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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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1 3
Assessing theInterrelationship ofMicrostructure, Properties, Drug
Release Performance, andPreparation Process forAmorphous
Solid Dispersions Via Noninvasive Imaging Analytics andMaterial
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
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
ASD Amorphous solid dispersion
cPAD Co-precipitated amorphous dispersion
FaSSIF-V2 Fasted-state simulated intestinal fluid version
HME Hot-melt extrusion
SD Spray drying
SDD Spray dried dispersion
RAM Resonant acoustic mixing
VDD Vacuum drum drying
XRM X-ray microscopy
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
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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The unexpected dissolution behaviour of amorphous diflunisal-chitosan solid dispersions (kneading method) with respect to the crystalline co-evaporated systems is the starting point of this research. This work is an in-depth study of the diflunisal release behaviour from either chitosan or carboxymethylchitosan dispersions. The microstructure is not usually considered when designing this type of products; however, it is essential to understand the process of solvent penetration and subsequent drug release through a polymeric system, as has been evidenced in this study. In accordance with the kinetic data analysed, it is possible to conclude that the porous structure, conditioned by the sample preparation method, can be considered the main factor involved in diflunisal release. The low mean pore size (1–2 μm), low porosity, and high tortuosity of the amorphous kneaded products are responsible for the slow drug release in comparison with the crystalline coevaporated systems, which exhibit larger pore size (8–10 μm) and lower tortuosity. Nevertheless, all diflunisal-carboxymethylchitosan products show similar porous microstructure and overlapping dissolution profiles. The drug release mechanisms obtained can also be related to the porous structure. Fickian diffusion was the main mechanism involved in drug release from chitosan, whereas an important contribution of erosion was detected for carboxymethylchitosan systems, probably due to its high solubility.
... 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]. ...
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The performance of a pharmaceutical formulation, such as the drug (API) release rate, is significantly influenced by the properties of the materials used, the composition of the final product and the tablet compression process parameters. However, in some cases, the knowledge of these input parameters does not necessarily provide a reliable description or prediction of tablet performance. Therefore, the knowledge of tablet microstructure is desirable to understand such formulations. Commonly used analytical techniques, such as X-ray tomography and intrusion mercury porosimetry, are not widely used in pharmaceutical companies due to their price and/or toxicity, and therefore, efforts are made to develop a tool for fast and easy microstructure description. In this work, we have developed an image-based method for microstructure description and applied it to a model system consisting of ibuprofen and CaHPO 4 ∙2H 2 O (API and excipient with different deformability). The obtained parameter, the quadratic mean of the equivalent diameter of the non-deformable, brittle excipient CaHPO 4 ∙2H 2 O, was correlated with tablet composition, compression pressure and API release rate. The obtained results demonstrate the possibility of describing the tablet dissolution performance in the presented model system based on the microstructural parameter, providing a possible model system for compressed solid dosage forms in which a plastic component is present and specific API release is required. Graphical Abstract
... 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. ...
The mechanical properties of polymer-based amorphous solid dispersions (ASDs) are susceptible to changes in different relative humidity (RH) conditions. The purpose of this study is to understand the impact of RH on both the mechanical properties and tableting performance of Celecoxib-polyvinyl pyrrolidone vinyl acetate co-polymer (PVP/VA 64) ASDs. The ASDs were prepared by solvent evaporation technique to obtain films for nanoindentation, which were also pulverized to obtain powder for compaction. Our results show that higher RH corresponds to lower Hardness, H, and Elastic Modulus, E. At a given RH, both the E and H increase with drug loading to a maximum and decrease with further drug loading. Using ASD powders produced with a narrow particle size range (d50 = 9 - 14 µm), we have demonstrated that increasing RH from 11% to 67% leads to improved tablet tensile strength for pure PVP/VA 64 and the ASDs. However, the extent of the increase in tablet tensile strength depends on their mechanical properties, H and E, and drug loading. At higher compaction pressure and higher RH, the effect of ASD mechanical properties on tabletability is less because the particles are sufficiently deformed, and tablet strength is mainly contributed by the inter-particulate forces of attraction. Understanding the impact of these key processing conditions, i.e., RH and compaction pressure, will guide the design of an ASD tablet formulation with robust manufacturability.
