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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

DOI:10.1007/s11095-022-03308-9
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Wei Jia
Wei Jia
Wei Jia
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Phillip D. Yawman
Phillip D. Yawman
Phillip D. Yawman
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Keyur M Pandya at Exelixis, Inc
Keyur M Pandya
Kellie Sluga
Kellie Sluga
Kellie Sluga
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Abstract and Figures

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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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
/ Published online: 3 June 2022
Pharmaceutical Research (2022) 39:3137–3154
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Most of the drugs currently discovered show low oral bioavailability due to poor water-solubility and belong to classes II and IV of the Biopharmaceutical Classification System (BSC) [1]. In order to resolve this drawback, the preparation of amorphous solid dispersions (ASD) using a variety of polymers has become a successful strategy to improve drug bioavailability after oral administration [2,3]. ...
... Other aspects resulting from the manufacturing process, such as porous structure, can be determinant in the dissolution behaviours of active ingredients formulated as solid dispersions. Thereby, a comprehensive study of drug release from solid dispersions would only be reached by a proper balance of all these factors, which will be involved to a different extent depending on the specific drug/carrier system and the frequently overlooked physical and microstructural properties of the solid dispersions [1]. The present study is an in-depth analysis of the factors involved in diflunisal release behaviour from DF-CS solid dispersions, considering the type of polymer employed and focusing especially on the interrelationship between the system microstructure, conditioned by the preparation method, and the dissolution behaviours. ...
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... On the other hand, the effect of particle properties and compression parameters on the tablet microstructure is more straightforward as it depends only on the mechanical properties of the materials used. The microstructure can be evaluated by overall tablet density/porosity and pore size distribution often measured by the mercury intrusion porosimetry [18] or by material (and porosity) distribution within the tablet where X-ray microscopy [19,20] and microtomography [5,21] and different chemical imaging methods come in. The most common ones would be methods based on vibrational spectroscopy -near-infrared and Raman mapping [22,23]; moreover, energy-dispersive X-ray spectroscopy based on scanning electron microscopy is also used frequently [6,24,25]. ...
Development of an Image-based Method for Tablet Microstructure Description and Its Correlation with API Release Rate
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... The ASD composition is expected to influence the mechanical properties, which in turn affect the tableting performance of the ASD powder (Sun, 2011;Patel et al., 2017). However, studies that highlight the impact of processing parameters, such as compaction pressure, or formulation variables on ASD product manufacturability are limited (Verreck et al., 2004;Patel et al., 2017;Jia et al., 2022;Zhang et al., 2022). In the absence of such fundamental understanding, formulation of an ASD-based tablet remains empirical and may lead to problems with manufacturing and tablet performance. ...
Effect of Drug Loading and Relative Humidity on the Mechanical Properties and Tableting Performance of Celecoxib–PVP/VA 64 Amorphous Solid Dispersions
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... Jia et al. 88 assessed the inter-dependence between microstructure, dissolution performance, and preparation process of cPASD by X-Ray Microscopy (XRM) analysis. The authors prepared cPASD of a BCS-II API, GDC-0810 with HPMC AS by RAM and studied the microstructure of the prepared cPASD. ...
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Active Pharmaceutical Ingredients (APIs) do not always exhibit processable physical properties, which makes their processing in an industrial setup very demanding. These issues often lead to poor robustness and higher cost of the drug product. The issue can be mitigated by co-processing the APIs using suitable solvent media-based techniques to streamline pharmaceutical manufacturing operations. Some of the co-processing methods are the amalgamation of API purification and granulation steps. These techniques also exhibit adequate robustness for successful adoption by the pharmaceutical industry to manufacture high quality drug products. Spherical crystallization and co-precipitation are solvent media-based co-processing approaches that enhances the micromeritic and dissolution characteristics of problematic APIs. These methods not only improve API characteristics but also enable direct compression into tablets. These methods are economical and time-saving as they have the potential for effectively circumventing the granulation step, which can be a major source of variability in the product. This review highlights the recent advancements pertaining to these techniques to aid researchers in adopting the right co-processing method. Similarly, the possibility of scaling up the production of co-processed APIs by these techniques is discussed. The continuous manufacturability by co-processing is outlined with a short note on Process Analytical Technology (PAT) applicability in monitoring and improving the process.
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... Jia et al. investigated the interrelationships among microstructure, properties, and drug dissolution performance of amorphous solid dispersions (ASD) prepared by two distinct processes, i.e., coprecipitation and spray-drying [8]. In addition to conventional techniques, they utilized X-ray microscopy (XRM) to characterize different ASD batches, which revealed a strong relationship between the total solid external surface area normalized by total solid volume and micro dissolution rate. ...
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... Additionally, while in some instances in vitro dissolution of cPAD particles and spray dried intermediate (SDI) are comparable, the wettability of cPAD bulk powder is often worse than SDI, which can challenge the ability to achieve a uniform suspension for formulations in toxicity studies or achieve complete dissolution. [25,26] Previous work has investigated precipitation conditions [18] and downstream unit operations such as dry granulation [27,28] to improve flow properties of cPAD. Recent work from our group demonstrated an approach to densify cPAD by briefly heating dispersions above their solvent-wetted glass transition temperatures. ...
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... In the past, traditional methods employed a large amount of API material to determine these properties. Considering recent advances, several material-sparing methods were developed for initial preformulation assessment [44,45]. As specified in the available literature, the difference in free energy is one of the notable properties that helps to understand the advantage of solubility for the amorphous form over the crystalline form. ...
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Characterizing the Impact of Spray Dried Particle Morphology on Tablet Dissolution Using Quantitative X-Ray Microscopy
Article
For oral solid dosage forms, disintegration and dissolution properties are closely related to the powders and particles used in their formulation. However, there remains a strong need to characterize the impact of particle structures on tablet compaction and performance. Three-dimensional non-invasive tomographic imaging plays an increasingly essential role in the characterization of drug substances, drug product intermediates, and drug products. It can reveal information hidden at the micro-scale which traditional characterization approaches fail to divulge due to a lack of resolution. In this study, two batches of spray-dried particles (SDP) and two corresponding tablets of an amorphous product, merestinib (LY2801653), were analyzed with 3D X-Ray Microscopy. Artificial intelligence-based image analytics were used to quantify physical properties, which were then correlated with dissolution behavior. The correlation derived from the image-based characterization was validated with conventional laboratory physical property measurements. Quantitative insights obtained from image-analysis including porosity, pore size distribution, surface area and pore connectivity helped to explain the differences in dissolution behavior between the two tablets, with root causes traceable to the microstructure differences in their corresponding SDPs.
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