To Study the effect of Cross linking of Sodium Alginate on the Rate of Drug Release

Aachal Kolhe*, Akshda Chauhan, Aishwarya Dongre

P.R. Pote Patil College of Pharmacy, Amravati, Kathora Road, Amravati-444604.

*Corresponding Author E-mail:

ABSTRACT:

Verapamil hydrochloride (VH) is a calcium channel blocking agent used in the treatment of hypertension, cardiac arrhythmia and angina pectoris. The short half life and high frequency of administration of VH makes it a suitable candidate for designing sustained drug delivery system. The aim of the present investigation was to develop a sustained release matrix tablet of verapamil hydrochloride (VH) using sodium alginate and cross linked sodium alginate and to evaluate the drug release kinetics. In order to achieve the required sustained release profile, the tablets were prepared by a wet granulation method. The formulated tablets were characterized for pre-compression and post-compression parameters and they were in the acceptable limits. The drug release data obtained after an in vitro dissolution study was fitted to various release kinetic models in order to evaluate the release mechanism and kinetics. The criterion for selecting the best fit model was linearity (coefficient of correlation). Drug release mechanism was found to follow a complex mixture of diffusion, swelling and erosion. The dosage form holds the potential to control the release rate of drug and extend the duration of action of a drug.

KEYWORDS: Verapamil HCL, Matrix Tablet, Cross Linking, Sodium Alginate, Drug Release.

INTRODUCTION:

Controlled release dosage forms are mainly designed to maintain therapeutic blood or tissue levels of the drugs that have a short elimination half life^1-2. The controlled release dosage forms offer a number of advantages over immediate release products, such as better patient compliance due to decrease in dosing frequency, portability, convenience and fewer side effects. Such dosage forms exhibit better pharmacological effect and prolonged therapeutic activity. Matrix tablets are one of the most commonly used controlled release dosage forms as they release the drug in a controlled manner³.

Verapamil hydrochloride (VH) is a calcium channel blocking agent used in the treatment of hypertension, cardiac arrhythmia and angina pectoris. The biological half life is 4‑6 h, and it is completely absorbed from the gastrointestinal tract. The usual dose of the drug is 40‑240 mg 3 times a day⁴. Hence, due to the short half life and high frequency of administration, VH was considered as a suitable candidate for designing sustained release tablets.

MATERIALS AND METHODS:

Verapamil HCL was procured from Yarrow Chem. Pvt. Ltd Mumbai, Sodium alginate and Calcium Chloride was obtained from Loba Chem, Mumbai, Croscarmellose Sodium was obtained as a gift sample from Maple Biotech Pune. All other chemicals, excipients and reagents used were of analytical grade and were used as obtained.

Cross-linking of Sodium Alginate:

All the glassware’s used were first washed and dried. 5gm of sodium alginate was taken in a beaker and 20ml of water was added to it and stirred continuously until a homogenous mixture is formed. After full mixing the solution was kept aside to remove all the air bubbles which might have been formed during the mixing process. In another beaker 100ml of 2% solution of calcium chloride was prepared and stirred till the calcium chloride is fully mixed. After this the solution of sodium alginate was incorporated into the 2% calcium chloride solution with continuous stirring for 2 hours. After this the cross linked sodium alginate was filtered out and dried in a hot air oven until completely dry. This dried mass was then crushed into mortar pestle until a fine powder is obtained. The dried powder was then stored in a zip lock pouch for further use^5-6.

Drug-Excipients Interaction Study:

The chemical and physical possible drug interactions between the drug and polymer were identified by the use of FTIR and DSC technique^7-9.

Standard Calibration Curve:

Standard Calibration Curve: The standard calibration curve of resveratrol was carried out on UV spectrophotometer by using phosphate buffer of pH 7.4 as the solvent. From the solution which is now having a concentration of 100 μg/ml samples of 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 and 5 ml were pipette out into 10ml volumetric flasks. The volume was made up to the mark with Phosphate buffer 7.4 to get the final concentration of 5, 10, 15, 20, 25, 30, 35, 40, 45 and 50 μg/ml respectively. The absorbance of concentration was measured at 230 nm¹⁰.

