Formulation and Evaluation of Simvastatin Solid Dispersions for Dissolution Rate Enhancement

Nakkala Balaji*, V. Sai Kishore and Kasani Hari krishna Gouda

Department of Pharmaceutics, Bapatla College of Pharmacy, Bapatla, Guntur (Dt), Andhra Pradesh, India. 522101

ABSTRACT:

Simvastatin (SIM) is a lipid lowering agent derived synthetically from a fermentation product of Aspergillus terreus. Simvastatin reversibly inhibit HMG-CoA reductase, which catalyzes a rate-limiting step in cholesterol biosynthesis. One of the major problems with this drug is its low solubility in biological fluids, which results into poor bioavailability after oral administration. Therefore, solid dispersions (SDs) of Simvastatin were prepared to increase its aqueous solubility using carriers such as lactose, urea. Simvastatin SDs was prepared in 1:1, 1:2, 1:3, 1:4 and 1:5 ratios of the drug to carrier (w/w). Solid dispersions were prepared by employing solvent evaporation and kneading methods. The prepared solid dispersion was evaluated for drug content, in vitro drug release studies and powder X- ray diffractometry. In vitro drug release profiles of all SDs were comparatively evaluated and also studied against pure Simvastatin. Faster dissolution was exhibited by solid dispersion prepared by solvent evaporation containing 1:4 ratio of Simvastatin: Urea. It was observed that kneading method was more effective than solvent evaporation. In vitro drug release studies revealed that there was progressive improvement in the drug release rate from solid dispersions systems compared to pure drug alone. The rate of drug release was depended on the type, ratio of drug to carrier and method of preparation of solid dispersions. The enhancement in dissolution rate of the drug may be due to increase in wettability, hydrophilic nature of the carrier and due to reduction in drug crystallinity.

KEYWORDS: Solid dispersions, simvastatin, solubility, carrier, solvent evaporation, kneading method.

INTRODUCTION:

A number of pharmaceutical active ingredients suffer from aqueous solubility problems. Although these molecules have potential pharmacodynamic property, they show low bioavailability due to poor aqueous solubility, because of these problems they may fail to reach the market. Thus, the enhancement of aqueous solubility, dissolution rate, and thereby improving the bioavailability of drug is a challenging task in dosage form development for these drugs.

Aqueous solubility is one of the key properties of a therapeutically active substance, which governs dissolution, absorption, and thus the in vivo efficacy¹. Various techniques have been employed to improve the dissolution and bioavailability of poorly water-soluble drugs such as micronization², solubilization³, salt formation, complexation with polymers, change in physical form, use of prodrug and drug derivatization, pH alteration, addition of surfactants, and others⁴.

Simvastatin (SIM) is a cholesterol lowering agent, which is a white, nonhygroscopic, crystalline powder having poor aqueous solubility and bioavailability. Simvastatin is a potential inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase. It catalyzes the conversion of HMG-CoA to mevalonate; this conversion is an early and rate-limiting step in the biosynthesis of cholesterol⁵. Being a BCS Class II drug, it often shows dissolution rate-limited oral absorption and high variability in pharmacological effects. Therefore, need to improve its solubility and dissolution rate thereby enhancing bioavailability⁶.

In the present study, solid dispersions were prepared by a solvent evaporation and kneading method using two different carriers at different drug–carrier ratios (lactose and urea) and evaluated for different parameters like drug content, in vitro drug release studies.

MATERIALS AND METHODS:

Materials:

Simvastatin was procured from Dr. Reddy’s Laboratories, Hyderabad, India as a gift sample. Lactose and urea were obtained from S.D. Fine Chemicals, Mumbai, India. All other reagents used were of AR grade and procured locally.

Preparation of Solid Dispersions:⁷

Solid dispersions of simvastatin were prepared by employing solvent evaporation and kneading methods.

Solvent evaporation:

Simvastatin and carriers (lactose and urea) in various proportions viz. 1:1,1:2,1:3,1:4 and 1:5 (drug: carrier) were prepared by solvent evaporation method as follows. To the solution of simvastatin in ethanol, the aqueous solution of carrier (lactose or urea) was added. Then allowed to evaporate the solvent by placing it in vacuum drier for 3 hours at a temperature of 40 ºC and the dried sample was stored in a desiccator for overnight. Then the dried sample was ground in a mortar and passed through an 80 # sieve.

Kneading method:

Simvastatin and carriers (lactose and urea) in proportions viz. 1:1,1:2,1:3,1:4 and 1:5 (drug: carrier) were prepared by kneading method as follows. To the mixture of drug and carrier, small amount of ethanol was added until paste like mass was obtained, later it was kneaded for 10 minutes. It is dried under reduced pressure at 40ºC. Dried mass was ground in a mortar, and passed through an 80 # sieve.

