3 research outputs found
Manufacturing Amorphous Solid Dispersions with a Tailored Amount of Crystallized API for Biopharmaceutical Testing
The
preparation of an amorphous solid dispersion (ASD) by dissolving
a poorly water-soluble active pharmaceutical ingredient (API) in a
polymer matrix can improve the bioavailability by orders of magnitude.
Crystallization of the API in the ASD, though, is an inherent threat
for bioavailability. Commonly, the impact of crystalline API on the
drug release of the dosage form is studied with samples containing
spiked crystallinity. These spiked samples possess implicit differences
compared to native crystalline samples, regarding size and spatial
distribution of the crystals as well as their molecular environment.
In this study, we demonstrate that it is possible to grow defined
amounts of crystalline API in solid dosage forms, which enables us
to study the biopharmaceutical impact of actual crystallization. For
this purpose, we studied the crystal growth in fenofibrate tablets
over time under an elevated moisture using transmission Raman spectroscopy
(TRS). As a nondestructive method to assess API crystallinity in ASD
formulations, TRS enables the monitoring of crystal growth in individual
dosage forms. Once the kinetic trace of the crystal growth for a certain
environmental condition is determined, this method can be used to
produce samples with defined amounts of crystallized API. To investigate
the biopharmaceutical impact of crystallized API, non-QC dissolution
methods were used, designed to identify differences between the various
amounts of crystalline materials present. The drug release in the
samples manufactured in this fashion was compared to that of samples
with spiked crystallinity. In this study, we present for the first
time a method for targeted crystallization of amorphous tablets to
simulate crystallized ASDs. This methodology is a valuable tool to
generate model systems for biopharmaceutical studies on the impact
of crystallinity on the bioavailability
Extraordinary Long-Term-Stability in Kinetically Stabilized Amorphous Solid Dispersions of Fenofibrate
Inhibition
of recrystallization of the drug substance in kinetically
stabilized amorphous solid dispersions (ASDs) within and beyond shelf
life is still a matter of debate. Generally, these ASD systems are
considered to be prone to recrystallization, but examples of their
long-term stability are emerging in the literature. Since, in some
cases, the formation of crystals may impact bioavailability, recrystallization
may present a relevant risk for patients as it potentially lowers
the effective dose of the formulation. This study shows that such
metastable formulations may indeed remain amorphous even after 15
years of storage under ambient conditions. A formulation of fenofibrate
stored for 15 years was compared to a freshly prepared batch. A complete
physicochemical characterization regarding content, purity, water
content and glass transition was conducted. The emphasis of this physicochemical
characterization was on crystallinity as a critical quality attribute:
polarized light microscopy (PLM) was used as the standard qualitative
method and X-ray powder diffraction (XRPD) as the standard quantitative
method. An investigation of the crystal growth kinetics by transmission
Raman spectroscopy (TRS) was conducted to build a predictive model.
The model was applied successfully to predict the observed physical
state of the 15-year-old samples. The observations presented here
demonstrate that kinetic stabilization alone is able to prevent crystallization
in ASDs over prolonged storage periods, suggesting the need for a
reassessment of the risk perception for this kind of ASD formulations
Dissolution Method Troubleshooting: An Industry Perspective
Quality control dissolution testing represents a key product performance test for solid oral dosage forms and is the most likely QC test to result in laboratory investigations because of the relatively complex relationship between the dissolution performance, the drug product properties, and the systems necessary to measure the quality attribute. The Dissolution Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) has pooled our collective knowledge to outline some common ways that dissolution methods can fail. Examples and case studies have been highlighted focusing on errors of equipment, method, materials, measurement, people, and the environment, while providing best practices for building method understanding and avoiding the exemplified issues. The case studies have highlighted the importance of buffer preparation, potential impact of contamination of the dissolution medium, additive-induced degradation, risks in the use of automation, differences between dissolution systems, and the effect of filter selection. By applying the learnings in this article and investing in analyst training programs, understanding the capabilities of your equipment portfolio, and well-designed robustness and ruggedness studies will reduce dissolution method investigations and improve compliance and productivity during the method lifecycle