Preparation of Tablet:

Matrix tablets of VH were prepared by the wet granulation method. For preparing granules, the specified amount of each component was passed through sieve no #60 [Table 1]. Then, the drug was mixed properly with the polymer and the granulating agent. The wet mass was passed through sieve no. #10 to obtain granules. The granules were oven dried at 40°C for 30 min. After drying, the granules were passed through sieve no. #36 and sieve no. #22. The granules were then lubricated with magnesium stearate and finally, talc was added to the blend^11-12.

Table 1: Formulation Chart of the Matrix Tablet of Verapamil HCl

Batch	Drug	Sodium Alginate	Cross-linked Alginate	Croscarmellose Sodium	Lactose	Talc	Magnesium Stearate
F1	40mg	20mg	-	10mg	26mg	2mg	2mg
F2	40mg	40mg	-	10mg	26mg	2mg	2mg
F3	40mg	60mg	-	10mg	26mg	2mg	2mg
F4	40mg	80mg	-	10mg	26mg	2mg	2mg
F5	40mg	-	20mg	10mg	26mg	2mg	2mg
F6	40mg	-	40mg	10mg	26mg	2mg	2mg
F7	40mg	-	60mg	10mg	26mg	2mg	2mg
F8	40mg	-	80mg	10mg	26mg	2mg	2mg

Pre-Compression Parameters¹³:

Bulk Density:

An accurately weighed sample was carefully introduced into a 10 ml graduated cylinder with the aid of funnel. Typically, the initial volume was noted. Carefully level the product without copacting, if necessary, and read the unsettled apparent volume V0, to the nearest graduated unit. Calculate the bulk density in g/cm³ by the formula.

Bulk Density = Weight of Sample/Volume of Sample

Tap Density:

The tapped density was obtained by dividing the mass of a powder by the tapped volume in cm³. The sample is carefully introduced into a 10ml graduated cylinder. The cylinder was dropped at 2 second intervals onto a hard wood surface 100 times from a height of 1 inch. The tapped density of each formulation was then obtained by dividing the weight of sample in grams by the final tapped volume in cm3 of the sample contained in the cylinder. It was calculated by using equation given below

Tap Density = Weight of Sample/Tapped Volume

Carr’s Index:

The Carr’s index was evaluated for the flow ability of the powder by comparing the pour density and tapped density of dispersion

Carr’s Index= Tap density-Bulk density/Tap density ×100

Hausner’s Ratio:

Hausner’s ratio (H), another index of flow ability (O'Donnell, P. et.al 1997)

Hausner’s Ratio = Tap density/Bulk density

Angle of Repose:

A weighed quantity of granules was passed through a funnel fixed on a stand at a specific height. A static heap of powder with only gravity acting upon it was tending to form a conical mound. The height of the heap (h) and radius (r) of lower part of cone were measured.

Tan θ = height of pile/radius of pile

Post-Compression Study^14-16:

Weight Variation Test:

For the weight variation test, 20 tablets from each batch were selected at random and their average weight was determined using an electronic balance. Then, the average weight was calculated and compared with the individual weight of each tablet.

Hardness Test:

A Monsanto hardness tester (Cad Mach) was used to determine the hardness of the tablets. Ten tablets were selected at random from each batch for the study. Each tablet was placed between the plungers and the handle was pressed, and the force of the fracture was recorded. Their crown to crown thickness was also determined using a vernier caliper.

Friability Test:

The friability was determined by placing 10 tablets in a Roche friability tester for 4 min at 25rpm. The tablets were dropped at a height of 6 inches in each revolution. Tablets were de‑dusted using a soft muslin cloth and reweighed. The friability was given by the formula:

Friability = (1-W_o/W) × 100

Where, Wo is the weight of the tablets before the test and W is the weight of the tablet after the test.

