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

S. Thakral; S. Koranne; R. Suryanarayanan

doi:10.1007/s11095-018-2499-x

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

S. Thakral, S. Koranne, R. Suryanarayanan

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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 not available: see fulltext.].

Original language	English (US)
Article number	214
Journal	Pharmaceutical research
Volume	35
Issue number	11
DOIs	https://doi.org/10.1007/s11095-018-2499-x
State	Published - Nov 1 2018

Bibliographical note

Funding Information:
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.

Publisher Copyright:
© 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Keywords

annealing
freeze-drying
intra-vial heterogeneity
mannitol
mannitol hemihydrate
synchrotron XRD

Publisher link

10.1007/s11095-018-2499-x

Find It

Find It at U of M Libraries

Cite this

@article{0f6b6074e0fa4e7392c830f7665a39cb,

title = "Intra-Vial Heterogeneity in Physical Form of Mannitol in Colyophilized Binary Systems",

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 {\AA}), 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 not available: see fulltext.].",

keywords = "annealing, freeze-drying, intra-vial heterogeneity, mannitol, mannitol hemihydrate, synchrotron XRD",

author = "S. Thakral and S. Koranne and R. Suryanarayanan",

note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2018, Springer Science+Business Media, LLC, part of Springer Nature.",

year = "2018",

month = nov,

day = "1",

doi = "10.1007/s11095-018-2499-x",

language = "English (US)",

volume = "35",

journal = "Pharmaceutical research",

issn = "0724-8741",

publisher = "Springer New York",

number = "11",

}

TY - JOUR

T1 - Intra-Vial Heterogeneity in Physical Form of Mannitol in Colyophilized Binary Systems

AU - Thakral, S.

AU - Koranne, S.

AU - Suryanarayanan, R.

N1 - Funding Information: 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. Publisher Copyright: © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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 not available: see fulltext.].

AB - 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 not available: see fulltext.].

KW - annealing

KW - freeze-drying

KW - intra-vial heterogeneity

KW - mannitol

KW - mannitol hemihydrate

KW - synchrotron XRD

UR - http://www.scopus.com/inward/record.url?scp=85053855588&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85053855588&partnerID=8YFLogxK

U2 - 10.1007/s11095-018-2499-x

DO - 10.1007/s11095-018-2499-x

M3 - Article

C2 - 30242778

AN - SCOPUS:85053855588

SN - 0724-8741

VL - 35

JO - Pharmaceutical research

JF - Pharmaceutical research

IS - 11

M1 - 214

ER -

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

Abstract

Bibliographical note

Keywords

Publisher link

Find It

Other files and links

Fingerprint

Cite this