IVIVC for Extended Release Hydrophilic Matrix Tablets in Consideration of Biorelevant Mechanical Stress

Abstract

Purpose When establishing IVIVC, a special problem arises by interpretation of averaged in vivo profiles insight of considerable individual variations in term of time and number of mechanical stress events in GI-tract. The objective of the study was to investigate and forecast the effect of mechanical stress on in vivo behavior in human of hydrophilic matrix tablets. Methods Dissolution profiles for the marketed products were obtained at different conditions (stirring speed, single- or repeatable mechanical stress applied) and convoluted into C-t profiles. Vice versa, published in vivo C-t profiles of the products were deconvoluted into absorption profiles and compared with dissolution profiles by similarity factor. Results Investigated hydrophilic matrix tablets varied in term of their resistance against hydrodynamic stress or single stress during the dissolution. Different scenarios, including repeatable mechanical stress, were investigated on mostly prone Seroquel® XR 50 mg. None of the particular scenarios fits to the published in vivo C-t profile of Seroquel® XR 50 mg representing, however, the average of individual profiles related to scenarios differing by number, frequency and time of contraction stress. When different scenarios were combined in different proportions, the profiles became closer to the original in vivo profile including a burst between 4 and 5 h, probably, due to stress-events in GI-tract. Conclusion For establishing IVIVC of oral dosage forms susceptible mechanical stress, a comparison of the deconvoluted individual in vivo profiles with in vitro profiles of different dissolution scenarios can be recommended.

Gel Strength of Hydrophilic Matrix Tablets in Terms of In Vitro Robustness

“…Since investigated extended-release hydrophilic matrix tablets are intended to release most of the active substance in the intestinal environment, USP phosphate buffer solution pH of 6.8 was used as the main dissolution medium. Dissolution testing was conducted using an USP Apparatus II with a paddle agitation speed of 50, 100 or 150 rpm (VK 7000, VanKel Industries, NJ, USA) in 900 mL dissolution medium under sink condition (26). Dissolution studies were performed in triplicate.…”

“…The erosion rate depends on the gel strength of the outer gel layer under certain release conditions (10,23,24). Among the different parameters affecting in vitro drug release, the hydrodynamic condition (agitation intensity) and mechanical destructive forces play a significant role in drug release from hydrophilic matrices (25,26). However, the in vivo drug release can differ from the predicted in vitro, due to extensive mechanical forces in the GI tract (26)(27)(28)(29).…”

“…Among the different parameters affecting in vitro drug release, the hydrodynamic condition (agitation intensity) and mechanical destructive forces play a significant role in drug release from hydrophilic matrices (25,26). However, the in vivo drug release can differ from the predicted in vitro, due to extensive mechanical forces in the GI tract (26)(27)(28)(29). Therefore, the design of a mechanically robust formulation (which can be defined by sufficient gel strength) is a key to achieve predictable in vivo plasma concentrations (6).…”

“…It has been reported that the tablets can undergo mechanical forces of 2 N or 1.2 N when passing through the human stomach and small intestine, respectively (25,31). These forces can accelerate the erosion and overall release from hydrophilic tablets (26,30,32,33) and in vivo drug release can significantly differ from that determined in vitro (34).…”

Magnetic Resonance Methods as a Prognostic Tool for the Biorelevant Behavior of Xanthan Tablets

“…Drug formulations administered orally pass through a series of gastrointestinal (GI) compartments with varied contraction forces [ 33 ]. It is reasonable to know if the gastrointestinal contraction forces affect hydrogel structure and drug release during GI transit [ 34 ]. An approach to distinguish between the role of hydrodynamics and mechanical stresses similar to the contraction forces of the GI tract on drug release from modified release dosage forms was presented by Takieddin’s group [ 35 ].…”