In Vitro Drug Release Study:

In vitro drug release study for the prepared coated matrix tablets was performed for the 12 h sample using a eight station United State Pharmacopoeia (USP)‑22 Type I dissolution apparatus at 37±0.5°C and at 50 rpm speed in 0.1 N HCl (900mL) as dissolution media. From the dissolution medium, 5mL of the sample was withdrawn at the specific time intervals and replaced with an equal volume of fresh medium (5 mL) to maintain constant media volume. After filtration, each sample was analyzed for VH using a UV spectrophotometer (λmax = 230nm). This study was performed in triplicate for each batch.

Release Profile Comparison (Similarity factor (f2)):

This factor was introduced by Moore and Flanner, and has been adopted by the Center for Drug Evaluation and Research (US Food and Drug Administration FDA) and by European Medicines Evaluation Agency (EMEA) as a criterion for the assessment of the similarity between two dissolution profiles.¹⁵

Difference factor (f1):

Difference factor measures the percent error between two drug release curves over all time points.¹⁵

Release Kinetics:

The in vitro drug release kinetics were characterized by fitting the data obtained from in vitro release studies of the coated matrix tablet from various batches to standard drug release kinetics equations (zero order, first order, Higuchi (Mt/M∞ <0.6), Korsmeyer Peppas model (Mt/M∞ <0.6) and Hixson Crowell model^17-18.

RESULTS AND DISCUSSION:

Drug-Excipient Interaction Study:

From the FTIR method it was identified that there were no new formation, mismatch, disappearance of any peak from the optimized formulation and the same peaks were identified in the graph of pure drug as well. The DSC study also revealed that there was no change in the melting point of the pure drug and the optimized formulation. These results were the proof that there was no possible physical or chemical interactions between the drug and polymer i.e. the drug and excipients were compatible with each other.

Figure 1: FTIR of A) Pure Drug B) Optimized Formulation

Figure 2: DSC of A) Pure Drug B) Optimized Formulation

Standard Calibration Curve:

The results of standard calibration curve revealed that it follows the beers lamberts law as the equation obtained was linear with the values of y =0.014x + 0.005 and the regression value of R² = 0.999.

Figure 3: Standard Calibration Curve of Verapamil Hydrochloride

Evaluation Parameters:

The flow properties of the granules indicated good compliance with the official standards. The AR of granules varied from 32.1°C to 36.3°C, and the flow property was fair. According to USP 2007, granules of batches F1, F3, F5 and F6 showed good and batches F2, F4, F7 and F8 granules showed fair CI (USP 2007). HR of granules of batches F1, F3, F5, F6 and F8 falls within the good range and that of batches F2, F4 and F7 falls within the fair range. Hardness, friability, weight variation and thickness of the formulated tablets were acceptable.

Table 2: Flow Properties of Granules for the Different Batches

Batch	*True density(g/mL)**	*Bulk density(g/mL)**	Carr index*	Hausner ratio*	*Angle of repose(°)**
F1	0.294±0.00	0.256±0.01	12.90±34	1.14±0.01	36.3±0.64
F2	0.303±0.03	0.244±0.00	19.40±42	1.24±0.00	34.0±0.76
F3	0.323±0.002	0.277±0.003	13.90±36	1.16±0.03	33.3±0.54
F4	0.303±0.00	0.244±0.01	19.40±31	1.24±0.05	32.1±0.67
F5	0.270±0.01	0.238±0.02	11.80±47	1.13±0.00	34.3±0.36
F6	0.303±0.03	0.263±0.03	13.20±33	1.15±0.01	35.3±0.56
F7	0.270±0.00	0.222±0.01	17.70±48	1.21±0.00	35.3±0.79
F8	0.270±0.001	0.227±0.02	15.90±43	1.18±0.02	33.3±0.46

