INTRODUCTION:

Advent of combinatorial chemistry and high through put screening provided highly potent drug substances for therapeutic use, which are poorly soluble in nature and hence have poor bioavailability. Several techniques has been invented to combat the bioavailability problems and hence to improve the therapeutic efficacy. Salt formation, particle size reduction, buffered tablets, self emulsification system, solid dispersion and polymorphism are the commonly practiced techniques to increase dissolution rate of the drug.^{1, 2,
6, 10}

The most common, and perhaps the oldest approach to improve the bioavailability of such drugs is to enhance their dissolution rate by the formation of a solid dispersion. Amidon et al. classified such drugs in the Biopharmaceutical Classification System as class II compounds.^{7- 9}

Ezetimibe – a lipid lowering agent belongs to BCS Class –II drugs and has very low water solubility but high permeability. The dissolution and overall bioavailability of the drug is poor. Ezetimibe (EZE) is a novel selective inhibitor of intestinal cholesterol absorption from dietary and biliary sources without affecting the absorption of fat soluble vitamins and triglycerides.

It is indicated in combination with an HMGCoA reductase inhibitor in patients with primary hypercholesterolemia and homozygous familial hypercholesterolemia. ^29-
32

Historically, water-soluble carriers such as high molecular weight polyethylene glycols and polyvinylpyrrolidones (PVP) have been the most common carriers used for solid dispersions. For solid dispersions PVP K30 (MW 2500–50,000) has been widely used. The high molecular size of the polymers favors the formation of solid solutions. ³³Solid dispersions were prepared by freeze drying method and characterized by powder X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC)Fourier transform infrared (FTIR) spectroscopy, and Scanning electron microscopy (SEM)²⁵

MATERIALS AND METHODS:

Materials: EZE was kindly supplied by Ajanta Pharma Pvt. Ltd (Mumbai, Maharashtra, India). Polyvinylpyrrolidone K30, PEG-6000 was provided by Loba Chemie Pvt. Ltd. (India). All other materials used were of analytical grade.

Methods:

Preparation of solid dispersions and physical mixtures:

Physical mixtures of EZE were prepared in different ratios (Table 1) by mixing EZE with PVP K-30 and PEG-6000 for three min in a mortar until a homogeneous mixture was obtained. The resulting mixtures were sieved through a 100 μm mesh and then stored in a desiccator at room temperature until use.

Solid dispersions of different ratios (Table 1) were prepared. EZE was dissolved in nonaqueous solvent and PVP K-30 and PEG-6000 were dissolved in water separately. Nonaqueous system was added to aqueous system of PVP K-30 and PEG-6000 with continuous stirring. Addition rate was maintained 6-8ml/min. Nonaqueous phase (dichloromethane) was evaporated using Rotary evaporator. This was then freeze dried after initial freezing. The freeze dried product thus obtained was passed through sieve No. 100 and stored in dessicator at room temperature.⁵²

Solubility measurements of EZE:

Solubility measurements were performed according to the method of Higuchi and Connors (1965). An excess amount of solid dispersion was added in 10ml distilled water taken in test tubes. The samples were sonicated for 1 hr at room temperature. Thereafter, the capped test tubes were shaken at 25 or 45±0.1°C for 24 hrs in rotary flask shaker. Subsequently, the suspensions were filtered through Whatman filter paper no. 41, and the filtered solutions were analyzed spectrophotometrically at 232.5 nm.⁵²

Dissolution studies:

Dissolution studies were performed using USP eight station dissolution test apparatus (Lab. India) employing USP type I apparatus. Dissolution study was carried out in a 900 ml of 1% SLS at 37 ± 0.5 °C at 100 rpm. Five ml samples were withdrawn at time intervals of 5, 10, 15, 20, 25, 30, 35, 40, 45 and 60 min. the volume of dissolution medium was adjusted to 900 ml by replacing each 5 ml aliquot withdrawn with 5ml of fresh 1% SLS. The concentrations of drug in samples were determined by measuring absorbance at 232.5 nm. Cumulative percent drug released was determined at each time interval. Pure EZE was used as control.⁵²

Powder XRD:

