Table 1: Formulation of solid dispersion

Ingredient	PVP				Co povidone (PLASDONE S 630)				HPMC E 5				PEG 6000
	F1 1:0.5	F2 1:1	F3 1:3	F4 1:5	F5 1:0.5	F6 1:1	F7 1:3	F8 1:5	F9 1:0.5	F10 1:1	F11 1:3	F12 1:5	F13 1:0.5	F14 1:1	F15 1:3	F16 1:5
Drug (mg)	100	100	100	100	100	100	100	100	100	100	100	100	100	100	100	100
Poly mer (mg)	50	100	300	500	50	100	300	500	50	100	300	500	50	100	300	500
Solvent (ml)	25	25	25	25	25	25	25	25	25	25	25	25	25	25	25	25

Solid dispersion may be deteriorated in presence of moisture and excessive temperature. Some polymers used in solid dispersion are hygroscopic in nature and may absorb moisture, that can result in crystal growth or the amorphous form may converted to crystalline state. Sometimes the metastable form of a drug may change to stable form. So there may be decrease in solubility and dissolution rate. Several systems have shown changes in crystallinity and a decrease in dissolution rate on ageing^[^10,11]. Prediction of shelf life of amorphous materials is difficult. The technology of solid dispersion is applied to obtain a homogeneous distribution of a small amount of drug in solid state, to stabilize the unstable drug, to dispense liquid (up to 10%) or gaseous compound in a solid dosage to formulate a fast release primary dose in a sustained released dosage form, to reduce presystemic inactivation of drug like morphine^[^12]. The aim of the present work was to screen four polymers of three different chemistries for their influence on the aqueous solubility of Raloxifene HCL from solid dispersions prepared by the solvent evaporation technique.

MATERIALS AND METHODS:

Materials required:

The sample of Raloxifene HCL was procured from EMCO Industries, Hyderabad. The other ingredients procured are of analytical grade. The other ingredients like Poly vinyl pyrrolidone, Cross povidone and Co Povidone are from Ashland Speciality Chemicals Ltd, USA, Hydroxy propyl methyl cellulose 6 CPS USP, HPMC K4M, HPMC K15M, HPMC K 100M are received from Dow Chemicals USA, Polyethylene glycol 6000 (PEG 6000) USP and Dichloromethane are procured from Merck, India, Magnesiun stearate, Microcrystalline cellulose and Lactose anhydrous are from DMV, Netherlands.

Methodology:

Pre-formulation studies:

The standard calibration curve of Raloxifene HCL in water and Raloxifene HCL in Water with 0.1% Tween were prepared. Different solvents have been tried for raloxifene HCL to know in which solvent it was freely soluble. The solvents such as Distilled water, Ethyl alcohol, Isopropyl alcohol, Dichloromethane were checked for the solubility of the drug^[^13].

Procedure for preparation of solid dispersion:

Solid dispersions of RALOXIFENE HCL were prepared by using different polymers such as polyethylene glycol 6000(PEG), hydroxy propyl methyl cellulose (HPMC), poly vinyl pyrrolidone (PVPK30), co povidone (PVP S630), in different ratios(1:0.5,1:1,1:3,1:5) and optimized the drug polymer ratio (Table 1).

First, accurately weighed drug (Raloxifene HCl) was dissolved in the solvent (dichloromethane),and then the polymer which was also weighed accurately allowed to dissolve completely in the same drug-solvent mixture and allowed the mixture for solvent evaporation by transferring it into china dishes at room temperature (static). Then the solidified mixture was scrapped from the dishes and pulverized using mortar and pestle, sieved and stored. The prepared solid dispersion was formulated into immediate release tablets^[14-16].

Formulation of immediate release tablets (IR)

Table 2: Formula for IR tablets

S. No	Ingredients	Quantity for 1 tablet (mg)
1	Solid dispersion	360
2	Lactose	110
3	Ac-di-sol	25
4	Magnesium stearate	5
	Total tablet weight	500

Procedure for preparation of immediate release tablets:

Immediate release tablets of 400mg were formulated by direct compression method, using solid dispersion equivalent to 60 mg of the drug, lactose, acid solution and magnesium stearate, which were blended together, sieved and compressed into tablets.

