INTRODUCTION:

The tendency to suffer recurring unprovoked seizures is known as epilepsy. A seizure is a brief burst of increased electrical impulses that results in temporary behavioural abnormalities. Neurons communicate with one another by chemical and electrical impulses, and they create networks with other neurons. Most seizures are caused by a limited number of aberrant neurons that generate alterations in other nearby or networked neurons.¹

The estimated average prevalence of epilepsy is 6.8 per 1000 people in US, 5.5 per 1000 people in Europe, and 1.5 to 14 per 1000 people in Asia, respectively. In India, it is estimated that out of over 1.23 billion people, there are around 6–10 million people with epilepsy.²

Carbamazepine (CBZ) is considered as a first line drug in the treatment of epilepsy. CBZ is an anticonvulsant and mood stabilizer that is primarily used to treat epilepsy, bipolar disorder (trigeminal neuralgia), and schizophrenia. The half-life of CBZ ranges from 10 to 20 h but diminishes with autoinduction to 4 to 12 h. The initial dose is 100mg, and the amount is gradually increased to the lowest effective maintenance dose, which is typically 600mg/day to 1.6g/day.³ CBZ, which displays dissolution dependent oral bioavailability, is an antiepileptic drug of ‘Class II’ in the Biopharmaceutical Classification System (BCS) with 3 polymorphs and low solubility in water (113μg/ml, 125°C) exhibiting slow and irregular gastrointestinal absorption.⁴

CBZ works pharmacologically by binding to and stabilising the voltage-gated sodium channel in its inactive state. This inhibits the channel from returning to its relaxed state, which would then be vulnerable to depolarization and subsequent repeated neuronal firing.⁵

AEDs are chosen depending on the type of ailment, the effectiveness and tolerability of the medication, and the patient's characteristics.⁶CBZ is the recommended drug for the treatment of partial seizures, but it has drawbacks such as the need for frequent dosage, dose-related adverse effects, and drug interactions.²

The use of traditional or immediate-release CBZ formulations has been linked to constant fluctuations in plasma levels. The current tendency is to treat epilepsy patients with extended-release (ER) formulations because of improved compliance, convenience, reduced dosage frequency, and a flat plasma concentration versus time curve.⁷

The matrix tablets can be made using the wet granulation process. Hydrophilic polymer matrix systems are widely employed in the formulation of matrix-based extended release (ER) drug delivery systems due to their versatility in achieving a suitable drug release profile, cost effectiveness, and widespread regulatory acceptability.⁸

Extended-release tablets are intended to extend the absorption of CBZ, which has a short half-life of 4 to 12 hours, allowing for longer dosage intervals while reducing changes in blood drug levels.⁹

The aim of this work was to prepare matrix tablet containing CBZ, using a combination of Hydroxypropyl Methylcellulose K 100M (HPMC K 100M) as hydrophilic polymer and Ethyl Cellulose as hydrophobic polymer to formulate extended-release tablets of CBZ.

MATERIALS AND METHODS:

Materials:

The active ingredient CBZ was purchased from Amoli organics, India. The excipients MCC 101, MCC-102, Croscarmellose Sodium were purchased from Gujrat Microwax Pvt. Ltd. India. Hydroxypropylmethyl Cellulose, Colloidal silicon Dioxide was obtained from Evonik, India. Ethyl cellulose, Opadry peach were procured from Colorcorn, Mumbai, India. Isopropyl alcohol, Methylene dichloride obtained from Fisher and Rankem, India respectively. Purified Talc and Magnesium Stearate were procured from Signet and Ligamed, India. The chemicals Hydrochloric acid, Sodium lauryl sulfate, Triethylamine was procured from Thomas Baker, India. Methanol, Acetonitrile and Ortho phosphoric acid were obtained from Merck and Spectrum Lab, India respectively.

Method:

Accurately weighed quantity of all intragranular ingredients such as CBZ, MCC 101, HPMC K100 M and Ethyl Cellulose were sifted through 40# mesh sieve. All the sifted ingredients were loaded into rapid mixing granulator, and dry mixing was carried out for 10 minutes at an impeller speed of 150 rpm. Binder solution was prepared by mixing and vortexing 40 gm of isopropyl alcohol, 6 gm of ethocel (7 cps) until the appearance of a clear solution. The prepared binder solution was added to the dry mixture with impeller speed of 200 rpm granulation is carried out for 5 minutes using parameters shown in Table 1. The wet mass was air dried for 10 minutes and sifted through 10 mesh sieve. Later, it was subjected for lyophilization. The dried granules were then sifted through 24 mesh sieve. Retained granules were milled using multimill and again sifted through 24 mesh sieve. Lubricants such as MCC 102, Cross-carmellose sodium, colloidal silicon dioxide and purified talc were also co-sifted through 40# mesh sieve. The intragranular ingredients were added to the 24 mesh sized granules and blending was carried out for 10 minutes at 15 rpm. Sifted via sieve number 60, magnesium stearate was added to the blender, and lubrication was performed for 5 minutes at 15 rpm. Compression was applied to the prepared mixture. The tablets were made using a coating solution made by dispersing and swirling opadry peach in filtered water for 30 minutes.¹⁰

