**3. Layered tablets**

The layered tablet is a combination of one or more APIs (Active Pharmaceutical Ingredients) along with excipients, cast in two or more layers to form a single unit dosage form. Formulating a combination of drugs in a single dosage form is appreciated in the case of long-term therapy like parkinsonism [4]. The noticeable feature is that the drug is released without any pharmacokinetic interactions with individual release rate [5]. It can greatly help in minimizing the dosing frequency and can also add to the synergistic effect [6].

The ideal properties expected for a layered tablet include sufficient mechanical strength, better chemical, and physical stability, and no interaction between the layers. The layered tablets exhibit increased patient compliance as the dosing burden is reduced [7]. Layers of the tablet can provide multiple release kinetics of the same or different drugs of the same or different physicochemical properties and showcase different release control mechanisms [8]. Generally, when two or more drugs are co-administered, they might possess the ability to enhance the effect of each other. The layered tablets are the potential in offering such a synergistic effect [6, 9]. These layered tablets also confer high product identification, as the layers are usually of different colours and enable patients to identify the tablets at ease. This also contributes to the attractive appearance of the dosage form.

The bigger advantage is that dual release profiles are obtained in a single unit dosage form. One layer can promote immediate release while the other may contribute to controlled or sustained release [10]. It is very much possible to avoid active-active, active – excipient and excipient - excipient interactions. The cost of production is reduced to a greater extent as the production of two or more tablets is merged into one. It is time-saving and production-friendly.

Accurate dosing and minimized inter-unit variability make it a potential candidate. Low production cost helps in reducing health care expenditure. Ease of packing and handling are added advantages. For a patient under multiple drug regimens, it is easier to carry a single unit compared to multiple units. For drugs with bitter/ obnoxious taste, the oral route may be less preferred. This can be overcome by adapting various taste-masking techniques. Incompatibility is a serious issue when various drugs are administered together. Two incompatible drugs can be administered together by adding an inert layer between the active layers [8]. Fillers constitute a majority of a tablet. When two or more drugs are administered in a single dosage form, there is a possible reduction in the use of excipients like fillers. Layered tablets are very much preferred in case of multiple drug therapy and long-term care.

When it comes to the disadvantages, the weight of the tablet remains a major concern. With all the fillers and inert separating layers, weight adjustment of each layer during a continuous batch is difficult. The layers should have sufficient binding capacity to hold the formulation together. This requires high throughput planning and pre-formulation. Lack of binding of two or more layers and separation of layers. High labor input and equipment sophistication are necessary. Based on the active ingredients, layered tablets are classified as bi-layered tablets with a single active ingredient or bi-layered with two different active ingredients. Tri-layered tablets have three different active ingredients. Based on formulation type, bi-layered tablets may contain one immediate release and another sustained-release layer; two immediate layers; one sustained release and another inert supporting layer; one sustained-release and another inert protecting layer.

### **4. Release aspect**

These bi-layered to multi-layered tablets are formulated to achieve desired release kinetics such as immediate-release, controlled release based on time, pH and related factors, zero-order sustained release, etc. [11, 12]. Bi-layered tablets comprise an immediate-release layer and another extended-release layer. The immediate-release layer disintegrates immediately on reaching the GIT and releases a loading dose. While the other layer stays for a longer period in GIT and maintains drug plasma concentration. The hydrophobic/hydrophilic polymer matrix layer in layered tablets is used in controlling the drug release pattern by hydrophobic polymer coating over the hydrophilic matrix to attain sustained release, whereas one-sided coating aid in controlled release of the drug. In the case of a combined release strategy, initial rapid release followed by prolonged drug release is required to maintain stable plasma concentration. Bimodal release tablets show an initial rapid drug release, followed by slow release of the drug substance, then a third phase of rapid drug release, i.e., tablets exhibit sigmoidal release profiles [11, 13–15].
