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Intra-Vial Heterogeneity in Physical Form of Mannitol in Colyophilized Binary Systems

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Abstract

Purpose

To study spatial heterogeneity in phase composition when mannitol is co-lyophilized with non-crystallizing lyoprotectant, such as sucrose or trehalose. To study the influence of formulation composition and processing conditions on the extent of mannitol hemihydrate (MHH) formation in the final lyophile.

Methods

We used synchrotron X-ray diffractometry (XRD) to spatially map and thereby comprehensively characterize mannitol phase composition in unperturbed lyophiles. Low temperature thermal analysis and XRD was used to study phase behavior of frozen systems.

Result

When colyophilized with sucrose, trehalose or lysozyme as a second solute, mannitol crystallized partially as MHH (mannitol hemihydrate). The MHH content, based on the intensity of characteristic MHH peak (d-spacing 4.92 Å), was highest in the middle region of lyophile. This heterogeneity, studied in detail in presence of sucrose, occurred irrespective of cosolute content. Annealing the frozen solution at −30°C for 2 h essentially eliminated the heterogeneity, accompanied by an overall increase in MHH content. From differential scanning calorimetry it was evident that annealing caused mannitol crystallization while XRD revealed the crystallizing phase to be MHH.

Conclusion

The intra-vial heterogeneity and total MHH content in the final lyophile is a complex interplay of formulation composition and processing conditions.

Figure depicting spatial heterogeneity in mannitol hemihydrate content, when mannitol is lyophilized with a cosolute, such as sucrose, trealose or lysozyme.

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Abbreviations

API:

Active pharmaceutical ingredient

MHH:

Mannitol hemihydrate

RT:

Room temperature

XRD:

X-ray diffractometry

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ACKNOWLEDGMENTS AND DISCLOSURES

The project was partially supported by the William and Mildred Peters endowment fund. Use of the Advanced Photon Source was supported by U.S. Department of Energy, Office of Science, Office of Basic Energy Science, under Contract No. DE-AC02-06CH11357. We thank Dr. Wenqian Xu and Dr. Andrey Yakovenko for their help during the beamline experiments. Parts of this work were carried out in the Characterization Facility, University of Minnesota, which receives partial support from NSF through the MRSEC program.

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Author notes

  1. S. Koranne

    Present address: Merck Research Laboratories, RY80T-A130, 126, East Lincoln Avenue, Rahway, New Jersey, 07065, USA

  2. S. Thakral and S. Koranne contributed equally to the work.

Authors and Affiliations

  1. Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, 55455, USA

    S. Thakral, S. Koranne & R. Suryanarayanan

  2. Characterization Facility, University of Minnesota, Minneapolis, Minnesota, 55455, USA

    S. Thakral

Authors
  1. S. Thakral
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  2. S. Koranne
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Correspondence to R. Suryanarayanan.

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Thakral, S., Koranne, S. & Suryanarayanan, R. Intra-Vial Heterogeneity in Physical Form of Mannitol in Colyophilized Binary Systems. Pharm Res 35, 214 (2018). https://doi.org/10.1007/s11095-018-2499-x

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  • DOI: https://doi.org/10.1007/s11095-018-2499-x

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