Formulation And Evaluation of Effervescent Based Gastro Retentive Floating Tablets of Nifedipine

Oral administration represents the most adaptable, convenient, and widely utilized method for delivering drugs intended for systemic effect. Recently, there has been a growing interest in oral controlled release drug delivery system within the pharmaceutical sector, aimed at enhancing therapeutic benefits such as ease of administration. Patient adherence, and formulation flexibility.^{2 3} A controlled drug delivery system that ensure an extended residence time in the stomach is particularly advantageous for medication that are locally active in the stomach, have a narrow absorption window within the gastrointestinal tract, are primarily absorb in the stomach and upper gastrointestinal tract, are unstable in the intestinal or colonic environment disrupt normal colonic microbiota and demonstrate low solubility at elevated pH levels. The retention of solid dosage forms in the stomach can be achieved through floating systems, which allow gastro-retentive dosage forms to remain in the gastric region for several hours, thereby significantly extending the gastric residence time of the drugs. This prolonged gastric retention enhance bioavailability, minimize drug wastage and improves the solubility of drug that are less soluble in high pH condition. Gastroretention facilities better availability of new products with appropriate therapeutic efficacy, offering substantial advantages for patients. Nifedipine, a selective calcium channel blocker, is utilized in the treatment of vasospastic angina, chronic stable angina, hypertension and reynaud`s phenomenon. It exhibits poor water solubility and high permeability, classified as Class II drug according to the biopharmaceutics classification system.^{13 17 1} The oral absorption of nifedipine is characterized as uniform, rapid and completed with a bioavailability of approximately 45-50% and an elimination half-life pf 2 to 4hours, necessitating dosing two to three times daily for many patients, which often results in non compliance. The development of floating (effervescent technology) nifedipine tablets involved the direct compression of natural polymers and the resulting formulation were assessed for a number of physico-chemical properties. These administration method helps to improve the sustained delivery of drugs with an absorption window in a specific area of the gastrointestinal tract by keeping them in the stomach. By constantly releasing the medication before it enters the absorption window, these system contribute to the best possible bioavailability, Additionally, the formulation is an economical procedure. ^{12 15 16}

Drug Profile:

Drug name: Nifedipine

Chemical structure:

        <a href="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250510185133-10.png" target="_blank">
            <img alt="1.png" height="150" src="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250510185133-10.png" width="150">
        </a>
Chemical Name : 3,5-dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-      dihydropyridine-3,5-dicarboxylate.

Chemical Formula : C17H18NO6

Molecular Weight :346.335g/mol.

Controlled drug delivery systems :

Regulate medication delivery methods in order to maintain the length of therapeutic activity, target the distribution of the medication to a tissue,  and or control the rate of drug as administration, controlled drug delivery systems have been created. In the medicine is given in repeated doses since nifedipine undergoes hepatic metabolism, which result in a very poor bioavailability (40-56%) and short half-life(2hour). Nifedipine is therefore best prepared as intragastric floating tablets to increase its bioavailability and lower its dosage.^{21 28 31}

 Floating system :

 Floating mechanism since their bulk density is lower than that of gastric fluids, floating drug delivery system (FDDS)float in the stomach without slowing down the rate of gastric emptying. While the body is floating on the content of the stomach , the medication is gradually removed from the system at the appropriate rate.^{22 26 4} Drug release 8 is followed by the emptying of the stomachs residual system. 

METHODOLOGY:

Formulation of Nifedipine Floating Tablets:   

In the presence of sodium bicarbonate was utilized as an effervescent gas-generating agent. At the optimized concentration of sodium bicarbonate(15mg), floating granules of nifedipine were prepared using various concentration of different grades of polymers, as detailed in Table 1. The drug and all other components were individually passed through a sieve #60 and thoroughly mixed by triturating for up to 15 minutes.^{7 8} The resulting powder mixture was lubricated with talc. The powder was then compressed using a direct compression method with a 7mm tablet punch. Six distinct formulation of tablets were created with varying concentration of different polymers. Based on subsequent physicochemical evaluation and in vitro drug release studies, the optimal formulation were identified.^{5 6} 

Formulation development of tablets :

Table 1. The Formulation Of different formulation F1-F6(mg/tablet)

Analytical Method: 

Standard calibration curve of Nifedipine was taken in simulated Gastric fluid (PH1.2) at 238nm. ^{9 10}

Table 1: Observation for graph of nifedipine in 0.1 N HCL

        <a href="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250510185133-9.png" target="_blank">
            <img alt="Standard graph of nifedipine in 0.1N HCL.png" height="150" src="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250510185133-9.png" width="150">
        </a>
Figure 1: Standard graph of nifedipine in 0.1N HCL

 Drug – excipient compatibility studies:

Fourier transform – infrared spectroscopy

        <a href="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250510185133-8.png" target="_blank">
            <img alt="nifedipine.png" height="150" src="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250510185133-8.png" width="150">
        </a>
 Figure 2: nifedipine

From the FTIR data it was evident that the dug and excipients does not have any interactions. Hence they were compatible . 

