Bilayer Tablets Research Articles

Composition and Drug Release Characteristics of Bi-layered and Multi-layered Tablets: A Comprehensive Review

Multilayer and Bilayer tablets are winning popularity over single-layer tablets because of their controlled release advantages. Since each layer of API must be compatible with the others and with excipients to extend the effects of the medication or drugs and improve patient compliance, technology for creating multilayers and bilayers is less widespread than that for single-layer tablets. Hydrophilic polymers are more frequently employed in the formulation of biliary and multilayer tablets as both medication carriers and release barriers. But the ratio of using polymer is different from each other in the drug barrier layer and carrier layer that can make alteration by a researcher to develop a difference in the release rate of different APIs in a single unit of the tablet. With a larger surface area and a faster rate of drug release over time, multilayer and biliary tablets can help mitigate the non-linearity and drug interactions that arise with diffusion-controlled matrix devices. This review article covers the different techniques used to create biliary and multilayered tablets as well as the challenges associated with their formulation. Keywords: Multi-layer tablets, Bi-layer tablets, Drug release, Tablet manufacturing

Implementation of Quality of Design for the Development of Bilayer Tablet

Different drug release properties for different drugs contained in each layer of a bilayer tablet are rarely achievable with regular tablets. Additionally, these tablets help avoid physicochemical incompatibilities between medications and excipients. The successful production of such more complicated dosage forms depends on screening the material qualities of APIs and excipients and optimizing the processing parameters of each unit operations of the manufacturing process. In order to meet safety and efficacy regulations, these operations need to be properly monitored and managed to produce a drug product with acceptable quality and performance. Blending, granulation, pre-compression, and main compression are critical stages when formulation qualities and production processes should be tuned to avoid problems like weight variation, segregation, and delamination of particular components. Bilayer tablets, as opposed to ordinary tablets, offer distinct drug release properties for certain medications that are housed in each layer. These tablets also help to avoid physicochemical incompatibilities between drugs and excipients. The successful manufacturing of such more complex dosage forms depends on screening the material attributes of API and excipients and optimizing the processing parameters of individual unit operations of the manufacturing process in order to achieve safon of layers, which is frequently encountered during the production of bilayer tablets. For the quality and performance of the medication product to be acceptable, these processes need to be properly watched over and managed. The main objective of this review is to establish the foundation for implementing the Quality by Design (QbD).

AN OVERVIEW OF 3D PRINTING TECHNOLOGIES FOCUSING MULTIDRUG-LOADED 3D PRINTED DOSAGE FORMS

Objective: This review focuses on multidrug-loaded dosage forms produced with three-dimensional printing (3DP) technologies since the confirmation of Spritam®, the first 3D printed dosage form, in 2015. Result and Discussion: The integration of multiple drugs within a single dosage form through 3DP offers substantial flexibility in design, allowing for the customization of dosage, drug release profiles, and geometric structures. These formulations offer significant design flexibility by combining different drugs in a single unit, and have the potential to optimize treatment strategies, especially for diseases requiring multiple drug use. The wide literature search reveals that the most commonly used method is Fused Deposition Modeling (FDM) to obtain 3D printed dosage forms with various geometries, such as multi-compartment capsules or tablets, bi-layered or multi-layered tablets exhibiting different release kinetics, and core/shell structured tablets. Multidrug-loaded 3D-printed dosage forms have significant potential for individualizing fixed-dose combinations and have become a promising tool for advancing personalized medicine and improving therapeutic outcomes for polypharmacy. This innovative approach can optimize therapeutic efficacy, reduce side effects, and improve patient compliance. As research continues to expand, these formulations represent a promising direction for the future of drug development and treatment strategies.

Release-modulating mechanism and comparative pharmacokinetics in beagle dogs of bethanechol-loaded oral dosage forms.

