Development of a Robust Control Strategy for Fixed-Dose Combination Bilayer Tablets with Integrated Quality by Design, Statistical, and Process Analytical Technology Approach

Control strategy and quality by design (QbD) are widely used to develop pharmaceutical products and improve drug quality; however, studies on fixed-dose combination (FDC) bilayer tablets are limited. In this study, the bilayer tablet consisted of high-dose metformin HCl in a sustained-release layer and low-dose dapagliflozin l-proline in an immediate-release layer. The formulation and process of each layer were optimized using the QbD approach. A d-optimal mixture design and response surface design were applied to optimize critical material attributes and critical process parameters, respectively. The robust design space was developed using Monte Carlo simulations by evaluating the risk of uncertainty in the model predictions. Multivariate analysis showed that there were significant correlations among impeller speed, massing time, granule bulk density, and dissolution in the metformin HCl layer, and among roller pressure, ribbon density, and dissolution in the dapagliflozin l-proline layer. Process analytical technology (PAT) was used with in–line transmittance near-infrared spectroscopy to confirm the bulk and ribbon densities of the optimized bilayer tablet. Moreover, the in vitro drug release and in vivo pharmacokinetic studies showed that the optimized test drug was bioequivalent to the reference drug. This study suggested that integrated QbD, statistical, and PAT approaches can develop a robust control strategy for FDC bilayer tablets by implementing real-time release testing based on the relationships among various variables.

A REVIEW OF CHALLENGES AND POSSIBILITIES OF BILAYER TABLET TECHNOLOGY

Bilayer tablet making process involves certain challenges as well as advantages. Bilayer tablets are the prescriptions which comprise of two same or various medications consolidated in a solitary portion for viable treatment of the illness. Persistent consistence and cost measure are two significant boundaries in treatments. Bilayer tablets manage these focuses adequately. To deliver a decent quality bi-layer tablet, the apparatus should be built according to GMP. Different hardware are accessible to beat normal bi-layer issues, for example, layer detachment, lacking hardness, weight control, cross defilement between the layers and so forth. Bilayer tablets give one of the significant plan approaches where inconsistent medications, with an alternate sign, and same medication with various delivery rate can be combined in a solid unit. Bilayer tablet is reasonable for consecutive arrival of two medications in blend, and for supported delivery tablets in which one layer is promptly delivered as introductory portion and the subsequent layer is a controlled portion. Controlled delivery dose structures have been broadly used to improve treatment with a few significant medications. Utilization of bilayer tablet is an altogether different viewpoint for calming and pain relieving drugs. This review article clarifies what are the outcomes to be looked and how to be faced during bilayer tablet production.

Technologies in Bilayer Tablet Manufacturing: A Review

Bilayer tablet is a recent time for the successful development of controlled release formulation along with various quality to provide a way of the successful drug delivery system. Over the past 30 years stated that the cost and complications involved in marketing new drug entities have increased, with consequent recognition of therapeutic advantages of controlled drug delivery, greater attention has been concentration on development of sustained or controlled release drug delivery systems. Bilayer tablet it is used in the different aspect for anti-inflammatory and analgesic. Bilayer tablet incidental release of two drugs in combination, separate two incompatible substance and also for sustained release tablet in which one layer is immediate release as initial dose and second layer is maintenance dose. Bilayer tablet is enhancing beneficial technology to control the shortcoming of the single layered tablet. There is various application used in the bilayer tablets.

The Challenges of Producing Bilayer Tablet: A Review

Bilayer tablets are the advanced form of conventional immediate release tablet system, which consist of either two similar or different drugs combined in a single dose for effective treatment of the disease improving patient compliance. However, the multilayer tablet technology is demanding It also necessitates meticulous selection of excipients and manufacturing conditions for each technological stage. The aim of this review is to provide an outline of state of art of bilayer tablet technology and emphasise the difficulties experienced during Bilayer tablet manufacturing along with its intend solutions for these challenges. Keyword: Bilayer tablet, Conventional release, Challenges encountered, Compliance.

A REVIEW ON AN EMERGIN TREND BILAYER FLOATING DRUG DELIVERY SYSTEM

NDDS is advanced drug delivery system which improves drug potency, control drug release to give a sustained therapeutic effect, provide greater safety, finally it is to target a drug specifically to a desired tissue. Novel drug delivery system have been developed to overcome the limitation of conventional drug delivery systems, such as of gastric retention by decreasing fluctuations in the concentration of the drug in blood,resulting in the reduction in unwanted toxicity and poor efficiency. As compared to traditional dosage forms bilayer tablets are more efficient for sequential release of two drugs that can be different or identical. Bilayer tablet is also capable of separating two incompatible substances and also for sustained release. Gastro retentive drug delivery system retains the period of dosage forms in the stomach or upper gastro intes-tinal tract ,as to improve bioavailability and the therapeutic efficacy of the drugs. Mainly the bilayer drug delivery system is suitable for drugs whose therapethic windows are narrow in the gastrointestinal tract (GIT) and also they have low elimination half life: 3-4 h. The purpose of this review is to disclose the challenges faced during the formulation of bilayer tablets. Finally, the whole article is firmly analyzed in a concluding paragraph. KEYWORDS: Conventional drug delivery systems, Bilayer tablet, Gastro retentive, Bioavailability

Assessment of a Once-Daily Controlled-Release Ibuprofen Matrix Tablets Prepared Using Eudragit®E100/Carbopol®971P NF Polymers and Their Salts Combinations.

Introduction: Hydrophilic polymers that swell or dissolve in aqueous media can have the potential to prepare controlled/sustained dosage forms for weakly acidic, poorly soluble drugs. Objective: The main objective of this study is to utilize Eudragit®E100 (EE) and Carbopol®971P NF (Cp) polymers and their salt forms in the preparation of a once-daily controlled-release matrix tablet for model drug, Ibuprofen (IB). Methods: Combinations of the polymers in their base forms (EE)/(Cp) or their salt forms (EEHCl/CpNa) were compressed with (IB) into single layer matrix tablets, or otherwise into bilayer tablets. Dissolution profiles were constructed using three different consecutive stages (pH 1.2, 4.8, and 6.8). Result: It was found that the incorporation of (EEHCl) modified the release rates of (IB) from (Cp) based matrix tablets. However, a major enhancement of (IB) release rates occurred when the polymers were combined in their salt forms at a 1:1 ratio by weight. In addition, a bilayer tablet was prepared wherein a relatively rapidly disintegrating layer composed of polymers salts (EEHCl and CpNa), and a second layer containing only (Cp) polymer in its base form at a 1:2 weight ratio possessed excellent release properties, and mechanical strengths. Conclusion: It was concluded that the prepared bilayer tablet could be of promise use in controlling the release rates of (IB) in an extended manner to allow once-daily administration with an improved pH-independent release behavior.