FORMULATION AND EVALUATION OF CARBAMAZEPINE BILAYER TABLET FOR BIMODAL RELEASE

FORMULATION AND EVALUATION OF CARBAMAZEPINE BILAYER TABLET FOR BIMODAL RELEASE

M. Shankrayya *, Sagar T. Kulakarni, D. M. Vinayaka, Sathwik, A. K. Sourav, Sabreen Taj and R. P. Kishor Rahul

Department of Pharmaceutics, S. C. S. College of Pharmacy, Harapanahalli, Karnataka, India.

ABSTRACT: Carbamazepine (CBZ) has long been a therapeutic option for bipolar disorder. Carbamazepine is used to treat acute manic and mixed episodes associated with bipolar I disorder.  In the present study, bilayer tablet was developed to improve dosing convenience and decrease daily fluctuations in serum CBZ concentration, thereby lowering the incidence of adverse events. In bilayer tablet one layer provides the loading dose by immediate drug release and another layer provides the maintenance dose up to 12 hrs by sustained release. The drug excipient compatibility study was carried out by FTIR and DSC techniques; there was no interaction found. Cross povidone was used as a superdisintegrant in the immediate release layer and controlled release fraction was formulated by using HPMC K 100 polymer. The prepared granules were evaluated for angle of repose, bulk density, tapped density, and compressibility index which showed satisfactory results. The prepared bilayer tablets were evaluated for thickness, hardness, friability and in-vitro release studies. In-vitro dissolution study was carried out for 12 hours using USP dissolution apparatus I using 1.2 pH and 7.4 phosphate buffer as dissolution medium. The bilayer tablet showed initial burst release to provide the loading dose of drug followed by sustained release up to 12 hours. Concentration of polymer and superdisintegrant ratio influenced drug release profile. As the polymer concentration was increased in sustained release layer the % drug release decreased.

Keywords: Carbamazepine, Bilayer tablet, HPMC K100, Cross povidone, Immediate release

INTRODUCTION: For decades, oral medication delivery has been acknowledged as the most extensively used route of administration among all the ways investigated for systemic drug delivery. Any drug delivery system's purpose is to provide a therapeutic amount of medicine to the patient at the right time for the length of treatment and then maintain the desired drug concentration ¹.

The conventional dosage form causes a wide range of drug concentration fluctuations in the bloodstream and tissues, reduced or lost therapeutic effectiveness, and increased adverse effects, which can lead to undesirable toxicity and inefficiency.

On the other hand, sustained or controlled drug delivery systems can reduce dosage frequency while increasing therapeutic effectiveness by localizing the drug at the site of action, lowering the dose necessary, and ensuring uniform drug delivery ². Bilayer tablet is a new approach for effectively developing sustained-release formulations, which includes an instant release (IR) layer and a sustained release (SR) layer.

It has a bimodal drug delivery characteristic (slow release / quick release / slow release) ³. A constant plasma concentration may not be achieved even if a dosage form with a zero-order in-vitro release is used. It's feasible that a delivery system that provides an initial burst release followed by a more constant or accelerated release at a later time may be a superior solution. A release profile such as pseudo-zero-order release with an initial burst or bimodal release may compensate for the lower absorption rate in the stomach and large intestine ^4-5. Based on these considerations, a new oral delivery device in the shape of a double-component tablet has been proposed, with one portion prepared to rapidly release the medication with the goal of attaining a high serum concentration in a short time. The second layer is a prolonged-release layer designed to keep an effective plasma level for a long time. Epilepsy is a neurological disorder in which brain activity becomes abnormal, causing convulsions or periods of unusual behavior, sensations, and sometimes loss of awareness. Diseases like epilepsy require immediate drug release for instant effect to manage the panic attack at its presentation. Then drug concentration has to be maintained to prolong the drug's effect ⁶.

For its anticonvulsant and antineuralgic properties, carbamazepine is employed. This medication's popularity is attributed to a number of positive traits, including its efficacy in managing various seizure types. It has a low bioavailability of less than 70%, irregular oral absorption, and poor water solubility. Additionally, the therapeutic window for carbamazepine is small, and there are variations in its bioavailability.

An effort to reduce the frequency of dosing necessary for chronic carbamazepine therapy and to lessen the variability in plasma concentration ^7-10. Hence, in the present study, a bilayer tablet for bimodal drug release in which one layer of immediate release and a second layer of sustained release of Carbamazepine was designed.

MATERIAL AND METHOD: Carbamazepine was purchased from Yarrow Chem. Pvt. Ltd. Cross povidone, HPMC K100, starch, lactose, talc, magnesium stearate were purchased from S.D Fines Chem. Ltd., Mumbai. All other ingredients, reagents, and solvents were of analytical grade.