Evaluation tests for IR tablets:

Hardness:

For each formulation, the hardness of 6 tablets was determined using the Monsanto hardness tester.

Table 4: Unit composition formula controlled release tablets

S.No	Ingredients	K4M (mg)				K15M (mg)				K 100M (mg)
		10%	15%	30%	45%	10%	15%	30%	45%	10%	15%	30%	45%
1	R-HCl solid dispersion	360	360	360	360	360	360	360	360	360	360	360	360
2	Polymer	80	120	240	360	80	120	240	360	80	120	240	360
3	Lactose DC 21	352	312	192	72	352	312	192	72	352	312	192	72
4	Magnesium stearate	8	8	8	8	8	8	8	8	8	8	8	8

The unit composition formula is given in Table 4

Friability:

Friability is the measure of tablet strength. This test subjects a number of tablets to the combined effect of shock abrasion by utilizing a plastic chamber which revolves at a speed of 25 rpm, dropping the tablets to a distance of 6 inches in each revolution.

% Friability = (Initial weight - Final weight / Initial weight) x 100

Weight variation:

To find out weight variation 20 tablets of each formulation were weighed individually using an electronic balance, average weight was calculated and individual tablet weight was then compared with average value to find the deviation in weight^[^17-21].

Table 3: Percentage deviation allowed in weight variation

Average weight of tablet	% Deviation allowed
80 mg or less	10
More than 80 mg but less that 250 mg	7.5
250 mg or more	5

Disintegration test:

The USP disintegration test is typical of most is described in detail in a monograph of that volume. Briefly it consists if an apparatus in which a tablet can be introduced into each of the six cylindrical tubes, the lower end of which is covered by 0.025 in. wire mesh. The tubes are then raised and lowered through a distance of 5.3 to 5.7 cm at a rate of 29 to 32 strokes per min in a test fluid maintained at 37±2 ºC. Continuous agitation of the tablets is ensured by this stroking mechanism and by the presence of a specially designed plastic disk, which is free to move up and down in the tubes.

Dissolution test:

Dissolution test was carried out by using USP type II dissolution test apparatus with distilled water. The samples of 5ml volume were taken at regular intervals i.e., 5mins, 10mins, 15mins, 30mins, 45mins, 60mins, 75mins. The absorbance is measured using a UV spectrophotometer at the λ_maxof 310 nm^[^22].

Formulation of controlled release tablets (CR)

Experiments on R HCL solid dispersions were carried out using different concentrations of the HPMC K4M, K15M and K100M and their effect on in-vitro dissolution was evaluated.

Blending and Compression Technique:

Figure 1:Flow chart for process of direct compression

All the tablets of HPMC matrix were compressed on 12.5 mm circular biconvex punch at Average Weight of 800mg, Thickness 4.8-5.2 mm, Hardness 5-7 kg /m².All the batches were tested for friability and the values were found to be below 0.3%.Every batch was subject to assay and the values were found to be between 97.5 and 98.7 %.Dissolution testing was performed in Water + 0.1% Tween using USP Type II apparatus. The samples were withdrawn at 1, 2, 4, 8, 12, 16 and 20 hours and the concentration of drug released was determined by UV sperctrophotometery by measuring the absorbance at 310 nm.

FTIR:FTIR spectra were obtained on a FTIR spectrometer (Nicolet5700) by the conventional KBr pellet method. The samples were ground gently with anhydrous K Brand compressed to form pellet. The scanning range was 400-4000cm^-1and there solution was _4cm^-1_.

Equilibrium solubility studies:

Equilibrium solubility studies were conducted in order to find out the solubility of the solid dispersions in water, by dissolving solid dispersions equivalent to 10 mg of the drug in 25 ml of distilled water. This solution was sonicated for 1hr and filtered through whatmann filter paper. The filtered solution was analysed for drug release from the solid dispersion by UV-Visible spectrophotometer at 225 nm^[^23,
24].

in vitro permeation study

Preparation of phosphate buffer pH 7.4:

The dissolution medium used is phosphate buffer pH 7.8.