... 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.
... 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. ...
... 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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Purpose Precipitation of amorphous solid dispersions has gained traction in the pharmaceutical industry given its application to pharmaceuticals with varying physicochemical properties. Although preparing co-precipitated amorphous dispersions (cPAD) in high-shear rotor–stator devices allows for controlled shear conditions during precipitation, such aggressive mixing environments can result in materials with low bulk density and poor flowability. This work investigated annealing cPAD after precipitation by washing with heated anti-solvent to improve bulk powder properties required for downstream drug product processing. Methods Co-precipitation dispersions were prepared by precipitation into pH-modified aqueous anti-solvent. Amorphous dispersions were washed with heated anti-solvent and assessed for bulk density, flowability, and dissolution behavior relative to both cPAD produced without a heated wash and spray dried intermediate. Results Washing cPAD with a heated anti-solvent resulted in an improvement in flowability and increased bulk density. The mechanism of densification was ascribed to annealing over the wetted Tg of the material, which lead to collapse of the porous co-precipitate structure into densified granules without causing crystallization. In contrast, an alternative approach to increase bulk density by precipitating the ASD using low shear conditions showed evidence of crystallinity. The dissolution rate of the densified cPAD granules was lower than that of the low-bulk density dispersions, although both samples reached concentrations equivalent to that of the spray dried intermediate after 90 min dissolution. Conclusions Hot wash densification was a tenable route to produce co-precipitated amorphous dispersions with improved properties for downstream processing compared to non-densified powders.
... 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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Amorphous solid dispersions (ASDs) are among the most popular and widely studied solubility enhancement techniques. Since their inception in the early 1960s, the formulation development of ASDs has undergone tremendous progress. For instance, the method of preparing ASDs evolved from solvent-based approaches to solvent-free methods such as hot melt extrusion and Kinetisol®. The formulation approaches have advanced from employing a single polymeric carrier to multiple carriers with plasticizers to improve the stability and performance of ASDs. Major excipient manufacturers recognized the potential of ASDs and began introducing specialty excipients ideal for formulating ASDs. In addition to traditional techniques such as differential scanning calorimeter (DSC) and X-ray crystallography, recent innovations such as nano-tomography, transmission electron microscopy (TEM), atomic force microscopy (AFM), and X-ray microscopy support a better understanding of the microstructure of ASDs. The purpose of this review is to highlight the recent advancements in the field of ASDs with respect to formulation approaches, methods of preparation, and advanced characterization techniques
Co-precipitation is an emerging manufacturing strategy for amorphous solid dispersions (ASDs). Herein, the interplay between processing conditions, surface composition and release performance was evaluated using grazoprevir and hypromellose acetate succinate as the model drug and ASD polymer, respectively. Co-precipitated amorphous solid dispersion (cPAD) particles were produced in the presence and absence of an additional polymer that was either dissolved or dispersed in the anti-solvent. This additional polymer in the anti-solvent was deposited on the surfaces of the cPAD particles during isolation and drying to create hierarchical particles, which we define here as a core ASD particle with an additional water soluble component that is coating the particle surfaces. The resultant hierarchical particles were characterized using X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy, and X-ray photoelectron spectroscopy (XPS). Release performance was evaluated using a two-stage dissolution test. XPS analysis revealed a trend whereby cPAD particles with a lower surface drug concentration showed improved release relative to particles with a higher surface drug concentration, for nominally similar drug loadings. This surface drug concentration could be impacted by whether the secondary polymer was dissolved in the anti-solvent or dispersed in the anti-solvent prior to isolating final dried hierarchical dry powders. Grazoprevir exposure in dogs was higher when the hierarchical cPAD was dosed, with ∼1.8 fold increase in AUC compared to the binary cPAD. These observations highlight the important interplay between processing conditions and ASD performance in the context of cPAD particles and illustrate a hierarchical particle design as a successful approach to alter ASD surface chemistry to improve dissolution performance.