Compatibility Studies: The compatibility studies of the drug with polymers are studied using FT-IR and DSC techniques ^11-12.

FT-IR Spectroscopy: FT-IR spectroscopy was used to determine whether the drug and excipients were compatible. A thermal Nicolet FTIR was used for infrared spectroscopy, and the spectrum was collected between 4000 and 400 cm^-1. The sample was squashed into discs using a hydraulic press at a pressure of 5 tonnes for 5 minutes using a 1:1 mixture of the drug and excipients in KBr (200-400mg). IR spectral investigations discovered the interaction between drug and excipients by looking for any changes in drug peak locations in the spectrum of a physical mixture of drug excipients.

DSC Analysis for Formulation: Shimadzu Limited's Different Scanning Calorimeter -60 was used to examine the thermal characteristics of both pure drug and the physical mixture of the drug and excipients. In aluminium pans with a thermic seal, the samples were heated. Each sample's heat runs were set between 25 and 350°C with a heating rate of 100°C/min and nitrogen as the blanket gas.

Preparation of Bilayered Tablets of Carbamzepine: The immediate release layer of the tablet was prepared by blending Carbamazepine uniformly with super disintegrant (Cross povidone) as per the formulae given in Table 1. The drug-superdisintegrant blend was then mixed with MCC using twin blender for 10 min. The final mass was lubricated with magnesium stearate ¹³. The sustained release layer of the tablet was prepared by wet granulation technique by mixing carbamazepine uniformly with different proportions of HPMC-K 100, magnesium stearate and starch as given in Table 2, PVP-K30 was used as a binder. The wet mass was passed through #30 to obtain granules. The granules were dried at 60ºC in a tray drier. The granules of 30 or 60# size were lubricated with magnesium stearate. The bilayer tablet was firstly compressed using a rotary tablet press for the sustained release layer and then again compressed with an immediate release layer over the sustained release layer.

Evaluation of Powder Blends: Flow properties of powder blend (before compression) were characterized by the bulk density and tapped bulk density, angle of repose, compressibility index (Carr's index), and Hausner's ratio. These tests were repeated 3 times for each formulation ^14-15.

Bulk Density: The apparent bulk density (b) was calculated by filling a graduated cylinder with presieved medication excipients blend and measuring the volume (Vb) and weight (M) as

ρb = M/Vb

Tapped Density: The measuring cylinder, which contained a known blend mass, was tapped for a predetermined amount of time. The cylinder's minimum volume (Vt) and the blend's weight (M) were both measured. The following formula was used to compute the tapped density (t).

ρt = M/Vt

Compressibility Index: The simplest way of measuring of free flow property of powder is compressibility, with which a material can be induced to flow is given by % compressibility which is calculated as follows:

C = (ρt – ρb) /ρt x 100

ρt - tapped density

ρb - untapped bulk density

Hausner’s Ratio: Hausner’s ratio is important to determine the flow property of powder and granules. It is calculated by following formula.

Hausner’s ratio = ρt / ρb

ρt - tapped density

ρb - untapped bulk density

Angle of Repose: Angle of repose is described as the maximum possible angle between the surface of a powder pile or granules and the horizontal plane. The granules were allowed to flow through a funnel fixed to a clamp at a definite height. The angle of repose (θ) was then calculated by measuring the height (h) and radius (r) of the formed granules heap and putting the values into the equation

𝛳 = tan^-1 (h/r)

Compression of Bilayered Tablets: The bilayer tablet of Carbamzepine was prepared using a Rotary Mini tablet press (Shakthi Pvt. Ltd., India) equipped with flat punches. The die was initially filled with the weighed amount sustained release portion and was lightly compressed. Over this compressed layer, the required quantity of the immediate release layer powder mixture was placed and compressed to obtain hardness of the tablet 4–6 kg/cm². It was observed that tablet compressed at this force did not show any layer separation. The total weight of the tablet was kept constant, i.e., 600 mg for all formulations.¹³

Evaluation of Bilayer Tablets: The following physicochemical tests were conducted to evaluate the post-compressional parameters of the tablet ^16-17.

General Appearance: The control of a general appearance of a tablet involves the measurement of a number of attributes such as a tablet’s size, shape, color.

Immediate release layer: Yellow color

Sustained release layer: White color

Thickness: The homogeneity of tablet size required a certain thickness of tablet. Digital screw gauze was used to determine thickness.

Hardness: In this five tablets were selected randomly and the hardness of each tablet was measured with Monsanto hardness tester. The hardness is usually measured in terms of kg/cm².

Friability Test: Friability test was carried out to instantly evaluate the hardness and stability. 10 tablets were weighed (W₀) initially and put in a tumbling and rotating apparatus drum. Then they were subjected for completion of 4 min or 100 rpm, the tablets were again weighed. The % loss in weight or friability (F) was calculated by the formula given below.

