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Formulating a heat and shear labile drug in an amorphous solid dispersion

Aug 4, 2021

Davis Jr, Daniel A., Dave A. Miller, Supawan Santitewagun, J. Axel Zeitler, Yongchao Su, and Robert O. Williams III. “Formulating a heat-and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity.” International Journal of Pharmaceutics: X (2021): 100092.


We seek to further addresss the questions posed by Moseson et al. regarding whether any residual crystal level, size, or characteristic is acceptable in an amorphous solid dispersion (ASD) such that its stability, enhanced dissolution, and increased bioavailability are not compromised. To address this highly relevant question, we study an interesting heat- and shear-labile drug in development, LY3009120. To study the effects of residual crystallinity and degradation in ASDs, we prepared three compositionally identical formulations (57–1, 59–4, and 59–5) using the KinetiSol process under various processing conditions to obtain samples with various levels of crystallinity (2.3%, 0.9%, and 0.1%, respectively) and degradation products (0.74%, 1.97%, and 3.12%, respectively). Samples with less than 1% crystallinity were placed on stability, and we observed no measurable change in the drug’s crystallinity, dissolution profile or purity in the 59–4 and 59–5 formulations over four months of storage under closed conditions at 25 °C and 60% humidity. For formulations 57–1, 59–4, and 59–5, bioavailability studies in rats reveal a 44-fold, 55-fold, and 62-fold increase in mean AUC, respectively, compared to the physical mixture. This suggests that the presence of some residual crystals after processing can be acceptable and will not change the properties of the ASD over time.

Terahertz time-domain spectroscopy
Intermolecular interactions were measured using terahertz time-domain spectroscopy (THz-TDS). Samples were gently dispersed into fine particles using a mortar and pestle. Polyethylene (PE) powder was added to the samples with a sample:PE ratio of 1:9, then mixed using an agate mortar and pestle by geometric mixing. PE is commonly used as a binder and diluent in THz measurements because PE is nearly transparent in the terahertz region [B].

The sample powder was compressed under a 2-ton load in a 13 mm flat-faced pellet die for 1 min using a hydraulic press. Three pellets were prepared for each formulation. Pure PE pellets were prepared for use as the reference for the terahertz measurements. The transmission terahertz measurements were performed at room temperature using a commercial TeraPulse 4000 spectrometer. Time-domain waveforms of 50 ps duration were recorded over a co-averaging time of 6.67 s, and the absorption spectra in the transmission were calculated following the Fourier transformation of the sample and reference waveforms. A constant flow of dry nitrogen gas was used to purge the sample compartment throughout the terahertz measurement to remove any residual water vapor. In order to avoid any artifacts due to potentially inhomogenous mixing, each pellet was measured at four locations to determine the variability in each pellet. The terahertz absorption spectra were obtained in the frequency range of 0.3–2.5 THz.

Full paper can be viewed here.