Formulation And In Vitro Evaluation Of Bilayer Tablets Of Sustained Release Gliclazide 30 mg And Immediate Release Simvastatin 40 mg

Oral drug delivery remains the most preferred and patient-compliant route of administration due to its ease of use, cost-effectiveness, and flexibility in dosage form design [1]. Among oral dosage forms, tablets are the most prominent. However, conventional immediate-release tablets often require frequent dosing, leading to poor patient compliance, especially in chronic conditions requiring long-term therapy such as diabetes and dyslipidemia [2].

Modified-release drug delivery systems (MRDDS) have been developed to overcome these limitations by controlling the rate and/or site of drug release, thereby optimizing therapeutic efficacy and improving patient adherence [3]. Bilayer tablet technology represents a significant advancement in this field, allowing for the combination of two different drugs or the same drug with different release profiles in a single dosage form [4]. This is particularly useful for combination therapy, where incompatible active pharmaceutical ingredients (APIs) can be physically separated, or for achieving sequential release—a loading dose from one layer and a maintenance dose from another [5].

Diabetes mellitus and dyslipidemia frequently coexist, creating a need for complex medication regimens. Gliclazide, a second-generation sulfonylurea, is widely used for managing type 2 diabetes by stimulating insulin secretion [6]. Simvastatin, an HMG-CoA reductase inhibitor, is first-line therapy for hypercholesterolemia [7]. The development of a bilayer tablet containing immediate-release simvastatin and sustained-release gliclazide could significantly simplify the treatment schedule, improve therapeutic outcomes, and enhance patient compliance.

Simvastatin

The statin family includes atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin and pitavastatin [8]. Statin drugs inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, a primary rate-limiting step in cholesterol biosynthesis in the body; this action is highly effective in lowering total cholesterol and low-density lipoprotein levels [9]. In addition, it has been discovered that statins can protect against ischemic injury and promote angiogenesis in normocholesterolemic animals [10]. Several mechanisms may explain the beneficial cardiovascular effects of statins, including modulation of endothelial function, antioxidant and anti-inflammatory effects, plaque stabilization, vasculogenesis, and effects on thrombosis [11]. In addition, statins have been reported to cause a decrease in tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and malondialdehyde (MDA), and an increase in superoxide dismutase (SOD), which is known for its antioxidant and cardioprotective effects [12]. Since statins have various pleiotropic effects (non-lipid modifiable effects) in addition to their lipid-lowering effects, they are now considered a new and unusual therapeutic modality for various pathological disorders such as psoriasis, sepsis, alopecia, wound healing and many inflammatory diseases [13]. Simvastatin is an oral HMG-CoA reductase inhibitor that is indicated as an adjunct to diet, exercise, weight loss and possibly other medications as part of a comprehensive lipid-lowering and cardiovascular health regimen. It is a semi-synthetic derivative of lovastatin, the first FDA-approved statin. Simvastatin helps to lower cholesterol production and reduce high levels of LDL cholesterol [14].

Gliclazide

Sulfonylureas are the oldest class of oral antidiuretic medication, dating back to the 1950s. [15] All sulfonylureas contain a phenyl-sulfonic-urea structure, which exerts the hypoglycemic effect. [16]. Patients with type 2 diabetes mellitus use sulfonylureas as monotherapy or in combination with other oral or injectable medications [17]. Sulfonylureas are divided into first-generation and second-generation. The first-generation sulfonylureas include chlorpropamide and tolbutamide. [18]. Chlorpropamide is no longer available in the United States [19]. The second-generation sulfonylureas include glyburide (also known as glibenclamide), glipizide, glimepiride, and gliclazide. Gliclazide is not available in the United States [20] .Glimepiride came to market in 1995, and it is the newest sulfonylurea. [21]. Some references list glimepiride as a third-generation sulfonylurea because its chemical structure has a larger substitution moiety than the other second-generation sulfonylureas. [22]. Sulfonylureas are comparable in efficacy and decrease the glycated hemoglobin A1C (HbA1c) by 1% to 1.25 % [23]. Second-generation sulfonylureas are among the most used anti-diabetic medications because they are inexpensive [23]. Providers rarely prescribe first-generation sulfonylureas nowadays. Sulfonylureas are not preferred for elderly patients or those with renal or hepatic impairment [24] Clinicians often prescribe sulfonylurea as an add-on to metformin [25]. This combination targets different mechanisms of action and improves glucose control; sulfonylureas stimulate insulin secretion, while metformin increases insulin sensitivity [26]. An advantage to this combination is the potential for a neutral effect on the patient's body weight since sulfonylureas cause weight gain while metformin causes weight loss [27].