Amorphous solid dispersions (ASDs) are an attractive option to improve the bioavailability of poorly water-soluble compounds. However, the material attributes of ASDs can present formulation and processability challenges, which are often mitigated by the addition of excipients albeit at the expense of tablet size. In this work, an ASD manufacturing train combining co-precipitation and thin film evaporation (TFE) was used to generate high bulk-density co-precipitated amorphous dispersion (cPAD). The cPAD/TFE material was directly compressed into tablets at amorphous solid dispersion loadings up to 89 wt%, representing a greater than 60% reduction in tablet size relative to formulated tablets containing spray dried intermediate (SDI). This high ASD loading was possible due to densification of the amorphous dispersion during drying by TFE. Pharmacokinetic performance of the TFE-isolated, co-precipitated dispersion was shown to be equivalent to an SDI formulation. These data highlight the downstream advantages of this novel ASD manufacturing pathway to facilitate reduced tablet size via high ASD loading in directly compressed tablets.
Amorphous solid dispersions (ASDs) are a well-documented formulation approach to improve the rate and extent of dissolution for hydrophobic pharmaceuticals. However, weakly basic compounds can complicate standard approaches to ASDs due to pH-dependent solubility, resulting in uncontrolled drug release in gastric conditions and unstabilized supersaturated solutions prone to precipitation at neutral pH. This work examines the release mechanisms of amorphous dispersions containing model weakly basic pharmaceuticals posaconazole and lumefantrine from a basic poly(dimethylaminoethyl methacrylate) copolymer (Eudragit EPO) and compares their dissolution behavior with ASDs stabilized by acidic and neutral polymers to understand potential benefits to release from a basic polymeric stabilizer. It was found that dissolution of Eudragit EPO ASDs resulted in supersaturation under gastric conditions, which could be sustained upon adjustment to neutral pH. However, the dissolution behavior of Eudragit EPO ASDs was sensitive to the initial pH of the gastric media. For lumefantrine, elevated initial gastric pH resulted in precipitation of amorphous nanoparticles; for posaconazole, elevated gastric pH led to crystallization of the pharmaceutical from solution. This sensitivity to gastric pH was found to originate from the impact of Eudragit EPO on gastric pH and the solubility of each pharmaceutical in the first stage of dissolution. In total, these data illustrate benefits and liabilities for the use of Eudragit EPO for ASDs containing weak pharmaceutical bases to guide the design of robust pharmaceutical formulations.
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Unlike the measure of the area in 2D or of the volume in 3D, the perimeter and the surface are not easily measurable in a discretized image. In this article we describe a method based on the Crofton formula to measure those two parameters in a discritized image. The accuracy of the method is discussed and tested on several known objects. An algorithm based on the run-length encoding of binary objects is presented and compared to other approaches. An implementation is provided and integrated in the LabelObject/LabelMap framework contributed earlier by the authors.
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Hollow SDD particles raise challenges with respect toappropriate and meaningful particle characterization. Whilstmeasurements of particle size and bulk density provide someinformation, the results can be confounded due to incorrectassumptions. Correspondingly, any correlation to powder/formulation properties may be erroneous or misleading.Quantitative knowledge about the size of the particle,the volume of solid contained within the particle, and themorphological habit is required to more adequately describethe range of morphological characteristics within an SDDsample and thereby a means to better understand theinfluence of the process conditions on the final particle andbulk powder properties.The work demonstrates an approach to utilizesubmicronCT measurements of particle and solid/void vol-umes for SDD particles to achieve a more appropriate meansto describe both the size and morphological habit of SDDparticles within a sample.The work also suggests a means to utilize the measuredsolid volume data to calculate the droplet size required tohold that volume of solid. This type of approach may enable afuture path to better model the link between droplet size andfinal particle size and thereby an understanding of theindividual droplet drying kinetics and particle formationmechanisms across an SDD sample as well as the parameterspace of SDD formulations.
