(M1430-11-74) Mechanism of Stabilization of Amorphous Solid Dispersion above the Overlap Concentration (c*): Delay of the First Nucleation Event

Purpose: Formulation of poorly aqueous soluble drugs as amorphous solid dispersions (ASDs) can preserve drug in a high energy state, which improves their solubility and hence bioavailability. One of the challenges in ASD formulation is to estimate the highest drug loading, in order to reduce pill burden and simplify the downstream processing. However, currently available methods for highest drug loading estimation, such as Flory-Huggins theory based method, have both theoretical and practical limitations. Recently, an alternative approach based on the concept of polymer overlap concentration (c*) has been proposed. Previous studies have shown that the c* values for ASDs correlate strongly with crystallization tendencies. The purpose of the current work is to study the mechanism of inhibition of crystallization (crystal nucleation and growth) of ASD using the c* concept.

Methods: Viscosities of ASDs of D-sorbitol with four grades of polyvinylpyrrolidone (PVP K12, K17, K25, K30), and various polymer concentrations, were determined above the melting temperature of D-sorbitol using a rotational rheometer. The resulting data were used to plot viscosity-composition diagrams, from which c* was determined. The first nucleation time (the time of formation of the first critical nucleus in a fresh prepared ASD) and the crystal nucleation and growth rates of D-sorbitol/PVP ASDs were determined using thermal stage microscopy.

Results: The determined c* values for D-sorbitol/PVP ASDs correlated strongly with crystallization tendencies. For polymer concentrations above c*, ASDs exhibited greatly enhanced stability against crystallization. With increasing polymer molecular weight, c* decreased. These results are in agreement with previous observations of celecoxib/PVP and loratadine/PVP ASDs. When polymer concentration was below c*, the first nucleation time of D-sorbitol/PVP ASDs was identical to that of neat amorphous D-sorbitol. The first nucleation time dramatically increased when polymer concentration exceeded c*.

Conclusion: Correlation between c* and crystallization tendency of ASDs has been verified using D-sorbitol/PVP system. When polymer concentration is below c*, ASDs show a strong tendency to crystallize, while ASDs with polymer loadings above c* exhibit elevated physical stability. This is due to the effective inhibition of the first nucleation event by polymer when c > c*.

References: A. Newman, G. Zografi. Considerations in the Development of Physically Stable High Drug Load API- Polymer Amorphous Solid Dispersions in the Glassy State. J. Pharm. Sci., 112 (2023), 8-18
P.G. de Gennes. Scaling Concepts in Polymer Physics. Cornell University Press (1979)
S. Song, C. Wang, B. Zhang, C.C. Sun, T.P. Lodge, R.A. Siegel. A Rheological Approach for Predicting Physical Stability of Amorphous Solid Dispersions. J. Pharm. Sci., 112 (2023), 204-212

Scheme of the effective inhibition of the first nucleation event in semidilute/concentrated (two panels on the right) polymer solutions. There is no effective inhibition of the first nucleation event in dilute (second from the left panel) polymer solutions due to gaps between isolated polymer coils.

Viscosity-composition diagram of D-sorbitol/PVP K12, K17, K25, and K30 at 155 °C. Arrows correspond to c*, where there is a break in the slopes of the individual viscosity-concentration curves.

The first nucleation time as a function of polymer concentration rescaled by c* at 34 °C. Dashed lines indicated the trend of increased first nucleation time observed by eye.