Bethanechol chloride (BTC), a quaternary ammonium compound used in bladder dysfunction treatment, requires challenges in developing optimal oral dosage forms due to its high water-solubility, short half-life, rapid elimination and four times a day administration. The aim of this study was to develop optimal BTC-loaded oral dosage forms that could provide both rapid onset and sustained therapeutic effects while reducing the frequency of conventional four-times-daily dosing (Mytonin® tablets). Four different BTC-loaded oral dosage forms were designed including gastro-retentive tablet (GRT), controlled-release tablet (CRT), bilayer tablet (BLT), and tablet-in-tablet (TIT). Then, release-modulating mechanism and in vivo pharmacokinetics in beagle dogs were compared. The release profiles of the four BTC-loaded dosage forms varied according to system design and formulation composition. The optimized GRT F-5 showed rapid buoyancy within 15 s and floated for 12 h, while continuously releasing the drug. CRT showed Fickian diffusion release, whereas BLT and TIT exhibited biphasic immediate and sustained release profiles. Polymer swelling behavior was analyzed using the Vergnaud model, where GRT F-5 and CRT showed n values < 0.5, confirming diffusion-controlled polymer hydration mechanism. In the instrumental analysis, the hydrogen bonding formation of BTC with release-modulating polymers, such as hydroxypropyl methylcellulose and polyethylene oxide and loosening of the polymer structure was crucial as the water influx increased. In pharmacokinetic studies in beagle dogs, the area under the plasma concentration-time curve (AUC) by normalizing dose for 48 h for GRT, CRT, BLT, and TIT were 90.2 %, 108.6 %, 83.8 %, and 76.4 %, respectively, compared with that of the reference drug (Mytonin® tablets, immediate release, four times a day). Interestingly, the plasma maximum concentration (Cmax) and AUC)0-12h of GRT F-5 and and Mytonin® tablets for the first 12-h period were much higher compared with that of other BTC-loaded CRT, BLT, and TIT. BTC was absorbed throughout the gastrointestinal tract, but is preferably absorbed in the stomach and upper intestinal sites. However, the GRT F-5 could provide more therapeutic potential for improving patient compliance in bladder dysfunction treatment by achieving both rapid onset and sustained drug release with reduced dosing frequency.

Selective laser sintering for printing bilayer tablets.

In this study Selective Laser Sintering (SLS) was used to produce bilayer tablets containing rosuvastatin and acetylsalicylic acid. Initially, monolithic tablets of each drug were manufactured using different laser intensities in order to identify their impact on the tablet's dissolution, friability and hardness. After the optimization, the final bilayer tablet was fabricated using a new method, that allowed the printing using different powder blends. For that, a 3D-printed casing was employed to maintain the compartments of the tablet in the correct position during the printing process. The results demonstrated that the increased laser intensities led to denser inner cores, enhanced hardness, decreased friability, and slower drug release. Moreover, the new method was able to produce bilayer tablets completely aligned, showing a minor impact on dissolution when the two compartments were printed together in a single tablet. The work demonstrated the feasibility of using SLS in the production of multi-material drug delivery systems.

The impact of volume of dissolution medium for biopredictive dissolution/permeation studies of enabling formulations: A comparison of two brands of telmisartan / amlodipine tablets.

For compendial dissolution testing of solid dosage forms, media volumes of 500 to 900 mL are used in apparatus I and II to ensure sink conditions. However, these volumes are considerably larger than those in the gastrointestinal tract. Thus, the experiments are not biomimetic and possibly not suitable for biopredictive dissolution testing. The present study investigates the influence of volumes of dissolution media in non-compendial dissolution/permeation settings. Dissolution/permeation studies of two commercial bilayer tablets (Twynsta® and Arrow) containing the active pharmaceutical ingredients telmisartan (40 mg) and amlodipine (10 mg) were evaluated using the MacroFlux tool with various biomimetic media mimicking fasted and fed states as well as biological variability ("biorelevant"). Particularly, the two-stage dissolution process of telmisartan from the tablets is interesting because the compound has a pH-dependent solubility, and 2-stage dissolution leads to supersaturation and precipitation upon pH shift. For telmisartan, lower dissolution volumes significantly induced precipitation, leading to lower permeation, while no precipitation was observed in the larger volume. The permeation of telmisartan was overly sensitive to both pH and micelle concentrations in the biomimetic media. Amlodipine showed complete dissolution under any conditions, which correlates with its known complete absorption in vivo. In conclusion, volumes of dissolution media (and their compositions) are key parameters and play a significant role for designing relevant biomimetic experiments used to predict the bioavailability of supersaturating systems.