The objective of this study was to develop and evaluate a novel bilayer tablet formulation containing an immediate-release layer of simvastatin (40 mg) to provide rapid pharmacological effect, and a sustained-release, gastro-retentive floating layer of gliclazide (30 mg) to maintain therapeutic levels over an extended period.

MATERIALS AND METHODS

• Simvastatin, Gliclazide, Croscarmellose, Sodium starch glycolate, Povidone
• Magnesium stearate, Talc, Microcrystalline cellulose, Sodium bicarbonate
• Guar gum, Hydroxyl propyl methyl cellulose, Ethyl cellulose, Carbopol
• PolyvinylpyrrolidineK30 were purchased from local company for pharmaceutical industry, Sudan.
• Tablet tester (Hardness) from CALEVA Germany
• Friability filter, Dissolution Apparatus, Filtration pump, Tableting machine, Fiblitor and Disintegration tester were obtained from Erweka, Germany.
• Sonicator from Qsonica Llc, U.S.
• Analytical balance KERN & Sohn GmbH, Germany

The immediate release layer was produced by direct compression, while wet granulation technology was used for the delayed release layer. For both layers, granulation was carried out separately as follows:

 Preparation of immediate release layer (IR)

All ingredients were precisely weighed and passed through a 60# sieve. To mix the ingredients thoroughly, the drug super disintegrate, microcrystalline cellulose, magnesium stearate and talc were mixed in a mortar and pestle. The powder was passed through a 60# sieve and pressed on a rotating tableting machine.

Preparation of sustained release layer (SR)

It was produced using the wet granulation method. The required amount of sustained release polymers (Guar gum and hydroxyl propyl methyl cellulose) were mixed with GLC and sieved through an 80 mesh sieve. The binding solution was prepared by dissolving the required amount of PVP K 30 in isopropyl alcohol (IPA). The mixed powders were granulated with the IPA solution and sieved through a 40 mesh sieve. The granules were dried in a tray dryer at 45 ?C for 30 minutes. Then lubricated with the required amount of talc and magnesium stearate. The lubricated granules were stored with a suitable label until further use.

The granules for the depot layer were lightly compressed with a 27 station double rotary compression machine using 13/32 inch round standard punches. Over this compressed layer, the required amount of the other immediate release layer was placed and compressed to achieve a hardness in the range of 4-8 kg/cm² to form a bilayer tablet of sustained release gliclazide and immediate release simvastatin. The compressed bilayer tablets were then evaluated.

Hardness test

Was carried out with the Erweka hardness tester. 10 tablets were tested and the average hardness was calculated. The acceptable range is 4-8kg/cm² (USP, 2014).

