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Characterization of Controlled Release Microspheres Using FIB-SEM and Image-Based Release Prediction
Abstract
For polymer-based controlled release drug products (e.g. microspheres and implants), active pharmaceutical ingredient distribution and microporosity inside the polymer matrix are critical for product performance, particularly drug release kinetics. Due to the decreasing domain size and increasing complexity of such products, conventional characterization and release test techniques are limited by their resolution and speed. In this study, samples of controlled release poly(lactic-co-glycolic acid) microspheres in the diameter range of 30–80 μm are investigated with focused ion beam scanning electron microscope imaging at 20 nm or higher resolution. Image data is quantified with artificial intelligence-based image analytics to provide size distributions of drug particles and pores within the microsphere sample. With an innovative image-based numerical simulation method, release profiles are predicted in a matter of days regardless of the designed release time. A mechanistic understanding on the impact of porosity to the interplays of drug, formulation, process, and dissolution was gained.
... generated by the ion source is accelerated by the ion gun and acts on the sample surface, while the atoms on the surface are stripped by the ion beam with strong current to achieve the nano surface topography processing without disrupting microspheres in the next layer. 29,85 Compared with mechanically-cut microspheres, FIB can provide higher accuracy and precision, thus obtaining a clean and artifact-free cross section for high-resolution SEM imaging. 8,98 For subsequent SEM imaging, the beam emitted by the electron gun passes through a pair of objective lens and aperture to form an extremely narrow high-energy electron beam, which is further focused on the sample surface through objective lens. ...
... After repeated FIB milling and subsequent SEM imaging, hundreds of SEM images are collected from the same microsphere, so that the internal microstructure of microspheres can be visualized at nanometer resolution in 3D. 29 Furthermore, microsphere reconstruction with AI-based image analytics combining with the 3D tomography allows the compute of quantitative information including volume fractions, spatial distribution homogeneity and particle/pore size distribution. 8,29 One of the most critical restrictions for this technique is the time-consuming nature. ...
... 29 Furthermore, microsphere reconstruction with AI-based image analytics combining with the 3D tomography allows the compute of quantitative information including volume fractions, spatial distribution homogeneity and particle/pore size distribution. 8,29 One of the most critical restrictions for this technique is the time-consuming nature. It takes several hours to obtain FIB-SEM images of a single microsphere and several days to analyze and compute images. ...
Long-acting injectable microspheres have been on the market for more than three decades, but if calculated on the brand name, only 12 products have been approved by the FDA due to numerous challenges in achieving a fully controllable drug release pattern. Recently, more and more researches on the critical factors that determine the release kinetics of microspheres shifted from evaluating the typical physicochemical properties to exploring the microstructure. The microstructure of microspheres mainly includes the spatial distribution and the dispersed state of drug, PLGA and pores, which has been considered as one of the most important characteristics of microspheres, especially when comparative characterization of the microstructure (Q3) has been recommended by the FDA for the bioequivalence assessment. This review extracted the main variables affecting the microstructure formation from microsphere formulation compositions and preparation processes and highlighted the latest advances in microstructure characterization techniques. The further understanding of the microsphere microstructure has significant reference value for the development of long-acting injectable microspheres, particularly for the development of the generic microspheres.
... Recognizing the critical role that microstructures can play in the performance of complex drug products (e.g., topical dermatologic products), the FDA has recommended comparative characterization of microstructure (Q3) studies as part of bioequivalence assessment when applicable, i.e., the demonstration of "a similar arrangement of matter" between a proposed generic product and the reference listed drug (RLD) [11]. In the case of PLGA microspheres, a major factor governing drug release and performance is the underlying structure of the formulation, including the microsphere size distribution, distribution of active pharmaceutical ingredient (API) within the spheres, and the presence of any porosity [12,13]. Accordingly, characterization of the microstructure of these microspheres can serve as a quantitative pathway toward establishing Q3 bioequivalence. ...