% Friability ₌ (Initial weight of tablets - Final weight of tablets) / Initial weight of tablets × 100

Weight Variation: This test was performed to maintain the uniformity of weight of each tablet, which should be in the prescribed range. This was done by weighing 10 tablets at random and the average weight was calculated. Not more than two of individual weight deviates from the average weight. The tablet weight data were analyzed for sample mean and percent deviation. IP limit for weight variation in case of tablets weighing 130 - 324 mg ± 7.5 % and more than 324 mg ± 5%.

Uniformity of Drug Content: 5 tablets were selected randomly, weighed and triturated, a tablet triturate equivalent to 100mg of drug weighed accurately, dissolved in 10 ml of methanol and diluted to 100ml. Further dilutions were done suitably and absorbance was measured at 284nm using UV spectrophotometer.

In-vitro Dissolution Studies: The USP-type I dissolution device operated at 50 rpm for the in-vitro dissolution trials. The dissolution medium was pH 1.2 for first 2 hours and pH 7.4 for 12 hours (900 mL) at a temperature of 37^oC. An aliquot (5mL) was taken out at predetermined intervals, and the drug content was measured using a Shimadzu 1800 UV-visible spectrophotometer at 285nm.

Kinetic Analysis of Dissolution Data: The release data were fitted into the zero order, first order, Higuchi equation, and Korsmeyer equation (which is frequently used to characterize drug release behaviour from polymeric systems) in order to explore the mechanism of drug release from the tablets.

RESULTS AND DISCUSSION: A successful attempt was made to formulate Carbamazepine bilayer tablets using crospovidone as immediate-release polymer and HPMC K-100 as release retardants using wet granulation method. Total of three formulations were prepared; the composition of each formulation is shown in Tables 1 and 2. The formulated tablets were characterized for various physicochemical parameters.

TABLE 1: COMPOSITION OF IMMEDIATE RELEASE LAYER OF CARBAMAZEPINE

TABLE 2: COMPOSITION OF SUSTAINED RELEASE LAYER OF CARBAMAZEPINE

Drug-Excipient Compatibility Study:

Fourier Transport Infrared Spectroscopy (FTIR): Infra red spectra of drug and excipients were recorded by the KBr disk method and the resulting spectra are shown in Fig. 1 to 3. All of the characteristic peaks of carbamazepine are present in the spectrum of the drug-excipient mixture, indicating compatibility between drug and excipients. Spectra confirmed no significant changes in the chemical integrity of the drug. Carbamazepine functional group peaks (N-H) stretch, C=C stretch, C=N stretch, and C-N stretch) were unchanged in all IR spectra and are summarized in Table 3. The DSC thermogram of carbamazepine shows a sharp endothermic peak at 196.01°C within 1.0°C, indicating that the sample is in pure form. The peaks for formulations containing Cp and HPMC K 100 showed no apparent change in the melting endotherms of carbamazepine (193.77°C and 189.34°C) compared to pure drugs. This observation further supports the IR spectroscopy results. This indicates that the stability of the formulation may not be affected and confirms that the drug is compatible with all excipients.

FIG. 1: FTIR SPECTRA OF PURE CARBAMAZEPINE

FIG. 2: FTIR SPECTRA OF PHYSICAL MIXTURE OF DRUG AND CROSS POVIDONE

FIG. 3: FTIR SPECTRA OF PHYSICAL MIXTURE OF DRUG AND HPMC

TABLE 3: FTIR SPECTRA OF DRUG AND FORMULATIONS

Evaluation Parameters:

Pre-compressional Parameters:

Bulk Density: The values of bulk density were found to range from 0.4 to 0.44 (IL) and0.534 to 0.54 (SL)

Tapped Density: The values of tapped density were found to range from 0.47 to 0.56 (IL) and 0.566 to 0.6 (SL).

Carr’s Consolidation Index: The results of the Carr’s consolidation index of all the formulations ranges from 7.1 to 18% (IL) to 5.3 to 10% (SL).

Hausner’s Ratio: It was ranging from 1.175 to 1.22 (IL) and 1.05 to 1.11 (SL). Lower the Hausner’s ratio better is the flowability, i.e., all the preparation showed that they had good flow properties.

Angle of repose (θ): The data obtained for angle of repose for all the formulations were tabulated in Table 4 and 5. All the formulations showed angle of repose value in the range of 16.85 to 19.25 (IL) and 17.7 to 20.25 (SL). The angle of repose value (< 30) indicated good flow properties.

TABLE 4: PRE-COMPRESSIONAL PARAMETERS OF IMMEDIATE RELEASE LAYER

TABLE 5: PRE-COMPRESSIONAL PARAMETERS OF SUSTAINED RELEASE LAYER

Post-Compression Parameters: Three formulations of carbamazepine were prepared using different concentrations of HPMC K-100, PVP K-30 and cross-povidone in different concentration were prepared.