Samples were evaluated by using a Philips Analytic X-Ray—PW3710 (Holland) diffractometer with tube anode Cu over the interval 5–80°/2θ. The operation data were as follows: generator tension (voltage) 40 kV, generator current 30mA and scanning speed 2°/min. X-ray powder diffractometry (XRD) were used to characterize the solid-state properties of EZE.⁴²

FTIR spectroscopy:

Infrared spectra were obtained using a Jasco 5300 FTIR spectrometer using KBr disks. The samples were previously ground and mixed thoroughly with KBr. The KBr disks were prepared by compressing the powder. The scanning range was kept from 4000 to 400cm−1.⁵³

Differential Scanning Calorimetry (DSC):

Thermograms of the pure drug and lyophilized powder samples of different formulations were studied on a TA instrument model SDT-2960, USA. An empty aluminum pan was used as a reference. DSC measurements were performed at a heating rate of 5ºC/min from 25 to 250ºC using aluminum sealed pan. The sample size was 5-10mg for each measurement. During the measurement, the sample cell was purged with nitrogen gas. ²²

RESULTS AND DISCUSSION:

Percent drug content study:

Percentage drug content was found to be in the range of 87.82 to 99.56. It shows uniform distribution of drug in all solid dispersions. ²¹(Table 2)

Saturation solubility studies:

All the binary systems of EZE showed enhancement in the aqueous solubility as compared to pure drug alone (Table 3). The 1:7 ratio of EZE with PVP K-30 showed higher solubility than all other ratios of EZE. The enhancement in the solubility of complex is mainly attributed to the formation of stable amorphous system of EZE with PVP K-30. These sample solutions were analyzed using Shimadzu-1700 UV/VIS Spectrophotometer at 232.5nm.²¹

Fourier transformation-infrared spectroscopy:

In order to further study the possibility of an interaction of EZE with PVP K-30 and PEG-6000 in the solid state, FTIR studies were carried out. Figure 1 illustrates the FTIR spectra of EZE, PVP K-30, PM and EZE–PVP K-30 system (1:7) FA3. The IR spectrum of pure EZE presented characteristic peaks at 3256.194 cm^-1 (Broad, intermolecular hydrogen bonded, O-H stretch), 2928.009 cm^-1 (Aromatic C-H stretch), 1717.188 cm^-1 (C=O stretch), 1615.827 cm^-1 (ring C-C stretch), 1398.226 and 1456.548 cm^-1 (C-N stretch), 1354.096 cm^-1 (in plane O-H bend), 1271.268, 1214.456, and 1155.346 cm^-1 (C-F stretch), 1140.539, 1065.278, and 1102.35 cm^-1 (C-O stretch of secondary alcohol), 1007.248 cm^-1 (ring breathing of cyclobutanes), 936.378 (ring vibration of alkyl cyclobutanes), and 829.3975 cm^-1 (ring vibration due to para-disubstituted benzene), respectively.

The presence or absence of characteristic peaks associated with specific structural groups of the drug molecule was noted .Any sign of interaction would be reflected by changes in characteristic peaks of EZE, depending on the extent of interaction. Solid dispersions (SDs) presented possibility of hydrogen bonding between EZE and PVP K-30.Each pyrrolidone moiety of PVP K-30 has two

groups (=N- and C=O) that can potentially form hydrogen bond with the drug at molecular level in SD formulation. However, steric hindrances preclude the involvement of nitrogen atom in intermolecular interactions thus making the carbonyl group more favorable for hydrogen bonding. Broad peak at 3553 cm^-1suggested hydrogen bonding interaction between free O-H group of EZE and carbonyl group of PVP K-30.Similarly it could be expected to have hydrogen bonding between the hydrogen atom of the OH of the drug and one of the lone pairs of the oxygen atom in PEG-6000.⁵⁵

X-ray powder diffractometry:

Powder X-ray diffraction spectroscopy (PXRD) has been used to assess the degree of crystallinity of the given sample. When complexes of drug and polymer are formed, the overall numbers of crystalline structure are reduced and more the number of amorphous structures are increased. So the final product sample shows less number as well as less intensity of peaks. This shows that overall crystallinity of complexes is decreased and due to more amorphous nature, the solubility is increased.