Table 3: Evaluation of Tablets

Batch	Hardness (kg/cm2)	Friability (%)	*Thickness(mm)**	*Weight variation(mg)**
F1	6.045±0.53	0.55	8±0.1	193.47±2.51
F2	7.082±0.34	0.39	7.9±0.1	191.98±2.39
F3	6.097±0.26	0.64	7.9±0.2	201.45±2.84
F4	7.032±0.46	0.45	7.9±0.1	196.30±2.19
F5	5.263±0.51	0.51	8±0.1	194.39±2.91
F6	6.324±0.61	0.59	8±0.2	202.15±2.35
F7	7.164±0.39	0.42	7.8±0.1	196.70±2.49
F8	7.201±0.73	0.30	8±0.1	193.27±2.74

Percent Drug Release:

The batch F1 exhibited a delayed release of the drug. Batches F1 and F3 prolonged the release of drug and did not show complete dissolution after a study period of 12h. This may be attributed to sustained release of the drug from the polymer matrix (due to slow erosion of these polymers). The comparison of the drug release from the various batches with the marketed product indicated better sustained release of drug from batches F1, F3 and F5. Batch F8 showed an equivalent drug release as shown by the marketed tablet. Batches F7 and F4 showed earlier drug release, which may be attributed to improper mixing of the polymers. The result of the release profile comparison indicates the success of the formulation along with the achievement of better results.

Figure 4: Percent Drug Release of the Prepared Tablets with Comparison with Marketed Formulation

Release Profile Comparison:

The factors f1 and f2 play a very important role in comparing the formulations’ release profile. When the two dissolution profiles are identical, the value of f2 is 100 and when the dissolution of one product (test or reference) is completed before the other begins, f2 can be rounded to zero. Thus, the value of f2 ranges from 0 to 100. If a difference between the test and the reference products is 10%, and this average absolute difference is substituted in the equation, f2 becomes 50. Two dissolution profiles are considered “similar” when the f2 value is between 50 and 100. A higher f2 value indicates closeness between the two dissolution profiles. However, the equation is only applicable in comparing curves in which the average differences between the reference and the test formulation profiles is less than 100 and the amount of drug released in percent. The percent error is zero when the test and the drug reference profiles are identical, and increases proportionally with the dissimilarity between the two dissolution profiles. It is generally accepted that values of F1 between 0 and 15 do not indicate dissimilarity.

Release Kinetics:

The data obtained from the drug release of the drug from the dissolution study was again studied for the drug release kinetics and it was seen that that the optimized formulation F8 was having zero order kinetics release.

Table 4: Release kinetics of Different Batches

Batch	Zero order (R2)	First order (R2)	Higuchi (R2)	Korsmeyer-Peppas (R2)	Hixson-Crowell (R2)	Best Fit Model
F1	0.925	0.916	0.754	0.905	0.919	Zero
F2	0.760	0.622	0.613	0.897	0.670	Korsmeyer-Peppas
F3	0.961	0.927	0.841	0.988	0.940	Korsmeyer-Peppas
F4	0.766	0.475	0.643	0.925	0.566	Korsmeyer-Peppas
F5	0.974	0.937	0.881	0.978	0.953	Korsmeyer-Peppas
F6	0.974	0.937	0.881	0.978	0.953	Korsmeyer-Peppas
F7	0.985	0.700	0.987	0.916	0.865	Higuchi
F8	0.992	0.847	0.923	0.964	0.936	Zero
Marketed Tablet	0.885	0.814	0.965	0.966	0.920	Korsmeyer-Peppas

CONCLUSION:

The batches prepared using polymers were found to extend the time of release of drug release. The sustained release formulations are quite different from the marketed tablet, and more sustained than the marketed tablet. It may thus be concluded that the sustained release formulation can be achieved using both cross-linked and non cross-linked polymers, which can also maintain the sustained release profile over an extended period of time. This also proves that cross-linking can affect the drug release rate of the drug i.e. the more is the cross-linking the more is the sustained drug release.

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Received on 15.09.2021 Modified on 20.01.2022

Res. J. Pharma. Dosage Forms and Tech.2022; 14(2):127-132.

DOI: 10.52711/0975-4377.2022.00020