Design and Characterization of bimodal Release Formulation of Valsartan and Metformin hydrochloride

A cardiovascular diseaseis mainlyreason for one third of global deaths and which is a leading and increasing contributor to the global disease burden. Hypertension is another risk factor for heart disease and is the single most risk factor for stroke. Patients with diabetes are 2-4 times more likely suffering and/or die of coronary heart disease. The aim of the research investigation is to design and characterization of bilayer tablets for bimodal drug release. Valsartan is selected as a drug of choice for immediate release layer preparation and for sustained release layer preparation metformin hydrochloride was selected. Bilayer tablets were prepared by double compression procedure. Immediate release tablets are prepared by physical mixing procedure to improve the drug solubility. All the tablets were characterized by Differential scanning calorimetry, Fourier transform infrared, X-Ray diffraction, Scanning electron microscopy. Among the three immediate release formulations IF2 containing 4% sodium starch glycolate shows 84.46% drug release in 30 mins and 99.69% drug release in 1hr. Among all the six sustained release formulations SF3 shows 99.76±0.9% drug release for an extended period up to 12hrs. Both optimized layers were considered to formulate bilayer tablets by direct compression technique. From the results it was concluded that combination dosage form can be achieved by bilayer tablet, the prepared bilayer tablet containing 4% SSG shows immediate action with improved oral bioavailability from IR layer and 16% hydroxy propyl methyl cellulose K100 shows drug release for prolonged period of time with improved bioavailability.

Formulation and Evaluation of Bilayer Tablets of Granisetron HCl and Ibuprofen for the Treatment of Migraine

Background of the Topic: The major purpose of this study was to produce a bilayer pill that contained Granisetron HCl (GSH) and ibuprofen (IBF) in distinct layers to minimize the possibility of adverse drug interactions and maximize the efficacy of both medications when they were combined to treat the symptoms of migraines. In contrast to the IBF layer, the GSH layer was intended to have a more gradual release of its contents. Methods: Microcrystalline cellulose, sodium starch glycolate, and croscarmellose sodium were the chemicals used to create the rapid-release layer. Isopropyl alcohol, magnesium stearate, and HPMC K 4M were among the polymers and gums that were used in the process of producing the continuous release layer. First, the fine-tuning process was performed on the tablet's two layers. After that, the layers necessary for quick as well as extended-release were put together. There were no adverse reactions caused by the active components interacting with the excipients. The rate at which a medicine is absorbed into the body may be sped up by using Croscarmellose sodium in a formulation. Results: A combination is given a delayed release influence by the addition of HPMC K 4M. The bilayer tablet forms from the improved (IR-4) batch were found to have strong linearity as shown by the regression coefficient of 0.9773, which is a first-order equation. According to the results, a bilayer pill that has both an increased IR-4 GSH immediate release layer and an SR-5 IBF sustained release layer would be an effective way to treat migraines. Conclusion: Bilayer tablets with releasing qualities provide a wide variety of benefits, some of which include the ability to localize medication administration, enhanced absorption, and improved effectiveness.