Preparation of 0.2M potassium dihydrogen phosphate:

Dissolve 27.28g of potassium dihydrogen phosphate in distilled water and then dilute it with water upto 1000ml.

Preparation of 0.2M NaOH:

Dissolve 8g of NaOH in 1000ml of distilled water.

Preparation of phosphate buffer of pH 7.4:

Place 50ml of 0.2M potassium dihydrogen phosphate in 200ml volumetric flask and add 39.1ml of 0.2M NaOH and then make up the volume with distilled water.

Procedure:

Permeation studies were conducted to find out the permeability of the solid dispersion of the R-HCl by using 10% HPMC(5cps) dispersion of solid dispersion through cellophane membrane for 5 hours in 250 ml dissolution media of phosphate buffer P_H 7.4. Sample of the dissolution media were removed at predetermined time interval (0, 1, 2 3, 4, 5hrs). Withdrawn samples were analyzed at310 nm^[^25-27].

RESULTS AND DISCUSSION:

Standard Calibration Curve of Raloxifene HCL in Water and water with 0.1% Tween: Calibration curve of Raloxifene HCL in water and water with 0.1% Tween were made in the concentration range of 1µg/ml to 10 µg/ml (for 0.1% Tween from 0.5µg/ml-10µg/ml).Beers Lambert lawwas obeyed in this concentration range.

Fig 2: Calibration of raloxifene HCl in water

_{Fig 3: Calibration curve of raloxifene HCl in}water with 0.1% tween

Selection of the solvent:

Based on this study it was determined that Dichloromethane (DCM) is the best solvent for making the soild dispersions of Raloxifene HCl. All the selected polymers are also soluble in DCM.

Table 5: Solubility of the drug in different solvents

Solvent	Dose (mg) of the drug
	10	20	30	40	50	60	70	80	90	100
Water	×	×	×	×	×	×	×	×	×	×
EtOH	ü	ü	×	×	×	×	×	×	×	×
IPA	ü	ü	×	×	×	×	×	×	×	×
DCM	ü	ü	ü	ü	ü	ü	ü	ü	ü	ü

Equilibrium solubility studies of solid dispersions in water:

This study was performed in order to determine which solid dispersion shows a significant enhancement in the aqueous solubility of Raloxifene HCL. The results are given in Table 7 and shown in Fig 4.

Table 6: Drug release from different solid dispersions in water

Ratios	PVP K30 (µg/ml)	PVP S630 (µg/ml)	HPMC (µg/ml)	PEG 6000 (µg/ml)
1:0	1.32	1.12	1.15	1.17
1:0.5	2.86	2.42	0.98	0.87
1:1	3.23	2.39	1.12	0.99
1:3	3.78	2.98	1.6	1.15
1:5	6.2	4.4	2.3	1.9

FIG.4: Equilibrium solubility studies

_{Table 7: Dissolution data of Raloxifene HCl (plain drug) and
its solid dispersions with different polymers at 1:5 ratio in water:mean} % percentage release of the drug:

S.No	Time(min)	Plain drug	PVP	PlasdoneS630	HPMC	PEG6000
1	0	0	0	0	0	0
2	5	15.3	68	26.6	7.3	6.1
3	10	18.6	74.0	33.3	9.6	6.6
4	15	21.3	74.2	35.1	11.6	8.4
5	30	21.8	74.5	35.6	16.6	11.6
6	45	22.6	74.8	38	17	17.3
7	60	24	75.08	38.6	25.6	25

Fig 5: Dissolution profile of solid dispersions in water (n=3)

Table 8: Permeation study of SD in pH 7.4 buffer

Time(Hr)	Drug	µg/ml	Flux	PVP (1:5)	µg/ml	Flux	Dg release	PVP S-630 (1:5)	µg/ml	Flux	Dg release
0	0	0	0	0	0	0	0	0	0	0	0
1	0.002	0.013	0.13	0.025	0.34	3.4	12.5	0.011	0.14	1.4	5.5
2	0.003	0.04	0.4	0.026	0.34	3.4	8.666667	0.012	0.16	1.6	4
3	0.003	0.04	0.4	0.032	0.43	4.3	10.66667	0.015	0.2	2	5
4	0.005	0.07	0.7	0.054	0.72	7.2	10.8	0.017	0.22	2.2	3.4
5	0.007	0.09	0.9	0.073	0.96	9.6	10.42857	0.019	0.25	2.5	2.714286

Fig 6: In vitro permeation studies

Table 9: Physical Properties and Assay for R-HCl 60 mg tablets from 1:5 solid dispersion with PVP and PVP S 630

Formulation

Description

Average weight (mg)

Thickness

(mm)

Hardness

(n)

D.T.

