Sharareh Salar-Behzadi is principal scientist atResearch Center Pharmaceutical Engineering (RCPE)GmbH, Graz, Austria.

Sharareh Salar-Behzadi

The gluing pills technology has recently been developed for the manufacturing of multilayer tablets by compressing single layers separately and joining them together using approved pharmaceutical excipients as a gluing agent. 

	This novel technology was developed in response to challenges involved in conventional manufacturing of multilayer tablets, including in-line control of the tablet weight, the tendency to delamination, direct contact between the two tablet layers, and cross contamination. The technology can easily be implemented on miniaturized equipment with reduced footprint for real-time production of individualized fixed-dose combinations and applied to both translational pharmaceutics and personalized medicine.

	The aim of the gluing pills technology (GPT) is to offer solutions to the increasing demand for flexible fixed-dose combinations (FDC) for improving patient adherence to therapy. A high level of patient adherence is a major success factor in the development of effective and cost-saving therapeutic strategies, especially for complex disease states that require polypharmacy such as cardiovascular diseases, pain therapy in cancer patients, metabolic diseases (e.g., diabetes mellitus type 2), HIV/AIDS, and multidrug-resistant infections.

	The most widely used FDC dosage forms are multilayer tablets. The development of multilayer tablets also suits life-cycle management (LCM) of pharmaceutical products. In addition to the conventional purpose of multilayer tablets, which is to have different APIs in different layers (e.g., to avoid stability problems), this dosage form can also be designed with the same API in the layers but with each layer having a different API release profile. 

	Currently, the established manufacturing technology for multilayer tablets poses substantial challenges. Multilayer tablets are typically produced via rotary tablet presses. Raw materials supplied as powders or granules are filled into a die separately and compacted either simultaneously or consecutively. Both methods have drawbacks. First, weight control via tablet thickness or compression force measurement is rather complex. Moreover, the adhesion of layers is often complicated by an elastic-modulus mismatch between the layers. These effects can lead to improper layer weights or layer ratios, as well as delamination. Relatively low production efficiencies and high rejection rates are unfavorable consequences. Additionally, the cross contamination of incompatible APIs and the missing of a clear boundary layer can pose a problem (1).

	A novel technology for manufacturing multilayer tablets, GPT, has been developed in response to these challenges. Each layer is compacted separately, and tablets are attached to each other in an automated process with a binding agent, which at the same time acts as a barrier against cross-contamination and interactions between the tablet layers. GPT offers more flexibility with regard to API combinations, reduced waste, and higher process efficiency compared to conventional multilayer tablet manufacturing. Moreover, different layers of different thickness can rapidly be combined in one dosage form without redevelopment of the process. GPT is, therefore, ideally suited to fulfill the demands of individualized medicine.

	The entire GPT is carried out in an automated process consisting of several steps, as schematically illustrated in 

. The main steps are feeding of the first tablet layer; application of gluing agent; feeding of the second tablet layer; hardening the gluing agent between the two tablet layers, which results in the production of bilayer tablets; and unloading of bilayer tablets. More tablet layers can be applied as well. 

 shows bilayer tablets produced using a prototype of this automated process.

	The system was developed based on quality-by-design principles, enabling the application of process analytical technology (PAT) tools for the in-line monitoring of the various manufacturing steps. This system includes the assurance of thickness and continuity of the binding layer. The correct amount of gluing agent and the adjustment of this layer on the tablet are monitored within the process. Therefore, the specified thickness and continuity of the binding layer is guaranteed.

	The nozzle system for glue application is a high-speed micro-dispensing system based on piezo technology. It has a heating unit for melting the gluing medium in the nozzle. Both aqueous and organic solutions of binding agents can be applied. Molten polymers can be used as a gluing agent by using the nozzle, combined with the heating unit.

	Despite a longer evaporation time, aqueous solutions are preferred in the pharmaceutical industry because they are environmentally friendly and fully comply with “green chemistry” measures (2, 3). The case study described in the following illustrates the use of GPT with aqueous binding solutions to produce bilayer tablets. 
	The automated GPT is available on two scales, ML7 and ML240, suitable for both industrial production and specific small-scale applications (see 

). The technical properties of ML7 and ML240 equipment are listed in 

 The bonding and the mechanical properties (e.g., Young’s modulus, Poisson ratio) of the API and selected excipients play a crucial role in the deformation layers of a conventional bilayer tablet. Because elastic mismatch of the layers can cause radial stresses and delamination of tablet layers (1), careful adjustment of the compression force is essential for conventional manufacturing of multilayer tablets. It has been reported that applying high compression force to the first layer can result in tablets with low porosity and a bonding strength of the layer that is higher than the interfacial strength of two layers, which may also cause delamination (4). 

