INTRODUCTION:

There is tremendous advancement in the oral drug delivery system as the most widely utilized route of drug administration among all the routes that have been explored for the systemic delivery of drugs via various pharmaceutical products of different dosage forms.

In conventional dosage forms, there is no precise control over the release of drug and the administered dose of drug directly enters the systemic circulation. The design of oral controlled drug delivery systems should primarily be aimed at achieving more predictable and increased bioavailability of drugs. Hydrogels are the main class of gels they are since the discovery of poly (2 hydroxyethyl methacrylate) by Wichterle and Lim in 1960, have been of great interest to biomedical scientists.

They are defined as two or multi component systems, consisting of three-dimensional networked hydrophilic polymer chains which are capable of swelling in aqueous mediums and retaining a large amount of water or biological fluids. The favorable property of hydrogels is their ability to swell, when put in contact with an aqueous medium. When a hydrogel in its initial state is in contact with solvent molecules, the latter attacks the hydrogel surface and penetrates into the polymeric network. So the release of drug from hydrogels is due to swelling controlled mechanism.^[1]

Figure 1: A typical hydrogel

Hydrogels have excellent application in the controlled drug delivery system delivery. These are prepared by cross liking the polymer by means of suitable cross linking agent, which leads to the variety of physicochemical interactions such as hydrophobic interactions, charge condensation, hydrogen bonding, stereocomplexation, or supramolecular chemistry. These cross linkers prevent burst release of the medicaments. So all these chemical interaction causes entanglements of the polymer which provides the controlled release of the drug for extended period of time.^[2]

Cellulose like HPMC and its derivatives, being biocompatible and biodegradable, are easily available in large quantity at low cost which makes them a promising choice for hydrogel-based delivery system. Cross linking is the formation of chemical links between molecular chains to form a three dimensional network of connected molecules. Cross linkers are selected on the basis of their chemical reactivities (i.e., specificity for particular functional groups) and compatibility of the reaction with the application. Citric acid can also be used as a cross linking agent in the preparation of hydrogels of cellulose based polymer. Cross linking agents are citric acid, PEG, glutaraldehyde, calcium chloride, sodium-borate.

These cross linkers prevent burst release of the medicaments from the dosage form. As compared to other many cross linking agents, citric acid is more feasible due to its non-toxicity and low cost. It has been found that presence of hydroxyl, carboxylic acid and hydrophilic polymer enhances its cross linking efficiency. Metoprolol succinate is a cardioselective β1-adrenergic blocking agent used to treat hypertension (high blood pressure). Hypertension is a serious problem now a day. For this many of the chemical moieties have been searched out to treat such a life threatening disease.^[3]

MATERIALS AND METHODS:

MATERIALS:

Metopolol succinate was obtained as gift sample from Wockhardt Ltd. Aurangabad, Citric acid was obtained as gift sample from Finar Chemicals Ltd. Ahmadabad and HPMC K4M was obtained as gift sample from Meditab Pharmaceuticals, Satara. All other chemicals/reagents used were of analytical grade, available commercially and used as such without further processing.

METHODS:

Compatibility study:

1. Infra-red spectroscopy (IR):

IR spectra of metoprolol succinate, HPMC, citric acid, physical mixture of metoprolol succinate and HPMC, physical mixture of metoprolol succinate and citric acid and optimized hydrogel formulation were performed on Fourier Transform Infrared Spectrophotometer (MIRacle 10). Small quantity of sample was taken and directly put on IR platform. Then the spectrum was scanned wavelength region of 4000 to 400 cm^-1.^[4]

2. Differential scanning calorimetry ( DSC):

Thermal analysis of metoprolol succinate, HPMC, citric acid and optimized hydrogel formulation were performed on a Shimadzu DSC 60, which was calibrated for temperature and enthalpy using pure indium. Drug (3-5mg) was crimped in nonfermeticAluminium pans with lids and scanned from 50-300ºC at a heating rate of 10ºC/minute under a continuously purged dry at nitrogen atmosphere (flow rate 20ml/min). The instrument was equipped with a refrigerated cooling system.^[5]

Formulation of hydrogel:

The formula of Metoprolol succinate hydrogel was developed by using HPMC K4M at concentration 2% W/V as a polymer with the use of citric acidat concentration 1-4% W/V as a cross linking agent (Table1). Initially metoprolol succinate, citric acid and HPMC K4M were weighed properly. Then the measured volume of water was poured in the beaker mounted on mechanical stirrer. Drug was dissolved in the beaker then polymer was dissolved in the drug solution with pinch by pinch addition. Once the viscous clear slurry gets prepared, it is followed by addition of citric acid.