Formulation and Evaluation of Extended-Release Bilayer Tablets Containing Empagliflozin and Metformin Hydrochloride for Diabetes Mellitus Management

Formulation and Evaluation of Extended-Release Bilayer Tablets Containing Empagliflozin and Metformin Hydrochloride for Diabetes Mellitus Management

Formulation and Evaluation of Gastroretentive Bilayer Tablets

Gastroretentive bilayer tablets were designed to prolong the gastric residence time after oral administration and to achieve immediate release of lansoprazole and controlled release floating layer of clarithromycin to treat gastric ulcers. Instant release layer has a combination of super disintegrating agents. A combination of effervescent mechanism is used. HPMC K5 was used as swelling polymer and citric acid, sodium bicarbonate as gas generating agent to reduce the floating lag time. Bilayer floating tablets were prepared with varying proportions of instant layer and sustained release floating approaches. The prepared formulations were evaluated for various tablet and floating parameters. Tablet properties were found to be within the limits according to procedures prescribed in USP. They had a floating lag time around 3-7 seconds and floating time more than 24 hours. The cumulative % drug release in simulated gastric fluids after 10 hours was 70% - 95%. The mechanism of drug release was analyzed by fitting the release data into various kinetic models. It was found that all the formulations best fit the Higuchi’s model. Keywords: Gastroretentive drug delivery system; Bilayer tables, Instant release layer, Floating layer, Lansoprazole, Clarithromycin.

Understanding Excipient-Induced Crystallization of Spray-Dried Amorphous Solid Dispersion

This study investigates the compatibility of excipients with the model system SDI-X and their role in the induced crystallization of the amorphous compound-X in tablet formulations. We aimed to establish a straightforward and practical screening approach for evaluating excipient-induced crystallization of SDI in tablet matrices. Three methodologies—binary powder mixture, binary compact, and bilayer tablets—were employed to qualitatively and quantitatively evaluate the recrystallization of SDI-X with various excipients under accelerated storage conditions. The results demonstrated that binary compacts, providing direct physical contact between SDI-X and excipients, are superior in reflecting realistic drug-excipient contact within pharmaceutical tablets, enabling a more accurate assessment of excipient-induced crystallization for SDI-X. In contrast, the broadly used conventional binary blends can significantly underestimate this risk due to insufficient proximity. In addition, the bilayer tablets further confirmed that crystallization initiates at the contact surface between SDI-X and the excipients. The study highlighted that not only hygroscopicity but also the type of excipient and its physical contact with SDI-X significantly influence the recrystallization extent and rate of SDI-X. Interestingly, less hygroscopic diluents such as mannitol and lactose induced much higher levels of crystallization of SDIs, contrary to expectations based on moisture content alone. This suggests that the excipient type and contact surface are more critical in inducing recrystallization than just the level of moisture. The findings emphasize the need for careful excipient selection, study design, and sample preparation to enable appropriate assessments of SDI-excipient compatibility.

Formulation and development of bilayer tablet containing irbesartan and metformin hydrochloride for diabetic hypertensive patients

Background: Hypertension is a common complication of type II diabetes. The present research work aimed to develop bilayer tablets that would manage type II diabetes patients with hypertension. The prepared bilayer tablet has an immediate-release layer of anti-hypertensive irbesartan and a sustained-release (SR) layer of anti-diabetic metformin hydrochloride. The purpose of these bilayer tablets was to increase patient compliance by converting two separate monotherapy to single combination therapy. Methodology: Several ratios of polymers, including HPMC K100M, EC, Eudragit, and Guar gum, were employed to prolong the drug release for twelve hours. An immediate-release layer of irbesartan was prepared by spherical agglomeration. The physical properties, drug content, solubility profiles, release kinetics, and stability of prepared bilayer tablets were assessed. Results and Discussion: The examination of SR granules and bilayer tablets revealed outstanding packing qualities and excellent flow properties, with bulk and tapped densities ranging from 0.39-0.46 g/cm³ and 0.42-0.55 g/cm³, respectively. In vitro dissolution tests revealed that the immediate-release layer gave an initial burst of Irbesartan. Still, the sustained-release layer of metformin showed controlled drug release over 12 hours at greater polymer concentrations. According to stability testing, the bilayer tablets' physical properties, drug content, and dissolving profiles did not change significantly. Conclusion: The bilayer tablet combination of Irbesartan and Metformin exhibited desired physical features, controlled drug release, and stability. This formulation represents a viable treatment option for diabetic hypertensive patients, offering effective and consistent management of both disorders while improving patient compliance.