... High resolution electron imaging combined with ion milling, i.e., focused ion beam (FIB) SEM, and AI image analytics have been shown to be powerful tools for directly quantifying the intra-sphere microstructure of PLGA microsphere samples [12,14]. Fig. 1c shows a representative image of a microsphere cross-section obtained using FIB-SEM, while Fig. 1d shows the AI assisted 3D reconstruction of hundreds of FIB-SEM images of the microspheres. ...
... Fig. 1c shows a representative image of a microsphere cross-section obtained using FIB-SEM, while Fig. 1d shows the AI assisted 3D reconstruction of hundreds of FIB-SEM images of the microspheres. Despite the powerful elucidation and quantification of intra-sphere microstructures, FIB-SEM is limited by its throughput as the technique requires several hours of imaging and analysis to determine the microstructure of one microsphere [12,13,15]. The time and cost required to determine the microstructure of a statistically representative number of microspheres would be prohibitive. ...
The intra-sphere and inter-sphere structural attributes of controlled release microsphere drug products can greatly impact their release profile and clinical performance. In developing a robust and efficient method to characterize the structure of microsphere drug products, this paper proposes X-ray microscopy (XRM) combined with artificial intelligence (AI)-based image analytics. Eight minocycline loaded poly(lactic-co-glycolic acid) (PLGA) microsphere batches were produced with controlled variations in manufacturing parameters, leading to differences in their underlying microstructures and their final release performances. A representative number of microspheres samples from each batch were imaged using high resolution, non-invasive XRM. Reconstructed images and AI-assisted segmentation were used to determine the size distribution, XRM signal intensity, and intensity variation of thousands of microspheres per sample. The signal intensity within the eight batches was nearly constant over the range of microsphere diameters, indicating high structural similarity of spheres within the same batch. Observed differences in the variation of signal intensity between different batches suggests inter-batch non-uniformity arising from differences in the underlying microstructures associated with different manufacturing parameters. These intensity variations were correlated with the structures observed from higher resolution focused ion beam scanning electron microscopy (FIB-SEM) and the in vitro release performance for the batches. The potential for this method for rapid at-line and offline product quality assessment, quality control, and quality assurance is discussed.
... Recently this image-based method has been used to investigate the microstructure of a commercial PLGA microsphere product, Arestin® [19]. Through image-based simulations it was shown that removal of the microsphere's native pore network resulted in a five times slower release [19]. ...
... Recently this image-based method has been used to investigate the microstructure of a commercial PLGA microsphere product, Arestin® [19]. Through image-based simulations it was shown that removal of the microsphere's native pore network resulted in a five times slower release [19]. This result has profound implications for the development of similar PLGA microsphere products, underscoring the significant role that microstructure plays in the API release kinetics of microsphere products. ...
... Image analytics were performed using DigiM™ I2S cloud-based image analysis platform (DigiM Solution, USA). Raw SEM images were corrected for stage drifting, non-uniform illumination, and curtaining artifacts due to the long imaging time, tilted imaging geometry, and material heterogeneity [19]. Microsphere internal structures were classified into three material phases: polymer, API, and pores. ...
The distribution of the active pharmaceutical ingredient (API) within polymer-based controlled release drug products is a critical quality attribute (CQA). It is crucial for the development of such products, to be able to accurately characterize phase distributions in these products to evaluate performance and microstructure (Q3) equivalence. In this study, polymer, API, and porosity distributions in poly(lactic-co-glycolic acid) (PLGA) microspheres were characterized using a combination of focused ion beam scanning electron microscopy (FIB-SEM) and quantitative artificial intelligence (AI) image analytics. Through in-depth investigations of nine different microsphere formulations, microstructural CQAs were identified including the abundance, domain size, and distribution of the API, the polymer, and the microporosity. 3D models, digitally transformed from the FIB-SEM images, were reconstructed to predict controlled drug release numerically. Agreement between the in vitro release experiments and the predictions validated the image-based release modelling method. Sensitivity analysis revealed the dependence of release on the distribution and size of the API particles and the porosity within the polymeric microspheres, as captured through FIB-SEM imaging. To our knowledge, this is the first report showing that microstructural CQAs in PLGA microspheres derived from imaging can be quantitatively and predictively correlated with formulation and manufacturing parameters.