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The present study explored vacuum drum drying (VDD) as an alternative technology for amorphous solid dispersions (ASDs) manufacture compared to hot-melt extrusion (HME) and spray drying (SD) focusing on downstream processability (powder properties, compression behavior and tablet performance). Ritonavir (15% w/w) in a copovidone/sorbitan monolaurate matrix was used as ASD model system. The pure ASDs and respective tablet blends (TB) (addition of filler, glidant, lubricant) were investigated. Milled extrudate showed superior powder properties (e.g., flowability, bulk density) compared to VDD and SD, which could be compensated by the addition of 12.9% outer phase. Advantageously, the VDD intermediate was directly compressible, whereas the SD material was not, resulting in tablets with defects based on a high degree of elastic recovery. Compared to HME, the VDD material showed superior tabletability when formulated as TB, resulting in stronger compacts at even lower solid fraction values. Despite the differences in tablet processing, tablets showed similar tablet performance in terms of disintegration and dissolution independent of the ASD origin. In conclusion, VDD is a valid alternative to manufacture ASDs. VDD offered advantageous downstream processability compared to SD: less solvents and process steps required (no second drying), improved powder properties and suitable for direct compression.
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Despite the ability to characterize the plasticity of powders in a material-sparing and expedited manner, the in-die Heckel analysis has been widely criticized for its sensitivity to several factors, such as particle elastic deformation, tooling size, lubrication, and speed. Using materials exhibiting a wide range of mechanical properties, we show that the in-die Py correlates strongly with three established plasticity parameters obtained from the out-of-die Heckel analysis, Kuentz-Leuenberger analysis, and macroindentation. Thus, the in-die Py is a reliable parameter for quantifying powder plasticity in a material-sparing and expedited manner.
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Within this study, tablets microstructure was investigated by X-ray microtomgraphy. The aim was to gain information about their microstructure, and thus, derive deeper interpretation of tablet properties (mechanical strength, component distribution) and qualified property functions. Challenges in image processing are discussed for the correct identification of solids and voids. Furthermore, XMT measurements are critically compared with complementary physical methods for characterizing active pharmaceutical ingredient (API) content and porosity and its distribution (mercury porosimetry, calculated tablet porosity, Focused Ion Beam-Scanning Electron Microscopy (FIB-SEM)). The derived porosity by XMT is generally lower than the calculated porosity based on geometrical data due to the resolution of the XMT in relation to the pore sizes in tablets. With rising compactions stress and API concentration, deviations between the actual and the calculated API decrease. XMT showed that API clusters are present for all tablets containing >1 wt% of ibuprofen. The 3D orientation of the components is assessable by deriving cord lengths along all dimensions of the tablets. An increasing compaction stress leads to rising cord lengths, showing higher connectivity of the respective material. Its lesser extent in the z-direction illustrates the anisotropy of the compaction process. Additionally, cracks in the fabric are identified in tablets without visible macroscopic damage. Finally, the application of XMT provides valuable structural insights if its limitations are taken into account and its strengths are fostered by advanced pre- and post-processing.
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Amorphous solid dispersions (ASD) have become a well-established strategy to improve exposure for compounds with insufficient aqueous solubility. Of methods to generate ASDs, spray drying is a leading route due to its relative simplicity, availability of equipment, and commercial scale capacity. However, the broader industry adoption of spray drying has revealed potential limitations, including the inability to process compounds with low solubility in volatile solvents, inconsistent molecular uniformity of spray dried amorphous dispersions, variable physical properties across batches and scales, and challenges containing potent compounds. In contrast, generating ASDs via co-precipitation to yield co-precipitated amorphous dispersions (cPAD) offers solutions to many of those challenges and has been shown to achieve ASDs comparable to those manufactured via spray drying. This manuscript applies co-precipitation for early safety studies, developing a streamlined process to achieve material suitable for dosing as a suspension in conventional toxicity studies. Development targets involved achieving a rapid, safely contained process for generating ASDs with high recovery yields. Furthermore, a hierarchical particle approach was used to generate composite particles where the cPAD material is incorporated in a matrix of water-soluble excipients to allow for rapid re-dispersibility in the safety study vehicle to achieve a uniform suspension for consistent dosing. Adopting such an approach yielded a co-precipitated amorphous dispersion with comparable stability, thermal properties, and in vivo pharmacokinetics to spray dried amorphous materials of the same composition.