This slurry is then transferred in to the porcelain dish mounted on thermostatic water bath at 80ºC. The reaction was continued for 2 hrs to evaporate entire water from the hydrogel. Finally obtained hydrogel is molded and kept at oven for drying.

Experimental design:

A 3²full factorial design which was augmented for 2 central points was used in this study using Design-Expert 8.0.7.1. Here two factors were evaluated each at three levels, and experimental trials were performed at eleven possible combinations including 2 repeated trials of augmentation. The concentration of citric acid (X1) and reaction time (X2) were selected as independent variables. Drug content, swelling index and t₇₅of % cumulative drug release and were selected as dependent variables.^[6]

Table 1: Formulation of batches in a 3²full factorial design (Augmented)

Variable Levels in coded form
Batch code	X1	X2
R1	-1	1
R2	1	-1
R3	0	-1
R4	0	1
R5	-1	-1
R6	0	0
R7	1	1
R8	1	0
R9	-1	0
R10	0	0
R11	0	0

Coded values	Actual values
Coded values	X1	X2
-1	1%	60 min
0	2.5%	90 min
1	4%	120 min

X1-Concentration of Citric acid

X2-Reaction time

Scanning electron microscopy (SEM):

Surface morphology of hydrogels formulated with three different concentrations of citric acid 1%, 2.5% and 4% was studied using scanning electron microscopy (JSM-5610LV; Jeol Ltd., Tokyo, Japan) to assess the cross linking. The samples were sprinkled on to double side tape, sputter coated with platinum and examined in the microscope at 10 kV.^[7]

Evaluation of hydrogels:

The formulated hydrogels were evaluated for different parameters like drug content, in vitro dissolution studies and swelling index.

1. Drug content:

200 mg. hydrogel was weighed and transferred to a beaker containing phosphate buffer pH 6.8 which was previously mounted on a mechanical stirrer. Continued the stirring for 12 hrs to dissolve the hydrogel completely in to solvent. Then obtained solution was filtered and made the dilutions in a proper manner. The resultant solutions were subjected to UV spectrophotometric analysis.^[8]

Drug content can be determined by using formula:

Practical Value

Drug Content (%) =------------------------------ X 100

Theoretical Value

2. Swelling index:

The swelling index of hydrogel was determined by placing the weighed hydrogel in the basket. For first 2 hrs the dissolution medium was 0.1N HCl then followed by phosphate buffer pH 6.8 for further study, at 37ºC ± 0.5ºC. Hydrogel samples were withdrawn at a time interval of 30 min, blotted with tissue paper to remove the excess water and weighed on the analytical balance (Shimadzu, AX 120). Swelling index was calculated by using the following formula:

Weight of swollen hydrogel – Weight of dry hydrogel

Swelling Index (%) = ---------------------------------- X 100

Weight of dry hydrogel

3. In vitro dissolution studies:

In vitro dissolution tests were conducted in triplicate for all formulations in a USP type II dissolution test apparatus under sink conditions. The dissolution medium used was 900 ml 0.1N HCl for 1hr, followed by phosphate buffer pH 6.8 at 37⁰C ± 0.5⁰C. The speed of rotation was maintained to 50 RPM at a predetermined time intervals, 7 ml sample was withdrawn every time, filtered through Whatman filter paper and 5 ml sample from the same was diluted to 10 ml. The absorbances of resultant samples of all intervals were measured at 222 nm using spectrophotometric method (Schimadzu UV).

Determination of t₇₅of % CDR:

In this study t₇₅ of %CDR is required to determine, for the optimization study. “t₇₅means time required to release 75% of drug from the formulation." This data provides the information regarding drug release pattern of formulation. Ultimately, it helps in the optimization study of hydrogels.

Table 2: Details of dissolution test

1.	Type of dissolution apparatus	USP Type II
2	Volume of medium	900 ml
3	Temperature	37⁰C ± 0.5⁰C
4	Paddle Speed	50 RPM
5	Dissolution medium	0.1 N HCl and Phosphate buffer pH 6.8
6	Aliquots taken at each time interval	7 ml

Release kinetic studies:

Analysis of drug release from swellable hydrogels must be performed with a flexible model that can identify the contribution to overall kinetics. The dissolution profile of all the batches was fitted to various models such as zero-order, first order, Korsmeyer Peppas and Higuchi to ascertain the kinetic modeling of drug release.^[9]

RESULTS AND DISCUSSION:

Compatibility study:

1. Infra-red spectroscopy (IR):

From figure 2, it is clear that, characteristic peaks in the IR spectra of metoprolol succinate with physical mixtures with HPMC and citric acid, 3138.18 cm^-1, 1556.55 cm^-1, 1238.30 cm^-1are at same wave number as they are in the metoprolol succinate alone. Thus it reveals that metoprolol succinate is compatible with HPMC and citric acid.