Friability Test:

The friability of the tablets was determined using the Erweka Friabilator. In this device, the tablets are subjected to the combined effects of abrasion and shock in a plastic chamber rotating at 25 revolutions per minute, with the tablets being dropped from a height of six inches at each revolution. A pre- weighed sample of 10 tablets was placed in the friabilator and subjected to 100 revolutions. The tablets were dedusted and weighed again. The acceptable limit for friability is 0.5-1% (USP, 2014). The friability was calculated using the following formula:

%Friability = (tablet weight before friability test-tablet weight after friability test)/(table weight before fribaility test)×100

Evaluation of Granules.
Angle of Repose:

Fifty grams (50 g) of the granules were placed in a sealed glass funnel at a distance of10 cm from the flat surface. The granules were then allowed to flow through the funnel opening by removing the cotton plug from the funnel opening. The height of the pile formed (h) as well as the radius of the pile (r) were noted. The angle of repose (Q) was calculated as follows

Q = tan^-1 h/r (9)

Bulk and Tapped Densities:

Both the loose bulk density (LBD) and the tapped bulk density (TBD) were determined. A quantity of 5 g of powder of each formulation which was previously gently shaken to break up any agglomerates that may have formed, was placed in a 50 ml graduated cylinder. After observing the initial volume, the cylinder was allowed to drop under its own weight at 2-second intervals from a height of 2.0 cm onto a hard surface.

The tapping was continued until no further volume change was observed. LBD and TBD were calculated using the following formulas.

LBD = weight of the powder/volume of the packing (10)

Tapped density=Wt. of sample in gm/Tapped volume (11)

Percentage Compressibility (Carr’s index) and Hausner’s ratio:

The percentage compressibility (CI) was calculated from the difference between the tap density (Dt) and the bulk density (Bt) divided by the tap density and the ratio expressed as a percentage. The Hausner ratio (HR) is the ratio between the tap density and the bulk density.

Cl = [(D_t-B_t)/D_t] × 100 (12)

HR = D_t/B_t (13)

Drug content uniformity

Twenty tablets accurately weighed and finely powdered. The powder corresponding to 40 mg of simvastatin and 30 mg of gliclazide was transferred to a 100 ml volumetric flask. 50 ml of pH 7.4 buffer was added to the powder and sonicated to dissolve completely. The volume was then made up to 100 ml with buffer and filtered. 1 ml of the filtered solution was taken and diluted to 100 ml with the buffer. The peak area of the sample solution was measured at 245 nm to calculate the concentration of the drug in the sample.

Disintegration Test:

Six tablets of each brand were placed in the basket of the dissolution apparatus and the basket was immersed in the dissolution medium (900ml of 0.1N HCL as medium, at a temperature of 37°C).

The disintegration time was recorded and compared with the accepted range (not more than 30 minutes) (USP, 2014). Floating of the tablets can be prevented by placing perforated plastic discs on each tablet

In vitro Buoyancy studies for floating tablets

The in-vitro buoyancy was determined by the floating time and the total floating time. The tablets were placed in a 100ml beaker containing 0.1N HCl. The time taken for the tablet to rise to the surface and float was determined as floating time (FLT) and the duration of time the tablet floats continuously on the dissolution medium was noted as total floating time (TFT).

 Swelling studies

The extent of swelling was measured in % of the weight gain of the tablet. One tablet of each formulation was weighed and kept in a Petri dish containing 50 ml of 0.1N HCl solution. At the end of the specified time intervals, the tablets were removed from the Petri dish and the excess buffer was blotted with tissue paper and weighed. The percentage weight gain of the tablet was calculated using the following formula:

Swelling index (%) = ((M_t– M₀)/M₀) X 100   (14)

Where:

 Mt – weight of tablets at time (t)

M0 – weight of tablets at time (0)

In vitro Dissolution Studies for immediate release layer of Simvastatin.

 In vitro drug release studies were carried out using a USP XXIV type II dissolution apparatus. 900 ml of dissolution medium was maintained at 37±1°C and 75 rpm for 1 hour. 0.1 N HCl was used as dissolution medium. 5 ml of the sample was withdrawn at specific time intervals and replaced with an equal volume of drug-free dissolution fluid. The withdrawn samples were filtered through a 0.45µ membrane filter and the drug release in each sample was analyzed.

