(W1030-12-70) A Rheological Approach for Determining Miscibility of Amorphous Solid Dispersions

Purpose: To develop a rheological approach of miscibility determination of ASDs based on the concept of overlap concentration (c*), which can be conveniently determined from the viscosity-composition diagram. The overlap concentration c*, the estimated lowest polymer concentration in an ASD, can be correlated with its miscibility limit.

Methods: Viscosities of ASDs of two model compounds, celecoxib (CEL) and loratadine (LOR), with four different grades of polyvinylpyrrolidone (PVP), i.e., PVP K12, PVP K17, PVP K25, and PVP K30, with various polymer concentrations were determined above the melting temperatures of drugs using a rotational rheometer. The resultant data was used to plot viscosity-composition diagrams, from which c* was determined. Crystallization tendencies of ASDs were assessed by (variable-temperature) X-ray powder diffractometry.

Results: The determined c* values for CEL/PVP and LOR/PVP ASDs correlated strongly with their crystallization tendencies. When polymer concentrations were above c*, ASDs exhibited greatly enhanced stability against crystallization. With increasing polymer molecular weight, c* decreased. A corresponding procedure of this methodology was provided to facilitate its broader adoption, which could be widely applicable for thermally stable binary drug/polymer combinations.

Conclusion: Correlation between c* and miscibility of ASDs has been demonstrated. The value of c* can be determined by measuring the viscosity of drug/polymer melt with various polymer concentrations and plotting the corresponding viscosity-composition diagram. When polymer loadings are below c*, ASDs show a strong tendency to crystallize, while ASDs with polymer loadings above c* exhibit elevated physical stability.

References: Newman, A.; Zografi, G. What Are the Important Factors That Influence API Crystallization in Miscible Amorphous API–Excipient Mixtures during Long-Term Storage in the Glassy State? Mol. Pharm. 2022, 19, (2), 378-391.

de Gennes, P. G., Scaling Concepts in Polymer Physics (1979). Cornell University Press.

Lodge, T.P., & Hiemenz, P.C. (2020). Polymer Chemistry (3rd ed.). CRC Press.

Sahoo, A.; Suryanarayanan, R.; Siegel, R. A. Stabilization of Amorphous Drugs by Polymers: The Role of Overlap Concentration (C*). Mol. Pharm. 2020, 17, (11), 4401-4406.

Acknowledgements:The authors declare no competing financial interest. S.S. thanks Prof. Masao Doi (BUAA, China) for delightful communication on c* and Dr. David Giles (Polymer Characterization Facility, UMN) for helpful discussion of viscosity measurement. Parts of this work were carried out in the Polymer Characterization Facility and the Characterization Facility, UMN, which receives partial support from the NSF through the MRSEC (DMR-2011401) and the NNCI (ECCS-2025124) programs. Funding from IPRIME is also acknowledged.


Illustration scheme of this work.


Viscosity-composition diagram of (a) CEL/PVP K12, K17, K25, and K30 at 165 °C and (b) LOR/PVP K12, K17, K25, and K30 at 145 °C. Each viscosity data was the average value for 3-5 measurements of at least three independent prepared samples.


X-ray diffraction patterns of CEL/PVP K12 ASD with various polymer loadings (a) 5% and 10% polymer loading (below c*), (b) 20% and 30% polymer loading (above c*) subjected to a controlled temperature program under ~60% RH. The temperatures at which the powder patterns were obtained are indicated. CEL crystallization is evident from the appearance of their characteristic peaks, which are marked in red.
X-ray diffraction patterns of LOR/PVP K12 ASD with various polymer loadings (c) 5% and 10% polymer loading (below c*), (d) 20% and 30% polymer loading (above c*) at day zero and after specified days stored at 60 °C and 0% RH. The days at which the powder patterns were obtained are indicated. LOR crystallization is evident from the appearance of their characteristic peaks, which are marked in red.