Precompression Parameters:

The quality of tablet, once formulated according to established guidelines, is primarily influenced by the physiochemical properties of the blends, which are assessed in accordance with pharmacopoeia standards prior to compression. ^{11 14 18}The formulation powder blends undergo evaluation for both bulk and tapped density, from which the compressibility index and hausner`s ratio are derived.Additionally ,the flow characteristics of the powder blend are determined through the angle of repose.^{19 20}

Bulk Density: 

Density is defined as the mass per unit volume. bulk density refers to the mass of the powder divided by its bulk volume, expressed in gm/cm³. The bulk density of a powder is largely influenced by the factors such as particle size distribution, particle shape, and the tendency of particles to clump together, the calculation for bulk density is given by formula : bulk density = M/V_0, where M represents the weight of the sample and V₀ denotes the apparent volume of the powder ^{23 24}. At 10 gm powder blend was sieved and placed into a dry 20mL cylinder without compaction . The powder was carefully leveled without compressing it, and the unsettled apparent volume, V₀, was recorded.²⁷

Tapped Density:

Following procedure for measuring bulk density, the cylinder containing the sample was subjected to tapping using a mechanical tapped density tester, which deliver 100 taps per minute. This process was continued until the difference between consecutive measurement was less than 2%. The tapped volume, V, was then measured to the nearest graduated unit.^{36 41} Tapped density was calculated in gm per L using the formula: Tapped Density=M/V, where M is the weight of the sample and V is the tapped volume of the powder.³⁰

 Measures of Powder Compressibility:

The Compressibility index, also known as Carr`s index, quantifies the tendency of a powder to be compressed. Materials with poorer flow characteristics typically exhibit stronger interparticle interaction, resulting in a more significant disparity between bulk and tapped densities.<sup>43 33</sup> The variation are evident in the compressibility index, which is determined using the formula: Carr`s index= [(tap – b)/tap]x 100, where b represent Bulk density and Tao denotes Tapped density.

The Angle of Repose:

The frictional force present in loose powder can be quantified by the angle of repose. The fixed funnel method was utilized for this measurement. A funnel was positioned with its tips at a specific height(h) above a sheet of graph paper placed on a level surface. The powder blend was carefully poured through the funnel until the peak of the conical pile made contact with the funnel`s tip. The radius(r) of the base of the conical pile was then measured. The angle of repose is calculated as follow: TanØ=h/r, where h is the height of the cone and r is the radius of the cone`s base.⁴⁴      

Post Evaluation Of Prepared Nifedipine Floating Tablets:

The quality control of the prepared tablets was assessed through various tests, including weight variation, tablet thickness, hardness, friability, assay, in vitro buoyancy, and vitro drug release studies.

Weight Variation :

A random selection of ten tablets from each batch was weighed individually to determine the average weight. ^{32 38 39}The individual weight were then compared to this average, allowing for the calculation of the percentage weight difference, which was subsequently evaluated against USP specification.   

Hardness and Friability :

The hardness of the tablets was measured using a Monsanto hardness tester. Ten tablets from each batch were randomly selected for this analysis, and both the mean and standard deviation were calculated. The firability test was performed using a Roche friabilator, where ten tablets were weighed and subjected to a combination of attrition and shocked within a plastic chamber that rotates at 25 rpm, dropping the tablets from a height of 6 inches with each revolution.^{34 35 37} After 100 revolutions, the tablets were cleaned of dust and reweighed to calculated the percentage of friability.  

Tablet Dimensions :

The thickness and diameter of the tablet were measured with calibrated dial calipers. Three tablets from each formulation were randomly chosen for this measurement , and the dimensions were recorded in millimeters ,along with the standard deviations. ⁴⁰

Determination of Drug Content:

The drug content of the compression – coated tablets was evaluated by finely powdering ten tablets . an amount of powder equivalent to the weight of one tablet of nifedipine was accurately weighed and transferred to a100mL. volumetric flask containing 50mL of water. The mixture was allowed to stand to ensure complete dissolution of the drug, after which the volume was adjusted to 100mL with water. ⁴²The solution was appropriately diluted, and the absorption was measured using a UV visible spectrophotometer. The drug concentration was then determined from the calibration curve. ^{45 46}

 In vitro Buoyancy Assessments: 

The assessment of in vitro buoyancy was conducted by measuring the floating lag time, following the methodology outlined by Rosa et al. Tablets were immersed in a 250mLbeaker containing 200mLof 0.1 N HCL . the duration taken for the tablet to ascend to the surface and achieve flotation was recorded as the floating lag time (FLT) ^{9 5}, while duration for which the tablet remained buoyant was noted as the total floating time(TFT).