In vitro dissolution studies for floating layer of gliclazide

In vitro drug release studies were carried out using a USP XXIV type II dissolution apparatus. 900 ml of solution medium was kept at 37±1°C and 50 rpm for 8 hours using 0.1 N HCl as the solution medium. 5 ml of the sample was withdrawn at specific time intervals and replaced with an equal volume of drug-free solution medium. The withdrawn samples were filtered and the drug release in each sample was analyzed by HPLC after appropriate dilution. Time intervals: 0.5, 2, 4, 6, 8, 10 and 12 hours.

The release kinetics of optimized simvastatin and gliclazide from the bilayer tablet were investigated by dissolution studies. Dissolution tests were carried out using a USP type II dissolution apparatus and 900ml of 0.1N HCL at 37± 0.5ºC at 75rpm for 30min and then changed to 50rpm. At 60 min intervals, 5 ml of sample was withdrawn, a sampling was performed and replaced with 5 ml of fresh buffer each time. The estimation was performed using the HPLC method. The optimized formulation was compared with the market product.

Drug Release Data Model Fitting:

*Zero order equation

Qt = Q₀ + K_{0t   (1)}

Where Q_t is the amount of drug dissolved in time t, Q₀ is the initial amount of drug in the solution (most times, Q₀ = 0) and K0 is the zero order release constant expressed in units of concentration/time

* Higuchi Square Root Law equation

 Q = KH x t ^1/2   (2)

Where, KH is the Higuchi dissolution constant.

*First order release equation

Log C_t = log C₀ - K_t / 2.303   (3)

Where C₀ is the initial concentration of drug, k is the first order rate constant, and t is the time

*The Korsmeyer Peppas equation

 M_t/M_α= K_{k t       (4)}

Where Kk is the Korsmeyer release rate constant, Mt / M is the fraction of drug released at time t, K is the Korsmeyer release rate constant and n characterizes the mechanism of drug release from formulations during diffusion process.

*Hixson-Crowell cube root law C₀^1/3 –C_t^1/3=K_{t   (5)}

Ct= amount of drug release in time t

C₀=initial amount of drug in tablet, K=rate constant.

2.2.4 Evaluation of Tablets:

2.2.4.1 Weight Variation Test

The weight variation test was carried out by weighing 20 tablets individually. The average weight was calculated, the individual weights were compared with the average weight and the standard deviation (SD) and the percentage deviation (RSD) were calculated. The percentage deviation in weight variation should be within the permissible limits (±5%) (USP, 2014). The standard deviation and percentage deviation were calculated as follows:

SD = ± √∑ (W - W?) ² / N-1    (6)

RSD= SDMean×100

Where:

W  ≡ weight of individual tablets

W?   ≡ mean weight of tablets

SD ≡ standard deviation 

RSD ≡ percentage deviation

RESULTS AND DISCUSSION

The prepared simvastatin immediate?release (IR) and gliclazide sustained?release (SR) formulations were evaluated with respect to precompression parameters, postcompression tablet properties, in vitro buoyancy and swelling, dissolution behavior, release kinetics and stability. The results confirmed that all optimized formulations met the required pharmacopoeial specifications and exhibited suitable performance for incorporation into bilayer tablets.

Precompression evaluation

The powder blends of simvastatin IR formulations (F1–F7) and gliclazide SR formulations (F1–F7) were evaluated for bulk density, tapped density, Hausner ratio, Carr’s index and angle of repose. As shown in **Table 3** (simvastatin) and **Table 4** (gliclazide), all formulations exhibited good flow and compressibility characteristics. The Carr’s index values were within the acceptable range for directly compressible powders, and the Hausner ratio values were close to 1.2, indicating low inter?particle friction and good packability. The angle of repose values also suggested that the blends possessed adequate flow for tablet compression without major flow problems. These findings confirmed that the selected excipient combinations and granulation processes produced blends suitable for robust tablet manufacturing.