Assessment and understanding of changes in particle size of active pharmaceutical ingredients (API) and excipients as a function of solid dosage form processing is an important but under-investigated area that can impact drug product quality. In this study, X-ray microscopy (XRM) was investigated as a method for determining the in situ particle size distribution of API agglomerates and an excipient at different processing stages in tablet manufacturing. An artificial intelligence (AI)-facilitated XRM image analysis tool was applied for quantitative analysis of thousands of individual particles, both of the API and the major filler component of the formulation, microcrystalline cellulose (MCC). Domain size distributions for API and MCC were generated along with the calculation of the porosity of each respective component. The API domain size distributions correlated with laser diffraction measurements and sieve analysis of the API, formulation blend, and granulation. The XRM analysis demonstrated that attrition of the API agglomerates occurred secondary to the granulation stage. These results were corroborated by particle size distribution and sieve potency data which showed generation of an API fines fraction. Additionally, changes in the XRM-calculated size distribution of MCC particles in subsequent processing steps were rationalized based on the known plastic deformation mechanism of MCC. The XRM data indicated that size distribution of the primary MCC particles, which make up the larger functional MCC agglomerates, is conserved across the stages of processing. The results indicate that XRM can be successfully applied as a direct, non-invasive method to track API and excipient particle properties and microstructure for in-process control samples and in the final solid dosage form. The XRM and AI image analysis methodology provides a data-rich way to interrogate the impact of processing stresses on API and excipients for enhanced process understanding and utilization for Quality by Design (QbD).
Active pharmaceutical ingredients (API) and excipients are often classified as ‘brittle’ or ‘ductile’ based on their yield pressure determined through the Heckel analysis. Such a brittle/ductile classification is often correlated to some measure of elasticity, die-wall stresses, and brittle fracture propensities from studies performed with a handful of model excipients. This subsequently gives rise to the presumption that all ductile materials behave similarly to microcrystalline cellulose (MCC) and that all brittle materials to lactose, mannitol, or dicalcium phosphate. Such a ‘one-size-fits-all’ approach can subsequently lead to inaccurate classification of APIs, which often behave very differently than these model excipients. This study compares the commonly reported mechanical metrics of two proprietary APIs and two classical model excipients. We demonstrate that materials classified as ‘ductile’ by Heckel's ‘standards’ may behave very differently than MCC and in some cases may even have a propensity for brittle failure. Our data highlight the complexity of APIs and the need to evaluate a set of mechanical metrics, instead of binary assignments of ductility or brittleness based on quantities that do not fully capture the tableting process, to truly optimize a tablet formulation as part of the overall target product profile.
An amorphous solid dispersion (ASD) of sorafenib (SOR) in hydroxypropyl methylcellulose acetate succinate (HPMC-AS), prepared by coprecipitation, was used to develop an immediate release tablet with improved oral bioavailability. An ASD of 40% drug loading with HPMC-AS (M grade), which exhibited superior physical stability and enhanced dissolution, was selected for tablet development. Systematic characterization of powder properties of the ASD led to the choice of the dry granulation process to overcome poor flowability of the ASD. The designed tablet formulation was evaluated using a material-sparing and expedited approach to optimize compaction conditions for manufacturing ASD tablets with low friability and rapid disintegration. The resulting SOR ASD tablets exhibited approximately 50% higher relative bioavailability in dogs than the marketed SOR tablet product, Nexavar®.
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.