Figure 3.1: DSC Thermogram of EZE: PVP K-30 (1:7) FA3 (a); DSC Thermogram of EZE: PEG-6000 (1:7) FB3 (b)

The power X-ray diffraction spectra of all the samples are shown in Figure 2 EZE showed major peak at 2q values of 7.9, 13.89, 15.81, 17.22, 18.66, 19.39, 20.64, 21.80, 22.91, 23.42, 24.52 and 26.32. The study of the spectras of formulations indicated that degree of crystallinity was decreased by addition of polymers i.e. PVP K-30 and PEG-6000. The decrease in degree of crystallinity means improvement in amorphousness of the samples. Degree of crystallinity was decreased to maximum extent in case of PVP K-30. Hence, from this discussion, it can be confirmed that freeze drying method was the best method for the preparation of solid dispersions.⁴²

Figure 4: Scanning electron microphotographs of pure EZE (a) and FA3 (b)

Differential Scanning Calorimetry (DSC):

Differential scanning calorimetry enables the quantitative detection of all processes in which energy is required or produced (i.e., endothermic or exothermic phase transformations). The thermograms of all samples are presented in Figure 3. The EZE showed a melting peak at 165°C (DH = -210.60mJ/g). DSC thermogram of PVP K-30 and PEG-6000 showed endothermic peak at 51.39°C and 63.50°C respectively, was resulted because of small amount of bounded moisture present in the polymer. DSC thermogram of formulations revealed the amorphous nature of the drug which was diagnosed by the absence of endothermic peak at 165°C, which represents the melting point of the drug.²²

Figure 5: Dissolution Profile of drug by Physical Mixing and Freeze Drying Method

a. In – vitro Cumulative % Drug Release by Physical Mixing

b. In – vitro Cumulative % Drug Release by Freeze Drying Method

Scanning Electron Microscopy (SEM):

SEM images of pure drug EZE and formulation FA3 are shown in figure 4. Pure drug showed crystalline nature. Individual EZE crystals were submicron size and rectangular shape and stabilized. EZE in particles showed lose aggregate and are in irregular shape. SEM images decrease in particle size of formulations as compared with pure drug size. ⁵⁶

Dissolution studies:

Dissolution tests were carried out in distilled water contained 1% SLS. EZE, being a poorly soluble drug, to assure the sink condition 1% SLS was incorporated in the dissolution medium. 1% SLS was selected as a dissolution media after checking solubility in other possible medias (Table 4). All the dissolution profiles showed that the drug release was dependent on the concentration of polymer as well as nature of the polymer. Dissolution studies showed that the solid dispersion formulation has profound effect on rate and extent of dissolution than the pure drug and physical mixture formulations. Dissolution studies revealed that solid dispersion formulations have profound scope in the development of clinically effective dosage form. Low dose of EZE, is the another advantage, which can be effectively utilized to improve the rate and extent of bioavailability. Dissolution profile of pure drug has shown that only 36% drug release with in 30 minutes. Low dissolution profile of drug was observed even on addition of 1% SLS in dissolution media. This result revealed that dissolution enhancement is the first prerequisite for clinically successful dosage form.

All the physical mixture formulations have shown better dissolution profile than pure drug but it was inferior to solid dispersions. Despite of the different concentrations of polymer in solid system, optimized concentrations from different polymers were considered for comparative analysis. Drug to polymer ratio of 1:7, 1:5, 1:3, 1:7 were considered for PEG-6000 and PVP K-30, respectively. Effects of both polymers were compared with the above mentioned optimized drug to polymer ratio in solid system.

