concluded that solid oral dosage forms of NFP with PVPK30 and PLX407 could be formulated with high dissolution rate, faster onset of action and improved bioavailability. REFERENCES AND NOTES

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Acknowledgement: The authors are very grateful to Dean, Lovely School of Applied Medical Sciences, Lovely Professional University, Phagwara, Punjab, India, for providing laboratory facilities.

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