(402a) In Situ Studies of Phase Separation in Amorphous Solid Dispersions (ASDs) Using the QCM-D

Amorphous drug dispersions are becoming more and more utilized within the pharmaceutical industry, along with their academic study ^1-2. Their primary use is in facilitating the intake of poorly water soluble drugs by patients ^3-4. There has been much research conducted recently to develop an understanding of their physiochemical characteristics and stability in a wide range of conditions ^{2, 5-7}. Of the research published ⁸, little has gone into real time studies of the physiochemical properties of ASD films. In particular, amorphous-amorphous phase separation (AAPS) that occurs due to moisture ingression⁹. In this study, we sought to utilize the Quartz Crystal Microbalance (QCM) to determine the kinetics and physiochemical property changes of drug blended films as these ASD films phase separate into drug rich and excipient rich regions due to the uptake of moisture.

The strength of the QCM-D lies in both its sensitivity and accuracy of the measurements taken from both its resonance frequency shift and dissipation ⁷. These can be modelled further to obtain quantitative data. Depending on the models used, notably the Sauerbrey and Viscoelastic models based on Kelvin-Voigt and Maxwell relations, different properties can be obtained including the thickness, density, and/or viscoelasticity. By using a humidity module, we can track the moisture uptake of ASD films at set relative humidity’s and the shifts observed with time.

The QCM requires the formation of thin layers to study (50 to 500 nm), so these were spun cast from solution onto the gold coated sensors. Ritonavir and copovidone were the drug and excipient chosen with drug loadings varied from 5 to 50%wt. The physical mixture was dried extensively and dissolved in 99.9% anhydrous methanol and pipetted onto the sensors for coating using a static deposition technique. Complimentary techniques were used to ensure that a homogeneous film was obtained, notably by using optical microscopy and atomic force microscopy (AFM). Both were also used to visualize the phase separation that occurred, and the AFM even gave physical properties on the different phases. Polarized microscopy was also used to identify the potential presence of any crystallinity in the films. The presence of both components was shown via fourier transform infrared spectroscopy (FTIR). Changes in the bonding behaviour between the two components, as documented in the literature with FTIR, also demonstrated the impact of AAPS on the intermolecular bonding ⁹.

Results from our work showed that phase separation occurs at high humidity (94%) for any drug loadings. The starting films could all be approximated as stiff, homogeneous, and therefore could be modelled with the Sauerbrey equation. The AAPS, which creates a heterogeneous film, dramatically increased the dissipation compared the frequency shift. This suggested little additional mass uptake (from the moisture) but the film becoming much softer. No crystallinity was observed in the films after being exposed to high humidity. This is crucial because the appearance of crystals in the film could cause a dramatic effect on both the dissipation and frequency shifts observed. Therefore eliminating such a possibility is important to making sure such shifts are due to the AAPS. Different drug loading contents had different kinetic regimes, which we believe to be related to the diffusion of both ritonavir and water through the polymer matrix. Further work is needed to deconvolute the effects of both. It is also believed that the thickness of the film could have an impact on the study of ASD thin films due to the interfacial interaction between the substrate and the film. This is suspected due to changes in the dissipation shifts for identical drug loadings but at different thicknesses. This could be directly connected to the effects of nanoconfinement on polymers and their cooperative chain movements (α-relaxation) ¹⁰.

This work showcases the strength of the QCM as a surface specific tool and its potential within the pharmaceutical industry in helping to optimize the combinations of excipients and active pharmaceutical ingredients and observe real time changes. Future studies could utilize alternative sensors, and ASD formulations to further expand our knowledge and understanding of these amorphous drug films.

References:

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