Multi-Analytical Framework to Assess the In Vitro Swallowability of Solid Oral Dosage Forms Targeting Patient Acceptability and Adherence

Abstract

A lack of effective intervention in addressing patient non-adherence and the acceptability of solid oral dosage forms combined with the clinical consequences of swallowing problems in an ageing world population highlight the need for developing methods to study the swallowability of tablets. Due to the absence of suitable techniques, this study developed various in vitro analytical tools to assess physical properties governing the swallowing process of tablets by mimicking static and dynamic stages of time-independent oral transitioning events. Non-anatomical models with oral mucosa-mimicking surfaces were developed to assess the swallowability of tablets; an SLA 3D printed in vitro oral apparatus derived the coefficient of sliding friction and a friction sledge for a modified tensometer measured the shear adhesion profile. Film coat hydration and in vitro wettability was evaluated using a high-speed recording camera that provided quantitative measurements of micro-thickness changes, simulating static in vivo tablet-mucosa oral processing stages with artificial saliva. In order to ascertain the discriminatory power and validate the multianalytical framework, a range of commonly available tablet coating solutions and new compositions developed in our lab were comparatively evaluated according to a quantitative swallowability index that describes the mathematical relationship between the critical physical forces governing swallowability. This study showed that the absence of a film coat significantly impeded the ease of tablet gliding properties and formed chalky residues caused by immediate tablet surface erosion. Novel gelatin- and λ-carrageenan-based film coats exhibited an enhanced lubricity, lesser resistance to tangential motion, and reduced stickiness than polyvinyl alcohol (PVA)-PEG graft copolymer, hydroxypropyl methylcellulose (HPMC), and PVA-coated tablets; however, Opadry^® EZ possessed the lowest friction-adhesion profile at 1.53 a.u., with the lowest work of adhesion profile at 1.28 J/mm². For the first time, the in vitro analytical framework in this study provides a fast, cost-effective, and repeatable swallowability ranking method to screen the in vitro swallowability of solid oral medicines in an effort to aid formulators and the pharmaceutical industry to develop easy-to-swallow formulations.

Keywords: acceptability; adherence; dysphagia; film coating; in vitro swallowability; solid oral dosage forms; swallowability index.

Figure A1

Schematic illustration of Kollicoat^® IR: gelatin:λ-carrageenan ternary network water imbibition theory exhibiting favorable surface coat properties for low friction, low adhesion, and soft texture formation. Phase I hypothesizes that the linear carrageenan chains coat the gelatin triple helix because gelatin possesses numerous relative hydrophobic amino segments that pair with carrageenan’s backbone. The blending of Kollicoat is believed to induce the gelatin: λ-carrageenan complex to associate with polyvinyl alcohol chains that are less hydrophilic than polyethylene glycol. Phase II shows that during water contact, carrageenan molecules readily bond with water molecules, thus resulting in phase III where intricate inter- and intra-hydrogen bonding creates a passage into gelatin’s triple helix that promotes extensive synergistic swelling.

Figure 1

Illustration of basic friction–adhesion model using the in vitro oral apparatus (left, A—lateral view, B—birds eye view) and in vitro shear adhesion device (right) and respective free body diagrams used to determine critical swallowability factor’s coefficient of sliding friction and work of adhesion. The in vitro oral apparatus required tablets to be introduced via an entry slot unwetted (1), a gated mechanism separated the tablet from the wetted ramp (2) maintained by a peristaltic pump (3), and a plexiglass environmental chamber (4) mounted onto a steam bath maintained the internal conditions, i.e., temperature (37 ± 2 °C) and humidity (65% relative humidity). The in vitro shear adhesion device used a 3DP tablet holder to affix 9 tablets on the underside to be dragged at a defined speed across a mucosa-mimicking surface (sodium polyacrylate or polytetrafluoroethylene (PTFE)). A frictionless and 10 N load cell was used to improve recording accuracy.

Figure 2

Quantitative analysis of the axial gel layer thickness over time of film-coated tablets, as calculated using a high-speed recording camera with macro lens and imaging software for 60 at 4 s intervals. Uncoated tablets commenced disintegration and did not swell when immersed in water. Graph (A) represents commercial grade film coats, gelatin formulations are shown in graph (B), λ-carrageenan shown in graph (C), gelatin: λ-carrageenan combination formulations are represented in graph (D).

Figure 3

In vitro shear adhesion profile plotted as a function of distance for uncoated tablets. The oral gliding performance of tablets can be determined using a modified Hounsfield tensometer friction sledge across two non-anatomical oral mucosa-mimicking surfaces wetted with artificial saliva (polytetrafluoroethylene as graph (A) and sodium polyacrylate as graph (B)). Uncoated tablets displayed an erratic creep profile caused by a stick–slip motion resulting in friction re-strengthening and the fragmentation of the tablet, as depicted by the frequent large stress drops of the shearing peaks in both oral mucosa-mimicking surfaces.

Figure 4

Graphs to show the in vitro oral gliding performance and shear adhesion profile of various film-coated tablets using a modified Hounsfield tensometer across an in vitro, non-anatomical model using artificial saliva wetted sodium polyacrylate (dashed lined) and polytetrafluoroethylene ramp surface (solid lines). HPMC and PVA possessed higher initiating detachment forces and displayed a greater gliding resistance in comparison to Opadry^® EZ (OEZ), which possessed the most optimal slippery profile in comparison to all film-coated formulations (ANOVA, p < 0.05). The addition of water-soluble polymers within KIR (Kollicoat^® IR) imparted lubricating properties, as substantially lower peak forces and gliding forces were recorded.

Figure 5

Determination of the sliding coefficient of friction (CoF) and mobility time of film-coated tablets with KIR as the control and fixed at 10% w/w. Coulomb’s friction model F_F = µF_N was used to determine the CoF by using the weight to run its course on a 3D SLA printed in vitro oral apparatus, and it can be seen that the binary and/or ternary addition of λ-carrageenan and/or gelatin in combination effectively reduced the in vitro friction forces exhibited by the control KIR. OEZ yielded the lowest resistance to tangential motion, exhibiting a relatively superior wet-slip profile than any film coating system (ANOVA, p < 0.05).