Table4: precompression parameters for Gliclazide

Post compression characteristics of single?layer tablets

The compressed simvastatin IR and gliclazide floating SR tablets were evaluated for average weight, hardness, thickness, friability, drug content and disintegration, as appropriate. The postcompression parameters for simvastatin IR formulations are summarized in **Table 5**, and those for gliclazide SR tablets in **Table 6**, while a detailed friability assessment for bilayer tablets is presented in **Table 7**.

All formulations complied with pharmacopoeial specifications for weight variation, with percent deviation within ±5% of the mean. The hardness of simvastatin IR tablets remained within 4–6 kg/cm² and that of gliclazide SR tablets around 5.5–5.9 kg/cm², ensuring adequate mechanical strength and resistance to handling. Friability values for all formulations were below 1%, confirming good mechanical integrity and low tendency to crumble during processing and packaging.

The drug content of simvastatin across F1–F7 was within approximately 94.75–98.7%, whereas gliclazide content ranged from about 95.5 to 99.0% (**Table 10**). These values are in line with official acceptance limits, indicating uniform distribution of drug within the tablets and reproducible manufacturing. Overall, the precompression and postcompression evaluations confirmed that all formulations met the basic pharmaco?technical quality requirements.

Table5: post compression parameters for immediate release tablets (for Simvastatin)

Table6: post Compression parameters for floating tablets (for Gliclazide)

Table7: friability test (10 tablets).

Friability of the three brands was well within the tolerable range of (less than 1%) #### Disintegration and buoyancy behavior.

The disintegration times of simvastatin IR tablets are summarized in **Table 8**. All IR formulations disintegrated rapidly, within 35–50 seconds, which is markedly less than the pharmacopoeial limit for conventional tablets (≤30 minutes) and suitable for an immediate?release layer intended to provide rapid onset of action.

Table8: Disintegration Test

For the floating SR gliclazide layer, in vitro buoyancy parameters, including floating lag time (FLT) and total floating time (TFT), are presented in **Table 9**. The formulations exhibited short lag times and prolonged total floating times, indicating that the gas?generating system and polymer matrix were effective in maintaining buoyancy in acidic medium. The optimized formulation demonstrated a combination of acceptable lag time and extended floating duration, which is essential for gastro?retentive delivery and prolonged residence time in the upper gastrointestinal tract.

In addition, swelling studies further supported the ability of the hydrophilic polymer matrix to absorb water, swell and form a gel barrier, which contributes to both floating behavior and controlled drug release. The gradual increase in tablet weight over time correlated with the hydration and gel layer formation of the polymeric matrix.

2.2.9. In vitro Dissolution studies:

Table9: Lag Time and Floating Time

Table 10: Assay

In vitro dissolution of simvastatin immediate?release layer

The in vitro drug release profiles of simvastatin IR formulations (F1–F7) were evaluated using 0.1 N HCl as dissolution medium, and the cumulative percentage of drug released over time is shown in **Table 11** and **Figure 1**. All formulations exhibited rapid drug release, with more than 80% of simvastatin released within the first 30–60 minutes.

Among the tested formulations, F6 showed the most favorable dissolution behavior, reaching approximately 99% cumulative release by 60 minutes and meeting pharmacopoeial requirements. The rapid disintegration and high release rate of F6 can be attributed to the optimized levels of hydrophilic binder (povidone) and superdisintegrant (sodium starch glycolate), which enhance water uptake, swelling and tablet breakup. Based on its superior dissolution profile and short disintegration time, F6 was selected as the optimized simvastatin IR formulation for incorporation into the bilayer tablet.

In vitro dissolution of gliclazide sustained?release floating layer

The dissolution profiles of gliclazide SR floating formulations (F1–F7) are presented in **Table 12** and **Figure 2**. The formulations were designed to provide sustained drug release over 12 hours in 0.1 N HCl. The cumulative drug release after 12 hours ranged from approximately 90.5% to 99.63% among the different formulations.