... In addition to training using temporal correlation imaging data, i.e., data acquired over time under aforementioned conditions, the training can also be conducted using process correlation (e.g, changes during tablet compaction elucidating particle morphology and interlocking mechanism evoluation 27 ), scale correlation (e.g, intra-particle characterization via FIB-SEM and inter-particle characterization via XRM 28 ), modality correlation (e.g, X-ray and Raman), and structuralchemical correlation (e.g., particle morphology via SEM and particle chemical composition via energy dispersion (X-Ray) spectroscopy (EDX) 29 . ...
Pharmaceutical drug dosage forms are critical for ensuring the effective and safe delivery of active pharmaceutical ingredients to patients. However, traditional formulation development often relies on extensive lab and animal experimentation, which can be time-consuming and costly. This manuscript presents a generative artificial intelligence method that creates digital versions of drug products from images of exemplar products. This approach employs an image generator guided by critical quality attributes, such as particle size and drug loading, to create realistic digital product variations that can be analyzed and optimized digitally. This paper shows how this method was validated through two case studies: one for the determination of the amount of material that will create a percolating network in an oral tablet product and another for the optimization of drug distribution in a long-acting HIV inhibitor implant. The results demonstrate that the generative AI method accurately predicts a percolation threshold of 4.2% weight of microcrystalline cellulose and generates implant formulations with controlled drug loading and particle size distributions. Comparisons with real samples reveal that the synthesized structures exhibit comparable particle size distributions and transport properties in release media.
... The sample was then coated with a thin layer of gold using an ion sputtering device to prevent charge accumulation and ensure accurate results. The micro-scale morphology of the polymer microspheres was observed using a scanning electron microscope (SEM), and micrographs of the dry microspheres were captured at different magnifications, documenting their microscopic shape and structure [44,45]. ...
Polymer microspheres with temperature and salt resistance were synthesized using the anti-suspension polymerization method, incorporating the functional monomers AMPS, AM, and AA. To enhance their self-gelling properties, the microspheres were designed with a core–shell structure. The shell is composed of a polymeric surfactant, fatty alcohol polyoxyethylene ether methacrylate (AEOMA), which serves as a thermosensitive crosslinking agent, enabling self-crosslinking upon shell decomposition, addressing compatibility with reservoir pore throat dimensions. Comprehensive characterizations including infrared spectroscopy, scanning electron microscopy, optical microscopy, and laser particle size analysis were conducted. The microspheres exhibited successful synthesis, a nanoscale size, and regular spherical morphology. They demonstrated excellent temperature and salt resistance, making them suitable for high-temperature, high-salinity reservoir profile control. With a stable three-dimensional network structure, the microspheres displayed good expansion behavior due to hydrophilic groups along the polymer chains, resulting in favorable water affinity. Even after aging, the microspheres maintained their gelling state with a distinct and stable microscopic network skeleton. They exhibited superior plugging performance in low-permeability reservoirs, while effectively improving water absorption profiles in reservoirs with permeability contrasts of 10 to 80, thereby enhancing oil recovery.
... At the same time the fluid enters the tablet through the pores and its network resulting in the disintegration of the tablet into smaller pieces and this stage is effectively controlled by the concentration of pores [242][243][244][245][246]293,[345][346][347]. By extracting the information of the pore network and its permeability from a SEM image, Zhang et al. [348] has shown that one can estimate the drug release rate by computational fluid dynamic simulation. Similarly, microtomography images are used to validate computational dissolution models such as in silico tools [349]. ...