2. Differential scanning calorimetry (DSC):

From figure 3, DSC thermogram of hydrogel formulation showed endothermic peaks at 136⁰C, 195⁰C and 153⁰C indicating melting point of metoprolol succinate, HPMC and citric acid respectively. There was a decrease in intensity of endothermic peak of citric acid in the hydrogel formulation. This suggests the formation of cross linking between HPMC and citric acid.

Scanning electron microscopy (SEM):

The hydrogel formulations R1, R4 and R7 have been formulated at reaction time 120min. by varying the concentration of citric acid 1, 2.5 and 4% respectively. Since from the surface morphology study (figure 4, 5 and 6) it can be suggested that there is more cross linking for hydrogel formulation R1 than R4 which is again more than R7 shown by rough surface of morphology. This is because cross linking occurs much higher at low citric acid concentration.

Evaluation of hydrogels:

Hydrogel formulations were prepared with different levels of concentrations of citric acid at different reaction times and tested for various evaluation parameters to optimize the best formulation.

1. Drug content:

The drug contents for all batches of hydrogels formulations were calculated. These are mentioned in table 3.

2. Swelling index:

Swelling indices for all batches of hydrogels formulations were calculated. These are mentioned in table 4.

3. In vitro dissolution studies:

% Cumulative drug release for all batches of hydrogels formulations was calculated. These are mentioned in table 5 and 6.

Determination of t₇₅of % CDR:

Time required to release 75% of drug from the hydrogel for all batches is shown in table 7.

Release kinetic studies:

Results of curve fitting of the in vitro metoprolol succinate release from hydrogels of all batches are shown in table 8.

The curve fitting results of in vitro drug release data indicated that release of metoprolol succinate from hydrogel follows Higuchi model (R²= 0.854-0.964). The values of release exponents (n) determined from in vitro metoprolol succinate release data of various hydrogels ranges from 0.315-0.640, indicating mostly the anamolous (nonfickian) diffusion mechanism of drug release. Thus it reveals that the formulation follows both diffusion controlled and swelling controlled drug release mechanism from hydrogel containing metoprolol succinate.

Experimental design:

Influence of independent variables on dependent variables:

The influence of independent variables such as citric acid concentration and reaction time on dependent variables such as drug content, swelling index and t₇₅of %CDR can be well explained by using 3D plot (surface response plot), 2D plot (contour plot) and polynomial equations given from figure 12-17.

Table 3: Drug content of metoprolol succinate hydrogels

Run	R1	R2	R3	R4	R5	R6	R7	R8	R9	R10	R11
Drug Content (%)	99.5	89.5	83.5	97.4	89.4	88.5	96.16	94.04	94.3	87.87	89.54

Table 4: Swelling index of metoprolol succinate hydrogels

Time (min)	Swelling index (%)
Time (min)	R1	R2	R3	R4	R5	R6	R7	R8	R9	R10	R11
30	24.76	18.9	28	11	8.98	24.14	17.54	28.1	13.1	31.04	33.38
60	45.76	50.2	41.78	34.54	36.9	41.26	36.98	45.26	37.32	39.18	46.84
90	76.96	71.88	81.94	60.04	56.48	55	61.12	68.56	61.42	59.06	77.46
120	101.44	107.72	111.82	83.98	83	85.08	86.84	80.32	83.38	81.08	86.82
180	129	123.12	136.88	109.96	110.92	113.06	120.46	104.78	118.82	111.22	120.86
240	158.24	138.08	161.82	146.22	124.44	140.48	134.96	135.28	145.66	142.32	149.9
300	173.04	147.54	183.8	163.24	157.42	163.06	163.4	159.32	164.52	168.24	177.54
360	212.98	158.2	194.12	201.62	196.14	175.58	169.94	164.56	199.3	172.98	178.78
420	238.24	-	197.92	203.96	223	189.06	-	-	240.58	193.08	186.76
480	265.36	-	-	208.98	247.08	205.02	-	-	255.42	199.84	206.16
540	276.74	-	-	-	-	-	-	-	-	202.74	208.84

Table 5: %Cumulative drug release (R1-R6)