(min)

Friability

%w/w

Assay

% w/w

PVP 1:5(IRF1)

10.5 mm Circular

white uncoated tablets

503 ± 2.5%

4.8 to 5.2

80 to 110

5 to 9

0.37

97.5

PVP S-630

(IF2)

10.5 mm Circular white uncoated tablets

507 ± 3.0 %

4.8 to 5.2

80 to 110

5 to 9

0.43

98.1

On the basis of the data of DSC, solubility, in vitro dissolution and in vitro permeation studies it was determined that Raloxifene HCl gives the best solid dispersion with 1:5 ratio of PVP. Hence this product was selected for further conversion to immediate release and controlled release tablets. Immediate release tablets were also prepared for plain drug as well as solid dispersions with PVP S630 for the sake of comparison. The physical properties of the immediate release tablets are given in Table 11.

In vitro dissolution:

The in vitro dissolution profile testing was performed both in water as well as the compendia media of water with 0.1% Tween. The results are given in Table 12 and 13 and shown in Fig 9 and 10.

_{Table 10: Dissolution data of
raolxifene HCl 60 mg (plain drug) and its solid dispersions with PVP and PVP s630 at
1:5 ratio in water:}percentage release of the drug:

S. No	Time (min)	Plain drug	PVP	PlasdoneS630
1	0	0	0	0
2	5	15.3	68	26.6
3	10	18.6	74.0	33.3
4	15	21.3	74.2	35.1
5	30	21.8	74.5	35.6
6	45	22.6	74.8	38
7	60	24	75.08	38.6

Fig 7: Dissolution profile of Raloxifene HCl 60 mg immediate release tablets

More than 70% of the practically insoluble drug is released from the immediate release table 1:5 solid dispersion of Raloxifene HCl and PVP. This indicates that immediate release tablets of solid dispersion show the same results the results which are matching to those of the solid dispersions alone.

Table 11: Dissolution data of immediate release tablets of raloxifene hcl 60 mg and its solid dispersions in water with 0.1% tween 80 percentage release:

S.No.	Time(min)	Plain drug	PVP K30	PVP S630
1	0	0	0	0
2	5	45	78	63
3	10	65	89	80
4	15	83	90	87
5	30	87	97	95
6	45	92	100	98
7	60	95	100	100

Fig 8: Dissolution profile of immediate release tablets of raloxifene hcl 60 mg and its solid dispersion in water with 0.1% tween

The dissolution profile indicates that the both the plain as well as the solid dispersion tablets release the drug to the same extent in the compendia medium. However, the rate of release is significantly faster in case of the tablets of soild dispersion of PVP and PVP S630

Physical properties of controlled release tablets:

Table 12: Physical Parameters of Raloxifene HCl :PVP Controlled release Tablets

Formulations	Average Weight (mg)	Thickness	Friability	Hardness (kg/cm²)
Formulations	Average Weight (mg)	( mm)	(%)	Hardness (kg/cm²)
K4M 10%	505	7.95	0.23	4.8
K4M 15%	500	7.26	0.21	5
K4M 30%	490	7.6	0.17	4.5
K4M 45%	510	7.67	0.18	4.9
K15M 10%	500	7.61	0.17	5.2
K15M 15%	515	7.62	0.22	3.6
K15M 30%	495	7.53	0.29	3.4
K15M 45%	485	7.59	0.27	4
K100M 10%	496	7.65	0.25	4.2
K100M 15%	500	7.69	0.26	3.5
K100M 30%	505	7.99	0.24	5.5
K100M 45%	504	7.67	0.25	5.2

Table 13: Dissolution Profile for Raloxifene HCl-PVP 1:5 Solid dispersion in the compendia medium