In-vitro dissolution studies proved that freeze dried product showed maximum drug release profile than any other method. Formulation contained PVP K-30 (1:7) showed better drug release profile than other formulations. T 50% of pure drug was found to be 60 min whereas less than 15 min. for formulation contained PVP K-30 (1:7) processed with freeze drying. T 90% of PVP K-30 formulation obtained for freeze dried product was found to be 40 min.²⁴

SUMMARY AND CONCLUSION:

Present study was aimed to improve the aqueous solubility and dissolution of Ezetimibe and hence improve the bioavailability. There was no method available in UV to determine the drug concentration. Hence 1% SLS was selected as a dissolution media after checking solubility in other possible medias. Solid dispersion formulation contained PVP K-30 (1:7) was selected as a best formulation that could not only improve physicochemical properties of EZE but also improves the bioavailability and hence clinical outcomes.

In present study initial characterization confirmed the presence of amorphous form of EZE. Further in all samples obtained by freeze drying formulations performed better than drug in improving saturation solubility, dissolution rate and suppressing crystallinity of EZE. FTIR studies revealed possible hydrogen bonding interaction in formulations, which was supported by XPRD and DSC observations.

Amorphization of Ezetimibe improved the solubility, dissolution rate. Thus it may be a potential approach for formulation research. Further studies necessary for these formulations include stability studies in vivo studies.

ACKNOWLEDGEMENTS:

The authors are thankful to Ajanta Pharma Pvt. Ltd. (Mumbai, India) for providing gift sample of Ezetimibe. Authors are very much thankful to Principal, Govt. College of Pharmacy, Karad, Principal Allana College of Pharmacy, Pune-1 Maharashtra, India, for providing laboratory and computer facilities and constant encouragement.

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Received on 04.07.2009 Modified on 09.08.2009

Asian J. Research Chem. 2(3): July-Sept., 2009, page 325-331

Sr. No	Drug	Polymers	Ratios	Preparation Code
Sr. No	Drug	Polymers	Ratios	Physical Mixing	Freeze Drying
1	Ezetimibe	PVP K – 30 A	1:3	PA-1	FA-1
2			1:5	PA-2	FA-2
3			1:7	PA-3	FA-3
4		PEG -6000 B	1:3	PB-1	FB-1
5			1:5	PB-2	FB-2
6			1:7	PB-3	FB-3

Freeze Dried Batches
Batch Code	*%Drug Content ± S.D.**
FA-3	99.56 ± 0.87
FB-3	87.82 ± 1.2

Polymers	Batch Code	Saturation Solubility (mcg/ml) *± S.D.
PVP K30	FA-1	366 + 1.45
	FA-2	707 + 0.81
	FA-3	77 0 + 1.02
PEG6000	FB-1	320 + 0.52
	FB-2	372 + 1.33
	FB-3	549 + 0.86

Time	*Cumulative % Drug Release± S.D.**
	Drug	Physical Mixing	Freeze Drying		Physical Mixing	Freeze Drying
		PVP K 30			PEG 6000
5	16.46± 2.7	25.24±2.4		32.93±2.6	18.65± 2.6		27.44± 4.3
10	20.85± 3.6	36.22±2.1		48.29±1.1	24.15± 2.5		36.22± 2.3
15	25.24± 3.2	46.09±3.2		71.34±1.5	32.93± 2.1		57.07± 3.6
30	36.22± 4.4	52.68±2.8		81.22±3.2	39.51± 3.2		65.85± 2.7
45	46.07± 1.6	57.07±1.5		92.19±2.1	49.24± 1.8		80.12± 2.2
60	54.81± 3.3	65.77±2.6		98.78±1.9	57.08± 1.2		88.90± 1.1

Table 1: Compositions of Formulation prepared by PHYSICAL MIXING and FREEZE DRYING Method

Sr. No

Drug

Polymers

Ratios

Preparation Code

Physical Mixing

Freeze Drying

1

Ezetimibe

PVP K – 30

1:3

PA-1

FA-1

2

1:5

PA-2

FA-2

3

1:7

PA-3

FA-3

4

PEG -6000

1:3

PB-1

FB-1

5

1:5

PB-2

FB-2

6

1:7

PB-3

FB-3

Polymers

Batch Code

Saturation Solubility (mcg/ml) *± S.D.

PVP K30

FA-1

366 + 1.45

FA-2

707 + 0.81

FA-3

77 0 + 1.02

PEG6000

FB-1

320 + 0.52

FB-2

372 + 1.33

FB-3

549 + 0.86