(T0930-01-02) A Physical Picture for the Dissolution Process of Copovidone ASDs

Purpose: The goal of this research was to explore the mechanisms by which a drug is released from amorphous solid dispersions (ASDs). One of the challenges of orally dosing drugs is their limited solubility. ASDs solve this by increasing the solubility and dissolution rate of the drug by using a polymer carrier to stabilize the drug’s amorphous state and facilitate it’s release into solution. However, the dissolution of ASDs is poorly understood and is much more complex than that of neat drugs. For example, ASDs can form nanoparticle suspensions, they release drug much more rapidly than the neat amorphous drug dissolution rate, and they cease to dissolve above a certain drug load that is drug specific, and which has been termed the limit of congruency (LoC). All three of these aspects are investigated herein with two model drugs and copovidone (PVPVA), a common polymer carrier.

Methods: Phenolphthalein (PHPH) and esterified phenolphthalein (MePHPH) were used as model drugs to prepare ASDs with PVPVA. Prodan (0.1 wt.%) and rhodamine 6G (0.05 wt.%) fluorescent dyes were included in the ASDs to visualize the dissolution interface in situ with a confocal microscope. Prodan is hydrophobic and rhodamine 6G is relatively hydrophilic, therefore, they are expected to label the drug and polymer phases, respectively, during phase separation. All ASDs were prepared by rotary evaporation from ethanol. Surface normalized dissolution was conducted in 50 mM, pH 6.8 phosphate buffer using an intrinsic dissolution apparatus. Nanoparticles formed during ASD dissolution were isolated by centrifugation and analyzed for composition. High performance liquid chromatography (HPLC) and size exclusion chromatography (SEC) were used for drug and polymer quantification, respectively.

Results: The weakly interacting MePHPH-PVPVA ASD, and the hydrogen bonding PHPH-PVPVA ASD showed LoCs of 40% and 5% drug loading, respectively. Above these drug loadings, neither drug nor polymer fully released from the ASD. In situ confocal micrographs revealed that the drug formed discrete nanoparticles at the dissolution interface when the drug loading was at or below LoC. However, the morphology of this hydrophobic phase changed to a connected network at drug loads above the LoC. This provides direct experimental evidence that drug release from an ASD is hindered by the formation of a continuous hydrophobic phase at the interface through amorphous-amorphous phase separation, as previously suggested. The composition of the hydrophobic phase was determined by measuring the concentration of polymer in the nanoparticles, which was found to be substantially higher for the PHPH-PVPVA system (~70 wt.% dry basis) than the MePHPH-PVPVA system ( < 5% wt.% dry basis). This suggests that a continuous hydrophobic phase is formed at a low PHPH loading because the hydrophobic phase contains a significant amount of PVPVA, which is directly attributed to the hydrogen bonding between PHPH and PVPVA.

Conclusion: PVPVA ASDs have a drug load threshold (LoC) above which drugs cannot fully release. The LoC has been reported to vary from 5 – 40% depending on the drug. It has been suggested that the LoC is the result of a hydrophobic barrier forming at the dissolution interface, however, direct evidence for how this barrier forms is lacking. Moreover, there is a limited understanding for how ASDs release drug and why the LoC is drug dependent. The dissolution interface of an ASD was studied in situ for the first time and a physical picture of the ASD release mechanism was established which helps explain the variability of the LoC as well as the formation of nanoparticles.

References: Han, Y. R.; Ma, Y.; Lee, P. I., Impact of phase separation morphology on release mechanism of amorphous solid dispersions. European Journal of Pharmaceutical Sciences 2019, 136, 104955

Ilevbare, G. A.; Taylor, L. S., Liquid–liquid phase separation in highly supersaturated aqueous solutions of poorly water-soluble drugs: implications for solubility enhancing formulations. Crystal growth & design 2013, 13 (4), 1497-1509.

Indulkar, A. S.; Gao, Y.; Raina, S. A.; Zhang, G. G.; Taylor, L. S., Exploiting the phenomenon of liquid–liquid phase separation for enhanced and sustained membrane transport of a poorly water-soluble drug. Molecular pharmaceutics 2016, 13 (6), 2059-2069.

Indulkar, A. S.; Lou, X.; Zhang, G. G.; Taylor, L. S., Insights into the Dissolution Mechanism of Ritonavir–Copovidone Amorphous Solid Dispersions: Importance of Congruent Release for Enhanced Performance. Molecular pharmaceutics 2019, 16 (3), 1327-1339.

Que, C.; Lou, X.; Zemlyanov, D. Y.; Mo, H.; Indulkar, A. S.; Gao, Y.; Zhang, G. G.; Taylor, L. S., Insights into the Dissolution Behavior of Ledipasvir–Copovidone Amorphous Solid Dispersions: Role of Drug Loading and Intermolecular Interactions. Molecular pharmaceutics 2019, 16 (12), 5054-5067.

Que, C.; Deac, A.; Zemlyanov, D. Y.; Qi, Q.; Indulkar, A. S.; Gao, Y.; Zhang, G. G.; Taylor, L. S., Impact of Drug–Polymer Intermolecular Interactions on Dissolution Performance of Copovidone-Based Amorphous Solid Dispersions. Molecular Pharmaceutics 2021, 18 (9), 3496-3508

Saboo, S.; Taylor, L. S., Water-induced phase separation of miconazole-poly (vinylpyrrolidone-co-vinyl acetate) amorphous solid dispersions: Insights with confocal fluorescence microscopy. International Journal of Pharmaceutics 2017, 529 (1-2), 654-666.

Saboo, S.; Moseson, D. E.; Kestur, U. S.; Taylor, L. S., Patterns of drug release as a function of drug loading from amorphous solid dispersions: A comparison of five different polymers. European Journal of Pharmaceutical Sciences 2020, 155, 105514.

Tachibana, T.; Nakamura, A., A methode for preparing an aqueous colloidal dispersion of organic materials by using water-soluble polymers: dispersion of β-carotene by polyvinylpyrrolidone. Kolloid-Zeitschrift und Zeitschrift für Polymere 1965, 203 (2), 130-133

Yang, R.; Mann, A. K.; Van Duong, T.; Ormes, J. D.; Okoh, G. A.; Hermans, A.; Taylor, L. S., Drug Release and Nanodroplet Formation from Amorphous Solid Dispersions: Insight into the Roles of Drug Physicochemical Properties and Polymer Selection. Molecular Pharmaceutics 2021.

Acknowledgements:The authors declare the following competing financial interest(s): Purdue University and AbbVie jointly participated in study design, research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication. Alexandru Deac and Chailu Que are graduate students at Purdue University. Qingqing Qi is a postdoctoral associate at Purdue University. Lynne S. Taylor is a professor at Purdue University. They all have no additional conflicts of interest to report. Anura S. Indulkar, Yi Gao, and Geoff G. Z. Zhang are employees of AbbVie and may own AbbVie stock.


Model compounds and polymer


In situ micrographs of the dissolution interface of PHPH-PVPVA tablets


In situ micrographs of the dissolution interface of MePHPH-PVPVA tablets