Thickness: The thickness depends on the size of punches and the weight of one tablet (600 mg). The value of thickness ranges between 6.804±0.009 to 7.20±0.015 mm.

Hardness: The hardness of all tablets was maintained within 4 to 6 kg/cm². The hardness of all formulations was almost uniform in specific methods and possessed good mechanical strength.

Friability (F): Another measure of tablet strength is friability. The values of friability test were given in Table 6.

The % friability for all the formulations was below 1%, indicating that the friability was within the prescribed limits; the results of friability test indicate that the tablet possesses good mechanical strength.

TABLE 6: POST-COMPRESSIONAL PARAMETERS OF CARBAMAZEPINE BILAYER TABLET

Weight Uniformity: All the tablets passed the weight variation test as the average weight variation was within the pharmacopoeial limit of ±5%. The weight of all the tablets was found to be uniform with a low standard deviation value.

Uniformity of Drug Content: The % drug content of carbamazepine in all the formulated tablets was found within the limits. % drug content value of carbamazepine was within 98±1.62 to 99.25±1.475%. The results are within the range, which indicates uniform mixing of drug.

In-vitro Dissolution Study: In-vitro studies were performed to study the drug release from the dosage form in the physiological condition and kinetics of drug release. The in-vitro drug release profiles of F1-F3 are shown in Fig. 4 to 7 Three formulations of carbamazepine with HPMC K-100, in different concentrations were studied. It was observed that the controlled type of polymer influences the drug release pattern. The formulations F1, F2, and F3 contain HPMC-K100 in varying concentrations. The higher initial drug release was observed in formulation F1 compared to F2 and F3, respectively. Bilayer tablets of F1, F2, F3 and marketed tablet showed the release of 93.67±2.876, 85.25±0.065, 81.9±2.876 and 99.42±1.328 % at the end of 12 hr, respectively. As the concentration of HPMC-K100 increased, drug release in the dissolution medium decreased. So, a varying amount of HPMC-K100 affects the drug release. As expected, the drug release rate depended on the polymer concentration used. The tablet containing an optimized concentration of HPMC-K-100 (formulation F3) showed better control of drug release over 12 hr. This controlled drug release from F3 could be attributed to the formulation of the thick gel structure that delays drug release from the Bilayer tablet.

FIG. 4: DSC SPECTRA OF PURE CARBAMAZEPINE

FIG. 5: DSC SPECTRA OF PHYSICAL MIXTURE OF DRUG AND CROSS POVIDONE   

FIG. 6: DSC SPECTRA OF PHYSICAL MIXTURE OF DRUG AND HPMC

FIG. 7: IN-VITRO DISSOLUTION PROFILE OF F1 TO F3 FORMULATION

Kinetic Study:

Drug Release Kinetics:  The release kinetics of bilayer layer formulations (F1-F3) was found to following clearly first order kinetics as the values for ‘r’ is (0.863-0.865).

In our experiments, the in-vitro release profile from all the formulations could be best expressed by higuchi’s equation as the plot showed high linearity (r²=0.9186-0.9125).

To confirm the mechanism the data was fitted in to Korsmeyer et al., equation all the formulation showed good linearity with slope (n values ranging from 0.6133 to 0.6508) which indicates that analomus diffusion mechanism.

CONCLUSION: Bilayer tablets of CBZ containing immediate and sustained release layers were successfully formulated. All the formulation batches tested for physical parameters like weight variation, hardness, friability and drug content were within the pharmacopeial limits. The bilayer tablet showed initial burst release to provide the loading dose of drug followed by sustained release. The formulation F₃ showed better control of drug release for more than 12 hr. This controlled drug release from F₃ could be attributed to the formulation of the thick gel structure that delays drug release from the bilayer tablet. The data obtained thus suggest that bilayer tablet can be successfully designed for sustained delivery of CBZ, which is suitable in controlling different types of seizures.

ACKNOWLEDGMENT: We thank Sha. Bra. Sri. Varasadyojatha Shivacharya Swamiji. President, T. M. A. E. Society and Dr. T. M. Chandrashekaraiah. Secretary, T.M.A.E. Society, for their encouragement through Principal, S.C.S. College of Pharmacy, Harapanahalli, Karnataka, for providing necessary facilities and help in carrying out this work.

CONFLICTS OF INTEREST: Nil

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    How to cite this article:

    Shankrayya M, Kulakarni ST, Vinayaka DM, Sathwik, Sourav AK, Taj S and Rahul RPK: Formulation and evaluation of carbamazepine bilayer tablet for bimodal release. Int J Pharm Sci & Res 2023; 14(10): 5017-24. doi: 10.13040/IJPSR.0975-8232.14(10).5017-24.

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