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Assessing the Interrelationship of Microstructure, Properties, Drug Release Performance, and Preparation Process for Amorphous Solid Dispersions Via Noninvasive Imaging Analytics and Material Characterization

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Purpose The purpose of this work is to evaluate the interrelationship of microstructure, properties, and dissolution performance for amorphous solid dispersions (ASDs) prepared using different methods. Methods ASD of GDC-0810 (50% w/w) with HPMC-AS was prepared using methods of spray drying and co-precipitation via resonant acoustic mixing. Microstructure, particulate and bulk powder properties, and dissolution performance were characterized for GDC-0810 ASDs. In addition to application of typical physical characterization tools, we have applied X-Ray Microscopy (XRM) to assess the contribution of microstructure to the characteristics of ASDs and obtain additional quantification and understanding of the drug product intermediates and tablets. Results Both methods of spray drying and co-precipitation produced single-phase ASDs. Distinct differences in microstructure, particle size distribution, specific surface area, bulk and tapped density, were observed between GDC-0810 spray dried dispersion (SDD) and co-precipitated amorphous dispersion (cPAD) materials. The cPAD powders prepared by the resonant acoustic mixing process demonstrated superior compactibility compared to the SDD, while the compressibility of the ASDs were comparable. Both SDD powder and tablets showed higher in vitro dissolution than those of cPAD powders. XRM calculated total solid external surface area (SA) normalized by calculated total solid volume (SV) shows a strong correlation with micro dissolution data. Conclusion Strong interrelationship of microstructure, physical properties, and dissolution performance was observed for GDC-0810 ASDs. XRM image-based analysis is a powerful tool to assess the contribution of microstructure to the characteristics of ASDs and provide mechanistic understanding of the interrelationship.
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Pharmaceutical Research
https://doi.org/10.1007/s11095-022-03308-9
RESEARCH PAPER
Assessing theInterrelationship ofMicrostructure, Properties, Drug
Release Performance, andPreparation Process forAmorphous
Solid Dispersions Via Noninvasive Imaging Analytics andMaterial
Characterization
WeiJia1· Phillip D.Yawman2· KeyurM.Pandya1· KellieSluga1· TaniaNg1· DawenKou1· KarthikNagapudi1·
PaulE.Luner2,3· AidenZhu2· ShawnZhang2· HaoHelenHou1
Received: 28 February 2022 / Accepted: 27 May 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022
Abstract
Purpose The purpose of this work is to evaluate the interrelationship of microstructure, properties, and dissolution perfor-
mance for amorphous solid dispersions (ASDs) prepared using different methods.
Methods ASD of GDC-0810 (50% w/w) with HPMC-AS was prepared using methods of spray drying and co-precipitation
via resonant acoustic mixing. Microstructure, particulate and bulk powder properties, and dissolution performance were
characterized for GDC-0810 ASDs. In addition to application of typical physical characterization tools, we have applied
X-Ray Microscopy (XRM) to assess the contribution of microstructure to the characteristics of ASDs and obtain additional
quantification and understanding of the drug product intermediates and tablets.
Results Both methods of spray drying and co-precipitation produced single-phase ASDs. Distinct differences in micro-
structure, particle size distribution, specific surface area, bulk and tapped density, were observed between GDC-0810 spray
dried dispersion (SDD) and co-precipitated amorphous dispersion (cPAD) materials. The cPAD powders prepared by the
resonant acoustic mixing process demonstrated superior compactibility compared to the SDD, while the compressibility of
the ASDs were comparable. Both SDD powder and tablets showed higher in vitro dissolution than those of cPAD powders.
XRM calculated total solid external surface area (SA) normalized by calculated total solid volume (SV) shows a strong cor-
relation with micro dissolution data.
Conclusion Strong interrelationship of microstructure, physical properties, and dissolution performance was observed for
GDC-0810 ASDs. XRM image-based analysis is a powerful tool to assess the contribution of microstructure to the charac-
teristics of ASDs and provide mechanistic understanding of the interrelationship.
KEY WORDS amorphous solid dispersion· coprecipitation· material characterization· microstructure-property-
performance-process interrelationship· spray drying
Abbreviations
ASD Amorphous solid dispersion
cPAD Co-precipitated amorphous dispersion
FaSSIF-V2 Fasted-state simulated intestinal fluid version
2
HME Hot-melt extrusion
SD Spray drying
SDD Spray dried dispersion
RAM Resonant acoustic mixing
VDD Vacuum drum drying
XRM X-ray microscopy
INTRODUCTION
In small molecule drug discovery and development port-
folios, approximately 75% of compounds are poorly water-
soluble and classified as Biopharmaceutical Classification
* Hao Helen Hou
hou.hao@gene.com
1 Small Molecule Pharmaceutical Sciences, Genentech Inc., 1
DNA Way, SouthSanFrancisco, California94080, USA
2 DigiM Solution LLC, 67 South Bedford Street, Suite 400
West, Burlington, Massachusetts01803, USA
3 Triform Sciences LLC, Waterford, Connecticut06385, USA
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