Evaluation of Solid Dispersions:

The formulated solid dispersions were evaluated for following parameters:

Analysis of simvastatin using a UV- Visible spectrophotometer:^{8, 9}

1000 μg/ml stock solution of simvastatin was prepared in methanol and further dilutions were made with Phosphate buffer P^H 7 containing 0.5% SLS. The concentrations of 2-10 μg/ml were prepared. The calibration curve was obtained by analyzed spectrophotometrically at 238nm by UV-Visible spectrophotometer. Calibration curve was plotted by taking concentration (μg/ml) on x-axis and absorbance on y-axis.

Drug content:^{9, 10}

Solid dispersions equivalent to 10 mg of simvastatin were accurately weighed and dissolved in the ethanol. The solution was filtered, suitably diluted and analyzed spectrophotometrically at 238 nm by UV-Visible spectrophotometer. The actual drug content was calculated using the following formula.

Actual amount present in solid dispersion X100

% Drug content = Theoretical amount present in solid dispersion

In vitro drug release studies:

In vitro drug release studies of pure drug as well as solid dispersions were performed using USP XXII type 2 dissolution apparatus (Electro lab, Mumbai, India). Solid dispersion equivalent to 10 mg of simvastatin was accurately weighed and subjected for dissolution in 900 ml of Phosphate buffer pH 7containing 0.5% sodium lauryl sulphate at a temperature of 37±0.5ºc and stirring speed of 50 rpm. Aliquot of 5ml was withdrawn at regular intervals of time (i.e 5 min) and replenished the same volume with fresh medium. The samples were analyzed spectrophotometrically at 238 nm by UV-Visible spectrophotometer.

Powder X-Ray Diffractometry:

The X-ray diffractograms were obtained using on X-Ray diffraction instrument (Philips Analytical X’Pert PRO) with Cu radiation, at a voltage of 40kV and current of 20mA.

Infra red spectrum:

IR spectrums of simvastatin and solid dispersions were carried out using FT-IR based on the KBr pellet method. The spectra were scanned over a wave number range of 2000 to 400 cm–1.

Table1: List of Solid dispersions (Simvastatin- Lactose) formulated by different methods at different ratios.

Formulation Code	Method employed	Simvastatin: Lactose
F1	Solvent evaporation	1:1
F2	Solvent evaporation	1:2
F3	Solvent evaporation	1:3
F4	Solvent evaporation	1:4
F5	Solvent evaporation	1:5
F6	Kneading method	1:1
F7	Kneading method	1:2
F8	Kneading method	1:3
F9	Kneading method	1:4
F10	Kneading method	1:5

RESULTS AND DISCUSSION:

Drug Content:

Drug content for all solid dispersions were in the range of 96.1-99.4 %. Higher the drug content in solid dispersions was shown that low standard deviations, indicates that the drug was uniformly dispersed in the formulation. These results revealed that the method used in this study appears to be reproducible for preparation of solid dispersion

In vitro drug release studies:

The dissolution profiles of simvastatin pure drug and solid dispersions with lactose and urea prepared by solvent evaporation and kneading method were shown in the table2, table4, and figure1-4. It was evident that solid dispersions exhibit faster dissolution than the free drug. The improvement in the dissolution rate varies with the method of preparation, carrier ratio. The in vitro dissolution studies of the solid dispersion prepared by kneading method with urea at 1:4 ratio showed 98.67% release in 20 minutes whereas solid dispersion with lactose by kneading method at 1: 4 ratio showed 98.93% release in 30 minutes. Enhancement in dissolution rate was may be due to improved wettability which can lower the interfacial tension between poorly soluble drug and dissolution medium.

Figure1: In vitro dissolution profiles of pure drug and simvastatin- lactose solid dispersions prepared by solvent evaporation method.

Figure2: In vitro dissolution profiles of pure drug and simvastatin- lactose solid dispersions prepared by kneading method.

Figure3: In vitro dissolution profiles of pure drug and simvastatin- urea solid dispersions prepared by solvent evaporation method.

Figure4: In vitro dissolution profiles of pure drug and simvastatin- urea solid dispersions prepared by kneading method.

Table2: In vitro Dissolution parameters of Simvastatin- lactose solid dispersions prepared by different methods at different weight ratios.