Time (min)	%Cumulative drug release (%)
Time (min)	R1	R2	R3	R4	R5	R6
15	10.53±0.8	21.20±1.5	12.83±0.8	15.13±0.8	13.80±0.5	17.80±1.5
30	24.35±0.5	31.01±1.8	30.53±0.9	32.35±.6	25.68±1.0	34.16±1.8
45	39.38±1.0	40.47±1.0	44.95±1.5	49.68±0.5	41.80±0.8	46.77±1.5
60	54.89±0.8	55.74±0.8	48.83±0.5	62.89±0.5	56.83±1.5	54.41±0.8
90	64.71±1.8	68.10±1.5	54.53±0.8	71.38±1.0	72.23±1.5	63.13±1.5
120	73.32±1.0	71.98±1.5	60.35±1.5	76.35±1.5	75.74±1.8	71.09±0.5
150	77.27±1.8	77.63±1.0	74.36±0.8	81.51±1.8	79.57±1.0	74.60±1.5
180	79.21±0.8	-	78.24±0.5	83.21±0.5	82.12±0.5	77.39±1.0
210	82.12±1.8	-	82.12±1.8	87.33±1.8	84.66±1.5	83.81±1.8
240	84.06±0.5	-	-	90.12±0.5	85.63±0.8	86.24±1.5
270	86.12±0.8	-	-	90.72±0.7	-	86.96±1.8
300	88.9±0.8	-	-	91.45±0.5	-	87.45±0.8
330	92.54±0.5	-	-	91.69±0.9	-	-
360	94.24±0.7	-	-		-	-

Table 6: %Cumulative drug release (R7-R11)

Time (min)	%Cumulative drug release (%)
Time (min)	R7	R8	R9	R10	R11
15	15.5±0.5	24.95±0.8	13.19±2	18.89±0.5	16.95±0.7
30	31.86±0.7	38.65±0.5	23.98±2.3	32.71±1.5	31.38±1.2
45	48.35±0.8	53.80±1.5	41.44±0.9	45.8±0.7	45.07±0.5
60	63.26±1.5	57.20±0.8	55.01±1.7	53.2±1.2	51.62±1.5
90	69.56±0.2	61.20±1.5	70.89±1.2	63.86±0.2	64.35±2.3
120	73.3±1.2	64.35±0.5	75.50±0.2	70.29±0.7	68.71±0.7
150	74.36±0.5	70.48±1.5	77.87±0.5	74.96±0.6	74.36±1.9
180	75.93±0.8	75.57±1.0	82.84±1.8	76.78±1.5	75.33±0.5
210	78.24±0.7	77.15±1.5	85.63±1.5	85.03±1.2	85.39±0.4
240	80.9±0.5	79.33±0.5	87.81±0.2	86.06±0.9	85.75±0.7
270	82.36±0.2	-	89.39±1	87.57±1.8	86.36±1.5
300	83.21±0.6	-	90.48±2	87.93±2.1	86.96±0.7
330	-	-	90.96±0.5	-	-
360	-	-	-	-	-

Table 7: t₇₅ of %Cumulative drug release (R1-R11)

Run	R1	R2	R3	R4	R5	R6	R7	R8	R9	R10	R11
t₇₅ (min.)	207.6	126.8	166.6	177.46	158.9	188.44	198.69	187.3	189.2	187.73	191.6

Table 8: Results of curve fitting of the in vitro release of metoprolol succinate from hydrogels

Run	R²				Release exponent (n)
Run	Zero order	First order	Korsmeyer Peppas	Higuchi	Release exponent (n)
R1	0.852	0.740	0.907	0.939	0.624
R2	0.907	0.823	0.947	0.964	0.574
R3	0.897	0.883	0.954	0.955	0.473
R4	0.807	0.720	0.890	0.909	0.485
R5	0.837	0.716	0.892	0.926	0.613
R6	0.858	0.824	0.957	0.945	0.436
R7	0.737	0.640	0.831	0.854	0.440
R8	0.821	0.794	0.908	0.908	0.315
R9	0.848	0.717	0.892	0.933	0.640
R10	0.868	0.812	0.952	0.952	0.458
R11	0.856	0.797	0.943	0.944	0.470

Table 9: Actual levels as per 3² full factorial design (Augmented) with observed responses

Run	X1	X2	Drug content (%)	Swelling index (%)	t₇₅of %CDR (%)
R1	1	120	99.5	276.64	207.6
R2	4	60	89.5	158.2	126.8
R3	2.5	60	83.5	197.92	166.6
R4	2.5	120	97.4	208.98	177.46
R5	1	60	89.4	247.08	158.9
R6	2.5	90	88.5	205.02	188.44
R7	4	120	96.16	169.94	168.69
R8	4	90	94.04	164.56	187.3
R9	1	90	94.3	255.42	189.2
R10	2.5	90	87.87	202.74	187.73
R11	2.5	90	89.54	208.84	191.6