Table 1: Composition of CBZ ER tablet

Formulation	F1	F2	F3	F4	F5
Intragranular contents (mg)
CBZ	400	400	400	400	400
MCC 101	40	20	20	20	20
HPMC K100M	80	64	56	48	48
Ethyl Cellulose	-	16	24	32	32
Ethocel 7 CPS	-	-	-	24	16
Isopropyl alcohol	-	Q.S.	Q.S.	Q.S.	Q.S.
Methylene Chloride	-	Q.S.	-	-	-
Lubrication contents (mg)
MCC 102	38	35	35	31	31
Ac-di-sol	20	20	20	18	20
Colliodal silicon dioxide	12	18	18	12	18
Talc	9	9	9	9	9
Magnesium stearate	6	6	6	6	6
Film coating contents (mg)
Opadry peach	18	18	18	18	18
Purified water	Q.S.	Q.S.	Q.S.	Q.S.	Q.S.

Evaluation of flow properties of granules:

Bulk density:

25g of CBZ was accurately weighed and put into a 100 ml graduated measuring cylinder. The volume of the mass was measured without compacting it. The unsettled apparent volume level was noted. The bulk density was calculated by the following formula.¹¹

Bulk Density = ----

where,

M =Weight of the test sample (g)

V_p = Unsettled Apparent volume (cm³)

Tapped density:

Accurately weighed 25g of CBZ was transferred into a 100ml graduated measuring cylinder without compacting. Using an appropriate mechanical tapped density tester that produces a set drop of 14mm at a nominal rate of 300 drops per minute, a cylinder holding a sample was mechanically tapped by elevating the cylinder and letting it drop under its own weight. The cylinder was originally tapped 500 times, and the tapped volume was measured to the closest graduated unit. The following formula is used to compute tapped density.¹¹

Tapped Density = -----

where,

M: Mass of powder (g)

Vt: Tapped volume of powder (cm³)

Compressibility Index and Hausner’s Ratio:

The bulk and tapped densities were used to calculate Carr’s compressibility index and the Hausner’s ratio to provide compressibility and a measure of the flow properties.⁹

Tapped density – Bulk density

Compressibility Index = ------------------------------- x100

Bulk density

Tapped density

Hausner’ s Ratio = ---------------------

Bulk density

Angle of repose:

Angle of repose was determined by fixed funnel method. The accurately weighed granules were taken in a funnel. The funnel's height was modified such that the tip of the funnel just touches the peak of the drug powder pile. The powdered drug was allowed to freely flow down the funnel and onto the surface. The powder cone's height and diameter were measured, and the angle of repose was computed using the formula below.¹⁰,¹¹

Tan Ɵ = -----

where,

θ: Angle of repose

h: Height (cm)

r: Radius (cm)

Evaluation of physical properties of compressed CBZ tablet:

Hardness:

Hardness is the force required to break a tablet by radial compression. It was determined using a hardness tester (Electrolab, India). The average hardness of 10 tablets was calculated and reported¹².

Friability test:

The friability was tested using the Friabilator (AcumenTech-solution Pvt. Ltd., Electrolab). Initially, 20 tablets were weighed and placed in the friabilator. The Friabilator was set at 25rpm for 4 minutes. After 4 minutes, the tablets were re-weighed and the % friability was determined. The friability was then determined using the formula below.¹⁰

W1 –W2

% Friability = -------------- x 100

where,

W1: Weight of tablets before test

W2: Weight of tablets after test

Weight variation test:

Twenty tablets were chosen at random and precisely weighed on an electronic weighing balance (RADWAG LC/GC). The weights of the individuals tablet were compared with the average weight.^13,14

Drug content:

Weighing randomly selected tablets and grinding them to a fine powder to obtain the drug content. The powder containing 10mg of CBZ was weighed and dissolved in 10ml of methanol in a volumetric flask with a magnetic stirrer, then the volume was raised to 100ml with phosphate buffer pH 6. 8¹⁵ and the solution was filtered. An aliquot of 1.0ml of solution was diluted to 10ml of phosphate buffer pH 6.8 in a separate volumetric flask. The drug content was measured spectrophotometrically using UV Spectrophotometer 1700 (Shimadzu, Japan) at 284nm.¹⁶

In-vitro dissolution testing:

USP Dissolution Testing Apparatus Type I (Dissolution apparatus TDT 8, Electrolab India) was used to perform in-vitro drug release. A basket apparatus (DT 720 Series; Erweka) with a rotation of 100rpm was employed. The tablets of optimized batches were analyzed for 24 h in 900ml of water at 37±0.5°C. 5ml of sampleswere withdrawn at time intervals of 0, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, and 24 hours. The withdrawn volume was replaced with 5ml of fresh dissolution medium. The amount of the released drug was detected in-line using a UV spectrophotometer 1700 (Shimadzu, Japan) at 284nm. The drug content was calculated on the basis of the calibration curve. The same study was also performed and compared with the Marketed tablet Tegretol-400 (Novartis Pharmaceuticals Ltd.^17,18

Stability Study:

The stability study of the optimized formulation was carried out at 40ºC/75% RH, 30ºC/65% RH and 25ºC/60% RH for 3 months. The samples were withdrawn and evaluated for in-vitro drug release¹⁹.