			K4M				K15M				K100M
Time (hours)	TPP LOW	TPP HIGH	10%	15%	30%	45%	10%	15%	30%	45%	10%	15%	30%	45%
0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
1	0	10	67.56	40.68	17.78	8.54	35.78	17.41	3.07	5.57	9.71	10.67	8.67	5.17
2	5	15	88.67	68.78	33.57	13.56	57.07	35.49	6.65	8.89	14.077	11.5	12.34	8.21
4	15	35	100	8.076	57.12	36.41	75.45	53.08	16.55	10.68	28.91	20.68	16.89	10.18
8	40	70	100.07	89.21	58.46	75.57	80.99	71.56	40.98	13.24	67.65	38.27	20.67	14.3
12	65	85	100	95.34	90.89	83.57	94.63	80.86	68.78	28.57	75.99	48.19	22.54	18.54
20	80	100	100	100	94.71	91.07	100	90.04	88.76	47.07	93.76	73.46	44.78	34.17

Tabel 14: Release rate kinetics for Raloxifene HCl-PVP controlled release tablets with 45% K4M

	RELEASE KINEITCS
	ZERO	HIGUCHI	PEPPAS	FIRST	Hixson Crowell
	1	2	3	4	5
	R(CvT)	R(CvRoot(T))	Log T vs Log C	TIME vs LOG % REMAINING	TIME Vs (Q1/3-Qt1/3)
Slope	4.905	24.253	0.873	-0.011	0.191
Correlation	0.9176	0.9618	0.9736	-0.9781	0.9864
R 2	0.8419	0.9251	0.9480	0.9566	0.9731

Fig 10: Hixon Crowell Plot defining the release rate kinetics of Raloxifene release from RaloxifeneHCl-PVP Solid dispersion with 45% HPMC K4M

Table 15: Release Rate Kinetics for Raloxifene HCl: PVP Controlled release tablets with 30% K15M

	RELEASE KINEITCS
	ZERO	HIGUCHI	PEPPAS	FIRST	Hixson Crowell
	1	2	3	4	5
	R(CvT)	R(CvRoot(T))	Log T vs Log C	TIME vs LOG % REMAINING	TIME Vs (Q1/3-Qt1/3)
Slope	4.791	21.955	1.182	-0.010	0.123
Correlation	0.9862	0.9580	0.9955	-0.9876	0.9826
R 2	0.9726	0.9179	0.9911	0.9753	0.9655

Fig 11: Peppas Plot defining the release rate kinetics of Raloxifene release from Raloxifene HCl-PVP Solid dispersion with 30% HPMC K15M

Table 16: Release rate kinetics for Raloxifene HCl PVP Controlled release tablets with 10% K 100M

	RELEASE KINEITCS
	ZERO	HIGUCHI	PEPPAS	FIRST	Hixson Crowell
	1	2	3	4	5
	R(CvT)	R(CvRoot(T))	Log T vs Log C	TIME vs LOG % REMAINING	TIME Vs (Q1/3-Qt1/3)
Slope	5.105	24.103	0.884	-0.016	0.144
Correlation	0.9696	0.9705	0.9852	-0.9496	0.9752
R 2	0.9402	0.9418	0.9706	0.9017	0.9510

Fig 12: Peppas Plot defining the release rate kinetics of Raloxifene release from RaloxifeneHCl-PVP Solid dispersion with 10% HPMC K100M

CONCLUSION:

Solid dispersion technique was successfully employed to enhance the aqueous solubility of Raloxifene HCL. The enhanced solubility also leads to enhanced permeability across artificial membrane. Immediate release as well as controlled release tablets can successfully be formulated from solid dispersions by the direct compression process. Stability studies and in depth in vivo experiments need to be done in order to successfully complete the study. It was proved that the PVP K30 and PVP S630 were the promising polymers which enhanced the solubility of the Raloxifene HCL in water through the solid dispersion technique enhancing the drug release of the drug.

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Received on 20.11.2015 Accepted on 18.12.2015

Asian J. Pharm. Tech. 2015; Vol. 5: Issue 4, Oct. - Dec., Pg 238-248

DOI: 10.5958/2231-5713.2015.00034.3