Formulation code	Method employed	Simvastatin: Lactose	Correlation coefficient		D.E20 (%)	K1 (Min^-1)	T50 (Min)	T90 (Min)
			Zero order	First order
		Pure drug			23.16	0.0168	41.2	137.0
F1	Solvent evaporation	1:1	0.9520	0.9549	33.10	0.0778	8.9	29.6
F2	Solvent evaporation	1:2	0.9446	0.9473	37.41	0.1007	6.9	22.9
F3	Solvent evaporation	1:3	0.9246	0.9785	50.53	0.1231	5.6	18.7
F4	Solvent evaporation	1:4	0.9594	0.9602	44.88	0.1091	6.4	21.1
F5	Solvent evaporation	1:5	0.8690	0.9681	42.4	0.0907	7.6	25.4
F6	Kneading method	1:1	0.9387	0.9437	37.24	0.0818	8.5	28.2
F7	Kneading method	1:2	0.9357	0.9559	39.22	0.1014	6.8	22.7
F8	Kneading method	1:3	0.8348	0.9731	54.04	0.1117	6.2	20.6
F9	Kneading method	1:4	0.4009	0.9558	73.56	0.1443	4.8	16.0
F10	Kneading method	1:5	0.7367	0.9286	55.78	0.0903	7.7	25.5

Powder X-Ray Diffractometry:

X-Ray Diffraction patterns of pure drug and solid dispersions were showed in the figure 5 and 6 respectively. The peak position (angle of diffraction) is an indication of crystal structure and the peak height is the measure of simple crystallinity. The pure drug shows a highly crystalline nature, indicated by numerous intense peaks. On the other hand solid dispersion was shown decrease in crystallinity, evidenced by the absence of several intense peaks.

Infrared spectroscopy:

FTIR spectroscopy was used to study the possible interactions between simvastatin and urea in the solid dispersion. There was no significant difference in the FTIR spectra of pure drug and solid dispersion (figure7 and 8). All major peaks of simvastatin observed at wave numbers 3551 cm-1 (free O–H stretching vibrations); 2961 cm-1 (C–H stretching vibrations); and 1704 cm-1 (stretching vibration of ester and lactone carbonyl functional groups) were also retained in case of solid dispersion, which clearly indicate that there was no interaction exists between pure drug and urea in solid dispersion.

Table3: List of Solid dispersions (Simvastatin- Urea) formulated by different methods at different ratios.

Formulation Code	Method employed	Simvastatin:Urea
F11	Solvent evaporation	1:1
F12	Solvent evaporation	1:2
F13	Solvent evaporation	1:3
F14	Solvent evaporation	1:4
F15	Solvent evaporation	1:5
F16	Kneading method	1:1
F17	Kneading method	1:2
F18	Kneading method	1:3
F19	Kneading method	1:4
F20	Kneading method	1:5

Figure5: X- ray diffraction pattern of Simvastatin.

Figure6: X- ray diffraction pattern of simvastatin urea solid dispersion (1:4).

Figure7: IR spectra of simvastatin.

Figure8: IR spectra of Simvastatin: urea solid dispersion (1:4)

Table4: In vitro Dissolution parameters of Simvastatin- urea solid dispersions prepared by different methods at different weight ratios.

Formulation code	Method employed	Simvastatin: Urea	Correlation coefficient		D.E20 (%)	K1 (Min^-1)	T50 (Min)	T90 (Min)
			Zero order	First order
		Pure drug			23.16	0.0168	41.2	137.0
F11	Solvent evaporation	1:1	0.7418	0.8738	62.42	0.1588	4.4	14.5
F12	Solvent evaporation	1:2	0.6673	0.9455	70.38	0.1735	4.0	13.3
F13	Solvent evaporation	1:3	0.6355	0.9730	66.91	0.1181	4.0	13.1
F14	Solvent evaporation	1:4	0.7054	0.9922	77.45	0.2119	3.3	10.9
F15	Solvent evaporation	1:5	0.5625	0.8166	67.15	0.1495	4.6	15.4
F16	Kneading method	1:1	0.6375	0.9290	65.09	0.1825	3.8	12.6
F17	Kneading method	1:2	0.7359	0.9930	75.98	0.2081	3.3	11.1
F18	Kneading method	1:3	0.7167	0.9346	72.44	0.1755	5.9	19.5
F19	Kneading method	1:4	0.6567	0.9747	78.61	0.2151	3.2	10.7
F20	Kneading method	1:5	0.5186	0.9544	67.41	0.1078	6.4	21.4

CONCLUSION:

The solid dispersions of simvastatin with two different carriers (lactose, urea) prepared by a solvent evaporation and kneading method showed significantly higher drug dissolution in comparison with pure drug. From the in vitro dissolution studies of the solid dispersions, the higher drug release was obtained from solid dispersions prepared by kneading method and with a carrier urea (1:4). FTIR studies showed no evidence of interaction between the drug and carrier. PXRD study confirmed amorphization of drug. The present work concluded that solid dispersion technology can be used successfully to enhance the dissolution rate of poorly soluble drug Simvastatin.

ACKNOWLEDGEMENTS:

The authors thankful to the Dr. Reddy’s Laboratories, Hyderabad, India for providing drug sample and Bapatla College of Pharmacy for providing necessary requirements

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Received on 17.05.2011

Accepted on 09.06.2011

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Research Journal of Pharmaceutical Dosage Forms and Technology. 3(5): Sept.-Oct. 2011, 210-214