TY  - JOUR
A1  - Uebbing, Lukas
A1  - Klumpp, Lukas
A1  - Webster, Gregory K.
A1  - Löbenberg, Raimar
T1  - Justification of disintegration testing beyond current FDA criteria using in vitro and in silico models
T2  - Drug design, development and therapy
N2  - Drug product performance testing is an important part of quality-by-design approaches, but this process often lacks the underlying mechanistic understanding of the complex interactions between the disintegration and dissolution processes involved. Whereas a recent draft guideline by the US Food and Drug Administration (FDA) has allowed the replacement of dissolution testing with disintegration testing, the mentioned criteria are not globally accepted. This study provides scientific justification for using disintegration testing rather than dissolution testing as a quality control method for certain immediate release (IR) formulations. A mechanistic approach, which is beyond the current FDA criteria, is presented. Dissolution testing via United States Pharmacopeial Convention Apparatus II at various paddle speeds was performed for immediate and extended release formulations of metronidazole. Dissolution profile fitting via DDSolver and dissolution profile predictions via DDDPlus™ were performed. The results showed that Fickian diffusion and drug particle properties (DPP) were responsible for the dissolution of the IR tablets, and that formulation factors (eg, coning) impacted dissolution only at lower rotation speeds. Dissolution was completely formulation controlled if extended release tablets were tested and DPP were not important. To demonstrate that disintegration is the most important dosage form attribute when dissolution is DPP controlled, disintegration, intrinsic dissolution and dissolution testing were performed in conventional and disintegration impacting media (DIM). Tablet disintegration was affected by DIM and model fitting to the Korsmeyer–Peppas equation showed a growing effect of the formulation in DIM. DDDPlus was able to predict tablet dissolution and the intrinsic dissolution profiles in conventional media and DIM. The study showed that disintegration has to occur before DPP-dependent dissolution can happen. The study suggests that disintegration can be used as performance test of rapidly disintegrating tablets beyond the FDA criteria. The scientific criteria and justification is that dissolution has to be DPP dependent, originated from active pharmaceutical ingredient characteristics and formulations factors have to be negligible.
KW  - API
KW  - dissolution
KW  - disintegration
KW  - DDDPlus
KW  - quality-by-design
KW  - product specification
KW  - model fitting
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/43239
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-432394
SN  - 1177-8881
N1  - © 2017 Uebbing et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
VL  - 11
SP  - 1163
EP  - 1174
PB  - Dove Medical Press
CY  - Albany, Auckland
ER  -