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Expedited Tablet Formulation Development of a Highly Soluble Carbamazepine Cocrystal Enabled by Precipitation Inhibition in Diffusion Layer

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Abstract

Purpose

To address the problem of precipitation of a poorly soluble drug during dissolution of highly soluble cocrystals by preparing granules intimately mixed with a water-soluble polymer.

Methods

Effectiveness of polymers as precipitation inhibitors during the dissolution of carbamazepine–nicotinamide (CBZ-NCT) cocrystal was assessed based on induction time of crystallization from a supersaturated solution in presence of different polymers at two concentrations. Dissolution was evaluated by both intrinsic dissolution rate (IDR) and USP dissolution method. Powder manufacturability was assessed using a shear cell and compaction simulator to assess flowability and tabletability, respectively.

Results

Hydroxypropyl methylcellulose acetate succinate (HPMCAS) was the most effective polymer against precipitation of CBZ and the IDR of a 1:1 (w/w) CBZ-NCT/HPMCAS mixture was the highest. The final formulation of 1:1 CBZ-NCT/HPMCAS granule exhibited excellent flowability, good tabletability, and significantly improved drug release rate than cocrystal formulations without HPMCAS or the CBZ formulation.

Conclusion

The particle engineering strategy of modifying the diffusion layer on the surface of highly soluble cocrystal with a polymer is effective for inhibiting premature precipitation of CBZ. Assisted with predictive tools for characterizing powder flowability and tabletability, the design of high quality tablet product with improved drug release rate and manufacturability can be achieved in an efficient manner.

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Abbreviations

ASD:

Amorphous solid dispersion

CBZ:

Carbamazepine

HPMCAS:

Hydroxypropyl methylcellulose acetate succinate

IDR:

Intrinsic dissolution rate

NCT:

Nicotinamide

PXRD:

Powder X-ray diffraction pattern

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Acknowledgments and Disclosures

Parts of this work were carried out in the Characterization Facility, University of Minnesota, a member of the NSF-funded Materials Research Facilities Network (http://www.mrfn.org) via the MRSEC program.

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Authors and Affiliations

  1. Pharmaceutical Science & Technology Labs, Pharmaceutical Technology, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, 305-8585, Japan

    Hiroyuki Yamashita

  2. Pharmaceutical Materials Science and Engineering Laboratory, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, 9-127B Weaver-Densford Hall, 308 Harvard Street S.E., Minneapolis, MN, 55455, USA

    Hiroyuki Yamashita & Changquan Calvin Sun

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  1. Hiroyuki Yamashita
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  2. Changquan Calvin Sun
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Correspondence to Changquan Calvin Sun.

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Yamashita, H., Sun, C.C. Expedited Tablet Formulation Development of a Highly Soluble Carbamazepine Cocrystal Enabled by Precipitation Inhibition in Diffusion Layer. Pharm Res 36, 90 (2019). https://doi.org/10.1007/s11095-019-2622-7

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