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Densifying Co-Precipitated Amorphous Dispersions to Achieve Improved Bulk Powder Properties

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Abstract

Purpose

Precipitation of amorphous solid dispersions has gained traction in the pharmaceutical industry given its application to pharmaceuticals with varying physicochemical properties. Although preparing co-precipitated amorphous dispersions (cPAD) in high-shear rotor–stator devices allows for controlled shear conditions during precipitation, such aggressive mixing environments can result in materials with low bulk density and poor flowability. This work investigated annealing cPAD after precipitation by washing with heated anti-solvent to improve bulk powder properties required for downstream drug product processing.

Methods

Co-precipitation dispersions were prepared by precipitation into pH-modified aqueous anti-solvent. Amorphous dispersions were washed with heated anti-solvent and assessed for bulk density, flowability, and dissolution behavior relative to both cPAD produced without a heated wash and spray dried intermediate.

Results

Washing cPAD with a heated anti-solvent resulted in an improvement in flowability and increased bulk density. The mechanism of densification was ascribed to annealing over the wetted Tg of the material, which lead to collapse of the porous co-precipitate structure into densified granules without causing crystallization. In contrast, an alternative approach to increase bulk density by precipitating the ASD using low shear conditions showed evidence of crystallinity. The dissolution rate of the densified cPAD granules was lower than that of the low-bulk density dispersions, although both samples reached concentrations equivalent to that of the spray dried intermediate after 90 min dissolution.

Conclusions

Hot wash densification was a tenable route to produce co-precipitated amorphous dispersions with improved properties for downstream processing compared to non-densified powders.

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Acknowledgements

The authors acknowledge Steve Crowley, Jim DiNunzio, Edi Meco, and Graciela Terife for work producing the Compound X SDI, Sebastian Escotet, Prapti Kafle, Grace Okoh, Andrew Parker, and Laura Wareham for engaging discussions in the preparation of this work, and Erin Guidry, Joe Kukura, Matthew Lamm, Ian Mangion, Becky Ruck, and Neil Strotman for support.

Funding

This work was funded by Merck & Co., Inc., Rahway, NJ, USA.

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Authors and Affiliations

  1. Process Research & Development, Merck & Co., Inc., Rahway, NJ, USA

    Derek S. Frank & Luke Schenck

  2. Analytical Research & Development, Merck & Co., Inc., Rahway, NJ, USA

    Ashish Punia

  3. Pharmaceutical Commercialization Technology, Merck & Co., Inc., Rahway, NJ, USA

    Mairead Fahy

  4. Formulation Sciences, Merck & Co., Inc., Rahway, NJ, USA

    Chad Dalton & Jasmine Rowe

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Correspondence to Derek S. Frank.

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The authors declare no conflicts of interest. The authors are employees of Merck & Co. Inc, Rahway, NJ, USA. Merck & Co. Inc. had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

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Frank, D.S., Punia, A., Fahy, M. et al. Densifying Co-Precipitated Amorphous Dispersions to Achieve Improved Bulk Powder Properties. Pharm Res 39, 3197–3208 (2022). https://doi.org/10.1007/s11095-022-03416-6

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