RESULTS AND DISCUSSION:

Flow properties of CBZ granules:

The prepared granules were characterized by their flow property. The results were as shown in Table 2. As per literature data, F4 has shown excellent and the remaining batches haveshown good flow property. F3 and F4 have shown fair and F1, F2 and F5 have shown passable compressibility.

Table 2: Flow properties of CBZ granules

Formulation	Angle of repose	Bulk density (g/ml)	Tapped density (g/ml)	Carr’s index (%)	Hausner’s Ratio
F1	28°	0.44	0.57	22.22	1.28
F2	29°	0.58	0.74	21.62	1.28
F3	25°	0.56	0.70	18.75	1.23
F4	23°	0.60	0.70	17.14	1.17
F5	28°	0.55	0.71	22.22	1.28

Physical properties of compressed CBZ tablet:

The compressed tablets were graded based on their weight, thickness, hardness, and friability. The average weight and thickness of compressed pills were 597.0–601.0 mg and 6.03–6.13 mm, respectively. The hardness of the prepared tablets was kept between 140 and 197 N. All batches had a friability range of 0.193–0.197 percent, which was within the acceptable range. The physical attributes of all batches revealed that all tablets had identical physical qualities.

Table 3: Physical properties of compressed CBZ tablet

Formulation	Average Weight (mg)	Thickness (mm)	Hardness (N)	Friability (%W/W)
F1	597.9	6.05	190	0.197
F2	598.4	6.03	197	0.194
F3	598.5	6.03	194	0.195
F4	601.0	6.06	180	0.193
F5	597.0	6.03	140	0.195

Drug Content:

As demonstrated in Table 2, the drug content varied between 98.76 and 99.51 percent. It indicates that all the tablets have the uniform drug content and are within the acceptable limit. The F4 tablet batch had the highest drug content at 99.51 percent.

Fig. 1: Drug content of compressed CBZ tablet

In-vitro dissolution testing:

After evaluating all the batches, F4 has been selected as an optimized batch and is being subjected to an in-vitro release study. In-vitro release studies were performed to determine the percentage of drug released from prepared CBZ and marketed tablet Tegretol-400. Results of the in-vitro release studies of tablet formulations are presented in Fig. 2. In-vitro release of compressed CBZ tablet was found to be 88.10%, whereas the CBZ release from marketed tablet was 90% at the end of 24 hours. The prepared tablet has shown sustained release for up to 24 hours.

Fig. 2: In-vitro dissolution profile of optimized CBZ tablet

Stability Study:

The stability study of the optimized formulation was carried out at 40±2ºC/75±5% RH, 30±2ºC/65±5% RH and 25±2ºC/60±5% RH for 3 months. Tablets did not show any remarkable effect on in-vitro release after the stability study. In-vitro drug release has been shown to be decreased after increasing the temperature and relative humidity.

Table 4: Stability study optimized batch

Time (hours)	F4 trial	40±2ºC/ 75±5% RH	30±2ºC/ 65±5% RH	25±2ºC/ 60±5% RH
Time (hours)	Initial	After 3 months
0	0	0	0	0
1	6	16.06	18.07	15.89
2	17.5	24.12	26.89	22.01
3	33	27.98	31.12	28.59
4	39.3	34.79	36.98	34.91
6	56.7	43.02	45.13	45.24
8	61.7	51.20	51.07	51.02
10	69.5	55.91	57.29	58.12
12	76.1	60.69	62.24	63.24
16	80.5	68.41	68.96	70.53
20	81.3	76.91	76.13	77.23
24	88.1	80.60	83.09	85.84

CONCLUSION:

Carbamazepine ER matrix tablet was prepared successfully using HPMC K 100M and ethyl cellulose as a polymer to retard release and achieve the required dissolution profile. Evaluation characteristics such as hardness, thickness, weight variation, friability, and drug content were determined to be adequate for all prepared formulations. Based on these results, the optimized batch was selected. The investigated ER matrix tablets were capable of maintaining a constant plasma CBZ concentration for 24 hours. The in-vitro dissolution study was compared with the marketed product and it was found that the drug release profile of the optimized tablet was nearly the same as the marketed product. This all can be expected to reduce the frequency of administration and decrease the dose-dependent side effects associated with repeated administration of conventional CBZ tablets.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGEMENTS:

The authors are thankful to the Management of R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur for providing the necessary facilities, support and encouragement.

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Received on 24.03.2022 Modified on 17.06.2022

Research J. Pharm. and Tech 2023; 16(6):2808-2812.

DOI: 10.52711/0974-360X.2023.00462