Formulation F7, which contained a specific combination of hydroxypropyl methylcellulose (HPMC), guar gum and ethyl cellulose, provided a desirable sustained?release profile, with about 99.63% of gliclazide released at 12 hours. The combination of hydrophilic (HPMC, guar gum) and hydrophobic (ethyl cellulose) polymers effectively controlled water penetration, matrix swelling and erosion, thereby modulating the drug release rate. Compared with formulations containing single polymers, the ternary combination in F7 produced more extended and controlled release, making it the optimized SR formulation for further bilayer tablet development.

Dissolution of bilayer tablets and comparison with marketed product

The dissolution behavior of the optimized bilayer tablet, containing F6 as the simvastatin IR layer and F7 as the gliclazide SR floating layer, is summarized in **Table 13** and illustrated in **Figure 11**. The bilayer tablet provided rapid release of simvastatin, with about 94.7% released within 15 minutes and almost complete drug release within 30 minutes, consistent with the performance of the single?layer IR formulation.

In contrast, gliclazide release from the bilayer tablet was sustained over 12 hours, with cumulative release values closely matching those of the optimized SR layer alone. The bilayer system thus successfully combined rapid onset of action for simvastatin with prolonged gliclazide release in a single dosage form.

The dissolution profile of the optimized bilayer formulation was compared with that of a marketed fixed?dose combination product, and the data are shown in **Table 14**. The bilayer tablet exhibited a release pattern for both simvastatin and gliclazide that was comparable to the marketed product over 12 hours, indicating that the developed formulation can achieve similar therapeutic performance while offering the advantages of a bilayer design and floating gastro?retentive behavior for the gliclazide layer.

Figure 1: cumulative % drug release dissolution profile for simvastatin.

Figure 2: cumulative % drug release dissolution graph for floating layer formulations of Gliclazide.

Figure 11: cumulative % drug release dissolution graph for bilayer tablets.

To elucidate the mechanism of drug release from the bilayer tablets, the dissolution data for gliclazide were fitted to various kinetic models, including zero?order, first?order, Higuchi, Korsmeyer–Peppas and Hixson–Crowell models. The calculated parameters and correlation coefficients (R²) are summarized in the kinetic data table and corresponding plots (**Figures 3–7**).

The release profiles showed good linearity with the Higuchi model, indicating that diffusion through a hydrated polymeric matrix was a major mechanism governing drug release. The Korsmeyer–Peppas analysis yielded an exponent (n) consistent with anomalous (non?Fickian) transport, suggesting that both diffusion and matrix relaxation (swelling/erosion) contributed to the overall release process. The Hixson–Crowell model also provided a reasonable fit, implying that changes in surface area and tablet geometry during dissolution may play a role. Collectively, these kinetic analyses confirm that the gliclazide SR layer of the bilayer tablet provides controlled, diffusion?driven drug release over an extended period.

Figure 3: Cumulative % Drug Release (Zero Order Release Kinetics)

Figure 4: Cumulative % Drug Release (First Order Release Kinetics)

Figure 5: Cumulative % Drug Release (Higuchi Diffusion Kinetics)

Figure 6:  cumulative % drug release (Korsmeyer Peppas equation)

Figure 7: Cumulative % Drug Release (Hixson Crowell Cube Root Equation)

Stability studies

The optimized bilayer formulation was subjected to accelerated stability testing at 40 ± 2 °C and 75 ± 5% relative humidity for up to six months, according to ICH guidelines. The results are summarized in **Table 16**. No significant changes were observed in physical appearance, floating behavior, disintegration time, assay values or dissolution profiles for either simvastatin or gliclazide throughout the study period. Drug content for both active ingredients remained within acceptable limits, and the in vitro release profiles after storage were comparable to the initial profiles, indicating that the formulation is stable under accelerated conditions. These findings support the suitability of the developed bilayer tablets for long?term storage without marked loss of quality or performance.