	Using GPT, the tablets are compressed separately, and controlling the compression force is easier than in conventional multilayer manufacturing. Tablets composing different formulations can be produced with predefined strength and surface porosity. By gluing the layers in an extra step, the interfacial strength of two layers is only a function of the selected binding agent and is no longer the function of bonding properties of the formulation and the applied compression force. At the same time, the gluing agent acts as a separation layer to prevent direct contact between the tablet layers and cross contamination.

 The tack, in term of adhesive strength, is dependent on the viscoelastic properties of the gluing agent, the evaporation time of the solvent, and the thickness of the applied gluing layer. These parameters should be screened, and a suitable range must be selected carefully. Moreover, the glass transition temperature of the gluing agent is an additional factor that determines the interfacial strength of the tablet layers after production and during storage. Surface properties, such as surface and interfacial tensions and surface roughness of tablet layers, affect the tack properties of the gluing agent. The primary type of interfacial bonding mechanism between the tablet layer and gluing agents with polar functional groups is the hydrogen bond formation. Dipole-dipole and dipole-induced dipole interactions are also possible (5).

 Ibuprofen free acid and caffeine monohydrate were used as model APIs for manufacturing bilayer tablets. Blends of each API (30% w/w) with Tablettose 70 (69.5% w/w) and magnesium stearate (0.5% w/w) were prepared in a blender (Stephan machinery GmbH). The blending time was 10 minutes, at a blending speed of 100 rpm. Blends were directly compressed with a Stylcam 200R with a compaction force of 10 kN for each mixture to generate thin layers of the respective API-excipient mixtures. Bilayer tablets composed of a layer of ibuprofen-free acid and a layer of caffeine monohydrate were produced via GPT using 5 µL of a 40% w/w aqueous solution of fish gelatin with a viscosity of 2.4 Pa-s. The friability and delamination tendency of these tablets were examined. Moreover, bilayer tablets were produced by gluing ibuprofen-free acid tablets and placebo tablets with fish gelatin as a gluing agent. They were used to investigate the API penetration through the gluing layer to confirm if the gluing layer can also act as a separation layer.

 show the hardness and friability of individual layers, and the delamination tendency of bilayer tablets, respectively. The hardness and friability tests were carried out according to the 

) 8.0, 2.9.7., and 2.9.8., respectively, both for single layers and bilayer tablets using 10 bilayer tablets (6). The delamination tendency was determined by considering the number of delaminated bilayer tablets after completing the friability test (Pharmatest) for bilayer tablets. As can be seen from 

, the friability of bilayer tablets was less than 1 % w/w and in full agreement with the 

 requirements. No delamination was observed after performing the friability test.

	Cross-contamination between two layers. To confirm that the glue layer between the individual tablet layers can act as a separation layer, bilayer tablets were produced as follows: a layer of ibuprofen free acid was glued to a placebo tablet containing Tablettose 70 and 0.5% w/w magnesium stearate without API. Fish gelatin was used as the gluing agent. The cross-section of bilayer tablets was analyzed via Raman microscopy. 

 shows such a cross-section where the gluing layer (blue color) also acts as a separating layer. It was observed that the API (green color) does not penetrate the gluing layer, demonstrating that the placebo layer is not contaminated.
	 

	GPT is a straightforward method of producing personalized medicine. It offers an efficient solution for flexible and individual combinations of APIs and doses and can be used in a host of novel applications. A major advantage of GPT is that it requires only a relatively small footprint for the real-time production of multilayer tablets and can easily be integrated in a continuous production line. This feature enables a rapid development and production of new combinations of APIs or individualized API FDCs. Examples are the development of new therapeutic strategies for treatment of HIV/AIDS and multidrug-resistant infections such as tuberculosis. The individualized FDC can be produced real-time on miniaturized equipment by non-governmental organizations in their missions. Real-time production on miniaturized equipment can be also accomplished in the field of translational pharmaceutics, immediately prior to clinical testing, creating the opportunity to modify dose and formulation compositions in response to emerging clinical data. 

 461 (1-2) 549-58 (2014). 
	2. D.J.C. Constable et al., 

 9 (5) 411-420 (2007).
	3. J.B. Manley, P.T. Anastas, and B.W. Ceu Jr., 

 16 (6) 743-750 (2008).
	4. I. Akseli et al., 

 236 30-36 (2013)
	5. L.A. Felton, J.W. McGinity, 

olid Dosage Drug Development and Manufacturing 2017

	When referring to this article, please cite it as S. Salar-Behzadi et al., "Gluing Pills Technology for the Production of Multi-Layer Tablets," 

olid Dosage Drug Development and Manufacturing

Articles

This novel technology was developed in response to challenges involved in conventional manufacturing of multilayer tablets, including in-line control of the tablet weight, the tendency to delamination, direct contact between the two tablet layers, and cross contamination.