In vitro Dissolution Assessments :

The in vitro dissolution assessment was carried out utilizing a united states pharmacopeia (USP) type ll (paddle) apparatus ,operating at a rotational speed of 100rpm . A total of 900mLof 0.1N HCL served as the dissolution medium , with the temperature maintained at 37 ± 0.5 ⁰C. At predetermined intervals over a 12-hour period , a 5mLsample was extracted from the dissolution apparatus , and an equivalent volume of prewarmed fresh dissolution medium was added to the volume.^{1 7} The samples were subsequently filtered through whatman filter paper (40µ) and diluted to an appropriate concentration with 0.1 N HCL. Absorbance of these solutions was measured at 238nm using UV spectrophotometer.^{4 3}

RESULTS AND DISCUSSION:   

This study focuses on nifedipine , a calcium channel blocker commonly prescribed for angina and Raynaud`s syndrome. Nifedipine has been identified as a promising candidate for reducing dosing frequency in solid oral controlled – release formulations , there by enhancing patients compliance in angina managements. Due to its poor solubility in water, efforts were made to enhance the drug`s solubility by incoperating various concentrations of natural gums. The aim was to develop gastroretentive floating tablets that would ensure a controlled and sustained release of the medication over a extended period. The preparation of nifedipine floating tablets involved dry blending of solubility modifiers to enhance the active drug`s solubility, along with varying concentrations of different polymers grades, sodium bicarbonate utilizing a direct compression technique.

Precompression Parameters  

The angel of repose measurements indicate that the powder blend exhibits favorable flow characteristics. The bulk density of all formulations ranged from  0.48 to 0.55 (gm/mL), further confirming the good flow properties of the powder.

Table 3: Preformulation parameter of powder blend.

The results of precompression evaluation parameters are displayed in (Table.3), and all formulations hand a tapped density in the range  0.56 to 0.65, indicating that the powder has good flow properties. The compressibility index of all formulations was found to be below 18, indicating that the powder has the good flow properties .

Quality Control Parameters for Tablets

 Tablet quality control tests such as weight variation, hardness, and friability, thickness, content and drug release studies were performed for floating tablets.

Table 4: Post compression parameters for tablets

The findings from the physiochemical characterizations are presented in  Table 4. The thickness of the tablets was assessed using a calibrated dial caliper. The average diameter and thickness of the tablets were consistent across all formulations, with measurements ranging from  3.3±0.156 to 3.4±0.130 mm, respectively. The standard deviation values suggest that all formulations maintained uniform thickness. The average weight for each formulation was documented, revealing consistency within the specification set by the USP. The weight of the tablets varied from 197 to 201mg. All tablets successfully passed the weight variations test, as the percentage weight variation remained within limit of ±2%. The hardness of the formulation ranged from 5.25±0.165 to 5.5±0.196 kg/cm². The standard deviation values indicate that the hardness across all formulation was relatively uniform, demonstrating adequate mechanical strength and hardness. The friability values for the prepared tablets are listed in table 3, with results ranging from 0.57% to 0.66%. All values are below 1%, indicating that the tablets from all formulations exhibits good compactness and sufficient resistance to mechanical shock and abrasion . Content uniformity was assessed for all 6 formulations, revealing that the percent drug content of the tablets ranged from 96.67% to 99.67% for nifedipine.

In Vitro Buoyancy Studies:

All intragastric floating tablet formulations were developed using an effervescent method. Upon immersion in a 0.1 N HCL solution at a Ph 1.2 and a temperature of 37±  0.5⁰C, all floating effervescent tablets floated immediately and remained buoyant for up to 7 hours without disintegrating. The in vitro buoyancy of the nifedipine tablets was achieved through the use of sodium bicarbonate, ensuring the integrity of matrix was maintained.

In Vitro Drug Release Studies : 

The xantan gum – prepared formulations had very little retardation capacity, they were disregarded. The F6 formulation was therefore deemed to be optimal formulation based on the above dissolution results because of its good release (91.98%) over a 7-hours period.

M8 Table 5: dissolution data of nifedipine tablets

        <a href="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250510185133-1.png" target="_blank">
            <img alt="In vitro drug release profile of formulation F1-F6.png" height="150" src="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250510185133-1.png" width="150">
        </a>
Figure 10: In vitro drug release profile of formulation F1-F6

CONCULSION:

The objective of developing gastroretentive floating drug delivery systems for nifedipine tablets is to ensure the drug`s therapeutics effect lasts for upto 7 hours. These gastro-retentive floating tablets were created using direct compression method, incoperating various natural polymers such as xanthan gum and gum tragacanth. The resulting formulation were assessed based on several criteria, including drug – excipients compatibility, weight variation, thickness, hess, content uniformity, in vitro buoyancy, and in vitro drug release studies conducted in 0.1N HCL over a period of 7 hours. Leading to the conculsion that formulation F6 exhibited the most favorable results. This study concludes that the gastro-retentive floating system may be an effective approach for the administration of nifedipine.