Table 10: Response summary

Factor	Response	Unit	Analysis	Minimum	Maximum
Y1	Drug content	%	Polynomial	83.50	99.50
Y2	Swelling index	%	Polynomial	164.56	276.64
Y3	t₇₅of %CDR	min.	Polynomial	126.8	207.6

Figure 2: Overlay IR spectra of Metoprolol succinate (A), HPMC (B), Citric acid (C), Physical mixture of metoprolol succinate and HPMC (D), Physical mixture of metoprolol succinate and citric acid (E), Hydrogel formulation (F)

Figure 3: Overlay DSC spectra of Metoprolol succinate (A), HPMC (B), Citric acid (C), Hydrogel formulation (D)

Fig 4: SEM analysis of hydrogel formulation (R1)

Fig 5: SEM analysis of hydrogel formulation (R4)

Fig 6: SEM analysis of hydrogel formulation (R7)

Fig 7: A photographic image of optimized batch (R1) of prepared hydrogel formulation

Figure 8: Comparison of swelling index from to R1-R6

Figure 9: Comparison of swelling index from to R7-R11

Figure 10: Comparison of % cumulative drug release from R1 to R6

Figure 11: Comparison of % cumulative drug release from R7 to R11

Figure 12: Response surface plot of drug content

Figure 13: Contour plot of drug content

Polynomial equation:

Drug Content = 90.59-0.58A+ 5.11B

Figure 14: Response surface plot of swelling index

Figure 15: Contour plot of swelling index

Polynomial equation:

Swelling index = 207.55-47.74 A+ 8.73B

Figure 16: Response surface plot of t₇₅of %CDR

Figure 17: Contour plot of t₇₅of %CDR

Polynomial equation:

t75 of % CDR = 183.78 - 7.15 A+ 21.91B

CONCLUSION:

In present research work, swellable hydrogel for metoprolol succinate was developed and optimized by using mathematical and statistical design. Metoprolol succinate was selected to treat hypertension (high blood pressure). Hypertension is a serious problem now a day. For this the chemical moieties was selected to treat such a life threatening disease.

Step by step studies were carried out to develop and optimize controlled release hydrogel for metoprolol succinate using hydrophilic polymer HPMC by means of citric acid as a cross linking agent. In this study HPMC concentration is kept at 2% W/V and design was applied to independent variables, concentration of citric acid 1-4% W/V and reaction time 60-120 min at 80ºC. Due to the cross linking reaction hydrogel gave good swelling as well as controlled release properties. Drug content, swelling index and t₇₅of % cumulative drug release were selected as dependent variables. From the results it can be concluded that the effect of citric acid concentration on drug content and t₇₅of % CDR was nonsignificant. But the effect of citric acid concentration on swelling index was much significant, means as citric acid concentration increased; there was decrease in swelling index of hydrogel. Again effect of reaction time on drug content as well as on t₇₅ of % CDR was much significant, means as reaction time increased; there was increase in drug content as well as t₇₅ of % CDR of hydrogel. But the effect of reaction time on swelling index was nonsignificant.

From all responses obtained, drug content, swelling index and t₇₅ of %CDR of run R1 are best. Drug content, swelling index and t₇₅ of % CDR of this run are 99.5%, 276.64% and 207.6 min respectively. So finally it can be concluded that the optimized formulation is run R1, which gave the best in vitro release up to 94.24% in 360 min (6 hrs). Again IR and DSC study shows no evidence on interaction between drug, polymers and other excipient. The in vitro data were fitted to different kinetic models. The drug release of almost all batches including metoprolol succinate hydrogels followed Higuchi model of release kinetics. The mechanism of drug release from hydrogel formulation was anomalous (nonfickian) diffusion. Thus it reveals that the formulation follows both diffusion controlled and swelling controlled drug release mechanisms. Thus the optimized dosage form can control the release, avoid dose dumping and extend the duration of action of a drug with prolong swelling time.

ACKNOWLEDGEMENT:

The authors would like to thanks YSPM College of Pharmay, Satara, Maharashtra (India) and Shri. Sureshadada Jain Institutes of Pharmaceutical Education and Research, Jamner Maharashtra (India) for supporting the fulfillment of this work.

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Received on 28.06.2017 Accepted on 01.09.2017

Asian J. Pharm. Res. 2017; 7(4): 247-255.

DOI: 10.5958/2231-5691.2017.00039.9