6 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
Frozen in Time: Kinetically Stabilized Amorphous Solid Dispersions of Nifedipine Stable after a Quarter Century of Storage
Kinetically stabilized
amorphous solid dispersions are inherently
metastable systems. Therefore, such systems are generally considered
prone to recrystallization. In some cases, the formation of crystals
will impact the bioavailability of the active pharmaceutical ingredient
in these formulations. Recrystallization therefore may present a significant
risk for patients as it potentially lowers the effective dose of the
pharmaceutical formulation. This study indicates that such metastable
formulations may indeed remain fully amorphous even after more than
two decades of storage under ambient conditions. Different formulations
of nifedipine stored for 25 years were compared with freshly prepared
samples. A thorough physicochemical characterization including polarized
light microscopy, differential scanning calorimetry, X-ray powder
diffraction, and transmission Raman spectroscopy was undertaken. This
in-depth characterization indicates no signs of recrystallization
in the stored samples. The observations presented here prove that
long-term stability of amorphous solid dispersions much beyond the
typical shelf life for pharmaceutical formulations is indeed possible
by kinetic stabilization alone. These findings implicate a reevaluation
of the propensity to recrystallize for kinetically stabilized amorphous
solid dispersions
Process analytical techniques for hot-melt extrusion and their application to amorphous solid dispersions
Newly developed active pharmaceutical ingredients (APIs) are often poorly soluble in water. As a result the bioavailability of the API in the human body is reduced. One approach to overcome this restriction is the formulation of amorphous solid dispersions (ASDs), e.g., by hot-melt extrusion (HME). Thus, the poorly soluble crystalline form of the API is transferred into a more soluble amorphous form. To reach this aim in HME, the APIs are embedded in a polymer matrix. The resulting amorphous solid dispersions may contain small amounts of residual crystallinity and have the tendency to recrystallize. For the controlled release of the API in the final drug product the amount of crystallinity has to be known. This review assesses the available analytical methods that have been recently used for the characterization of ASDs
and the quantification of crystalline API content. Well established techniques like near- and mid-infrared spectroscopy (NIR and MIR, respectively), Raman spectroscopy, and emerging ones like UV/VIS, terahertz, and ultrasonic spectroscopy are considered in detail. Furthermore, their advantages and limitations are discussed with regard to general practical applicability as process analytical technology (PAT) tools in industrial manufacturing. The review focuses on spectroscopic methods which have been proven as most suitable for in-line and on-line process analytics. Further aspects are spectroscopic techniques that have been or could be integrated into an extruder