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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.
In the scientific literature, the use of a surfactant is recommended for both designing quality control tests for water insoluble or sparingly water soluble drugs and for predicting the bioavailability of drugs from various types of formulations. Since the number of poorly soluble drugs is increasing, the selection of adequate dissolution test for these becomes more and more important. The aim of the present study was to develop predictive and discriminatory test methods based on surfactants that are recommended in the literature. Particular respect was given to the use of sodium lauryl sulfate and Tween 80, the two most commonly used surfactants for this purpose. Tamoxifen was used as a model drug. Dissolution experiments were performed using various concentrations of the two surfactants in buffer media typically used to prepare biorelevant test media. Results were then compared with those deriving from the same test formulations in biorelevant and simplified “biorelevant” media. Results from this study indicate that the concentration of surfactant has a huge impact on both the rate and extent of drug release from the formulation and also on the discriminatory power of the test. However, they also indicate that a well designed and validated test medium containing SLS or Tween 80 can be useful in terms of establishing a discriminatory test medium that possibly could also be used to assure batch to batch bioequivalence. Therefore, the approach described in the present paper might be very helpful for developing predictive and discriminatory methods in early formulation development for poorly soluble drugs and which could also be adopted for QC.
Currently, a wide variety of complex non-oral dosage forms are entering the global healthcare market. Although many assays have been described in recent research, harmonized procedures and standards for testing their in vitro performance remain widely unexplored. Among others, dialysis-based techniques such as the Pharma Test Dispersion Releaser are developed for testing the release of drugs from nanoparticles, liposomes, or extracellular vesicle preparations. Here, we provide advanced strategies and practical advice for the development and validation of dialysis-based techniques, including documentation, analysis, and interpretation of the raw data. For this purpose, key parameters of the release assay, including the hydrodynamics in the device at different stirring rates, the selectivity for particles and molecules, as well as the effect of excipients on drug permeation were investigated. At the highest stirring rate, a more than twofold increase in the membrane permeation rate (from 0.99 × 10−3 to 2.17 × 10−3 cm2/h) was observed. Additionally, we designed a novel computer model to identify important quality parameters of the dialysis experiment and to calculate error-corrected release profiles. Two hydrophilic creams of diclofenac, Voltaren® Emulgel, and Olfen® gel, were tested and provide first-hand evidence of the robustness of the assay in the presence of semisolid dosage forms.