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Probing the Molecular-Level Interactions in an Active Pharmaceutical Ingredient (API) - Polymer Dispersion and the Resulting Impact on Drug Product Formulation

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Abstract

Purpose

An investigation of underlying mechanisms of API-polymer interaction patterns has the potential to provide valuable insights for selecting appropriate formulations with superior physical stability and processability.

Materials and Methods

In this study, copovidone was used as a polymeric carrier for several model compounds including clotrimazole, nifedipine, and posaconazole. The varied chemical structures conferred the ability for the model compounds to form distinct interactions with copovidone. Rheology and nuclear magnetic resonance (NMR) were combined to investigate the molecular pattern and relative strength of active pharmaceutical ingredient (API)-polymer interactions. In addition, the impact of the interactions on formulation processability via hot melt extrusion (HME) and physical stability were evaluated.

Results

The rheological response of an API-polymer system was found to be highly sensitive to API-polymer interaction, depending both on API chemistry and API-polymer miscibility. In the systems studied, dispersed API induced a stronger plasticizer effect on the polymer matrix compared to crystalline/aggregated API. Correspondingly, the processing torque via HME showed a proportional relationship with the maximum complex viscosity of the API-polymer system. In order to quantitatively evaluate the relative strength of the API-polymer interaction, homogeneously dispersed API-polymer amorphous samples were prepared by HME at an elevated temperature. DSC, XRD, and rheology were employed to confirm the amorphous integrity and homogeneity of the resultant extrudates. Subsequently, the homogeneously dispersed API-polymer amorphous dispersions were interrogated by rheology and NMR to provide a qualitative and quantitative assessment of the nature of the API-polymer interaction, both macroscopically and microscopically. Rheological master curves of frequency sweeps of the extrudates exhibited a strong dependence on the API chemistry and revealed a rank ordering of the relative strength of API-copovidone interactions, in the order of posaconazole > nifedipine > clotrimazole. NMR data provided the means to precisely map the API-polymer interaction pattern and identify the specific sites of interaction from a molecular perspective. Finally, the impact of API-polymer interactions on the physical stability of the resultant extrudates was studied.

Conclusion

Qualitative and quantitative evaluation of the relative strength of the API-polymer interaction was successfully accomplished by utilizing combined rheology and NMR.

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors are grateful to MRL for the grant and support of this research.

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  1. Fengyuan Yang

    Present address: Ashland Inc., 500 Hercules Road, Bldg. 8162/204, Wilmington, Delaware, 19808, USA

Authors and Affiliations

  1. MRL, Merck & Co., Inc., West Point, Pennsylvania, USA

    Fengyuan Yang, Yongchao Su, James Small, Chengbin Huang, Andrew M. Farrington, James DiNunzio & Chad D. Brown

  2. School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin, USA

    Chengbin Huang

  3. MRL, Merck & Co., Inc., Rahway, New Jersey, USA

    Gary E. Martin & James DiNunzio

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Yang, F., Su, Y., Small, J. et al. Probing the Molecular-Level Interactions in an Active Pharmaceutical Ingredient (API) - Polymer Dispersion and the Resulting Impact on Drug Product Formulation. Pharm Res 37, 94 (2020). https://doi.org/10.1007/s11095-020-02813-z

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