Quality by design-based development and in vitro evaluation of dual release tablet of etoricoxib and thiocolchicoside: A novel chronotherapeutic approach for arthritis pain management

The traditional drug delivery system is not much effective when treating chronopathological diseases like arthritis. Consequently, there is a gap in the market for a delivery system that can provide an explicit treatment following the chronopharmacology of this disorder. The present study is based on the objective to develop Eudragit coated dual release bilayer tablet designed by the quality by design (QbD) and based on the chronotherapeutic approach. The dual release tablet contained an immediate release layer of etoricoxib and a sustained release layer of thiocolchicoside. The quality target product profile (QTTP) of the formulation was established along with critical quality attributes (CQA). The optimization of the dual release layer was done using a three-level, three-factor Box-Behnken design. A total of thirteen formulations of etoricoxib (ET1-ET13) and thiocolchicoside (TH1-TH13) were developed based on the design composition of etoricoxib, sodium starch glycolate and sodium bicarbonate for the immediate release (IR) layer and thiocolchicoside, HPMC E5 LV and magnesium stearate for the sustained release (SR) layer respectively. The developed dual release layers were compressed to form a bilayer tablet. The bilayer tablets were further coated with pH-dependent polymer Eudragit S-100 to avoid drug release in upper GIT. The initial characterization and drug-excipient interaction studies were performed initially using infra-red (IR) spectroscopy and X-ray diffraction studies (XRD). Formulations showing good micrometric properties, disintegration and drug release were selected for final compression of bilayer tablets. Formulation ET13 showed the fastest drug release (88%) at 15minutes and quick disintegration time (21s). The sustained release thiocolchicoside tablet layer (TH1-TH13) had a hardness that varied from 4.01 to 4.45kg/cm2. Formulation TH12 had the highest hardness, whereas TH6 showed the lowest hardness. The sustained release layer showing 97.63% of drug release after 8hours was selected for the compression to bilayer tablet. The developed dual layer tablets were investigated for quality parameters like hardness, percentage friability, weight variation, disintegration and dissolution. A high level of patient compliance is ensured through the current design as the patient does not need to get out of bed at night to take the medication.

Tandem Queue and Its Applications in the Production of Bi-layer Tablets

Tandem Queue and Its Applications in the Production of Bi-layer Tablets

Design and evaluation of oseltamivir phosphate dual-phase extended-release tablets for the treatment of influenza

In this study, once-daily extended-release tablets with dual-phase release of oseltamivir phosphate were developed for the treatment of influenza. The goal was to improve patient adherence and offer more therapeutic choices. The tablets were manufactured using wet granulation, bilayer tablet compression, and enteric membrane-controlled coating processes. Various polymers, such as hydroxypropyl methylcellulose (HPMC K100MCR, K15MCR, K4MCR, K100LV), enteric polymers (HPMC AS-LF, Eudragit L100-55) and membrane-controlled polymers (OPADRY® CA), were used either individually or in combination with other common excipients. The formulations include enteric-coated extended-release tablet (F1), hydrophilic matrix extended-release tablet (F2), semipermeable membrane-controlled release tablet (F3) and a combination extended-release tablet containing both enteric and hydrophilic matrix (F4). The in vitro drug release profile of each formulation was fitted to the first-order model, and the Ritger-Peppas model suggested that Fickian diffusion was the primary mechanism for drug release. Comparative bioequivalence studies with Tamiflu® (oseltamivir phosphate) capsules revealed that formulations F1, F2, and F3 did not achieve bioequivalence. However, under fed conditions, formulation F4 achieved bioequivalence with a relative bioavailability of 95.30% (90% CI, 88.83%-102.15%). This suggests that the formulation F4 tablet could potentially be a new treatment option for patients with influenza.

Formulation and evaluation of floating bilayer tablet of Aceclofenac and Esomeprazole

Formulation and evaluation of floating bilayer tablet of Aceclofenac and Esomeprazole

Formulation and Evaluation of Bi-Layered Tablet of Divalproex Sodium

Formulation and Evaluation of Bi-Layered Tablet of Divalproex Sodium

Chitosan-based buccal mucoadhesive bilayer tablets enhance the bioavailability of tizanidine hydrochloride by bypassing the first-pass metabolism

Tizanidine hydrochloride (TZN) is an antimuscarinic agent used in the treatment of pain-related spasms, multiple sclerosis, and stroke-related spasticity. It has low oral bioavailability (40 %) due to excessive first-pass metabolism in the liver. The aim of this project was to enhance the systemic bioavailability of TZN by developing buccal mucoadhesive bilayer tablet formulations using chitosan salts with molecular weights of 136 kDa (7 cP) and 169 kDa (10 cP). Structural characterisation of chitosans and their salts was performed by FTIR, 1H NMR, DSC, TGA, and XRD analyses. Soluble chitosan salts, chitosan glutamate and chitosan chloride, for the adhesive layer, and insoluble ethyl cellulose for the impermeable backing layer were selected as polymers to fabricate the buccal tablets by direct compression method. The tablets containing TZN demonstrated high swelling and good mucoadhesion characteristics as well as released all the drug within 8 h. While TC10, formulated with 10 cP chitosan chloride, showed the highest swelling properties, TG10, prepared with 10 cP chitosan glutamate, exhibited the highest mucoadhesion. Chitosan glutamate tablets (TG7 and TG10) demonstrated better mucoadhesive characteristics and stability than chitosan chloride ones (TC7 and TC10) in the buccal medium based on the results of swelling and drug release studies. The permeability studies performed by Franz diffusion cell demonstrated that the amount of TZN passing through the bovine buccal mucosa was between 13.4 and 14.4 %. Stability studies conducted at 5 ± 2 °C, 25 ± 2 °C and 40 ± 2 °C for 6 months showed that no changes in the content uniformity and pH were observed. The in vivo comparative bioavailability studies in female New Zealand rabbits were performed and TZN-containing buccal mucoadhesive bilayer tablets fabricated with both chloride (TC10) and glutamate (TG10) salts of chitosan demonstrated three times higher bioavailability than the commercial TZN product (Sirdalud® oral tablet) administered by the gastrointestinal route.

Optimization and evaluation of bilayer tablet of probenecid

The main objective of my research work is to develop a bilayer tablet of Probenecid, in which one layer is immediate layer for immediate action and second layer is the sustain release layer for maintaining the dose of the drug. Probenecid is frequently administered up to 3 times in a day. So, the reducing dosing frequency by sustained release tablet.

IN VIVO EVALUATION OF OPTIMIZED FORMULATION OF DAPAGLIFLOZIN AND SAXAGLIPTIN BILAYERED TABLETS

Combining dapagliflozin and saxagliptin presents a promising strategy for managing type 2 diabetes mellitus by leveraging their distinct, yet complementary, mechanisms of action. A novel bilayer tablet with a 5 mg sustained release layer of saxagliptin and a 10 mg immediate release layer of dapagliflozin was developed. Live animal studies (in vivo) were conducted on rabbits to evaluate the effects of an optimized formulation. Based on in vivo performance, the novel bilayer tablets demonstrated greater bioavailability. A new, easy-to-use technique was created to simultaneously measure the two drugs (dapagliflozin and saxagliptin) in rabbit blood plasma. Evaluation of the technique’s parameters were done on rabbit plasma in accordance with ICH guidelines. The parameters for pharmacokinetic analysis were (AUC0-∞), (Cmax), Tmax and others. Direct calculations of the Cmax and Tmax were made using experimental plasma concentration versus time data. The AUC0-∞ was produced by adding the computed AUC0-24h using the trapezoidal rule. Using sample analysis of variance or independent sample t tests, average data variation was compared (one way analysis of variance). Statistical significance (p=0.05) was assessed using a 95% confidence interval.