Solid dosage forms such as tablets are extensively used in drug administration for their simplicity and large-scale manufacturing capabilities. High-resolution X-ray tomography is one of the most valuable non-destructive techniques to investigate the internal structure of the tablets for drug product development as well as for a cost effective production process. In this work, we review the recent developments in high-resolution X-ray microtomography and its application towards different tablet characterizations. The increased availability of powerful laboratory instrumentation, as well as the advent of high brilliance and coherent 3rd generation synchrotron light sources, combined with advanced data processing techniques, are driving the application of X-ray microtomography forward as an indispensable tool in the pharmaceutical industry.
... The image stack from FIB-SEM can be reconstructed into a 3D volume, which can help to understand in nanoscale. This technique has been explored for release profile prediction, drug particle distribution, and pore size uniformity of PLGA microspheres [49]. The 3D reconstruction of the image obtained from FIB-SEM showed the distribution of drug particles (risperidone) throughout the microspheres, with 41% of the volume of PLGA (PLGA Expansorb Ò 75-7E) by risperidone and 23% porosity. ...
Long-acting injectable (LAI) delivery technologies have enabled the development of several pharmaceutical products that improve patient health by delivering therapeutics from weeks to months. Over the last decade, due to its good biocompatibility, formulation tunability, wide range of degradation rates, and extensive clinical studies, polyester-based LAI technologies including poly(lactic-co-glycolic acid) (PLGA) have made substantial progress. Herein, we discuss PLGA properties with seminal approaches in the development of LAIs, the role of molecular dynamic simulations of polymer–drug interactions, and their effects on quality attributes. We also outline the landscape of various advanced PLGA-based and a few non-PLGA LAI technologies; their design, delivery, and challenges from laboratory scale to preclinical and clinical use; and commercial products incorporating the importance of end-user preferences.
... The application of AI to the 3D grey scale images additionally allows for understanding of not only the API component but also of the excipients and the intermediate powder or granule or the finished dosage form. Furthermore, the ability to then use the image based microstructural data to "measure" porosity and permeability (38) and also conduct mechanistically based performance simulations (64) can reduce the need for time-consuming specialized ancillary testing. ...
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.
... In this work, an artificial intelligence-based image segmentation algorithm (AIBIS) developed by DigiM was used to overcome the limitation of the conventional approach. The method has been discussed and validated extensively in a variety of pharmaceutical applications [27][28][29][30][31][32]. In brief, the AIBIS algorithm mimics the ability of the human eyes which can recognize a feature not only based on the greyscale value of pixels, but also its relationship with its surrounding pixels. ...
Imaging-based characterization of polymeric drug-eluting implants can be challenging due to the microstructural complexity and scale of dispersed drug domains and polymer matrix. The typical evaluation via real-time (and accelerated in vitro experiments not only can be very labor intensive since implants are designed to last for 3 months or longer, but also fails to elucidate the impact of the internal microstructure on the implant release rate. A novel characterization technique, combining multi-scale high resolution three-dimensional imaging, was developed for a mechanistic understanding of the impact of formulation and manufacturing process on the implant microstructure. Artificial intelligence-based image segmentation and imaging analytics convert “visualized” structural properties into numerical models, which can be used to calculate key parameters governing drug transport in the polymer matrix, such as effective permeability. Simulations of drug transport in structures constructed on the basis of image analytics can be used to predict the release rates for the drug-eluting implant without running lengthy experiments. Multi-scale imaging approach and image-based characterization generate a large amount of quantitative structural information that are difficult to obtain experimentally. The direct-imaging based analytics and simulation is a powerful tool and has potential to advance fundamental understanding of drug release mechanism and the development of robust drug-eluting implants.
... [4][5] Numerical drug formulations can be constructed from the real image data, evaluating factors such as optimal drug loading and porosity. 6 The numerical model allows a pharmaceutical scientist to rapidly traverse multi-variable parameter space, and narrow down formulation parameters and optimal processing conditions. The I2S platform has been utilized and validated for a variety of dosage forms and challenge areas. ...
... The XeF2 dry etching and the CO2 laser exposure also can fabricate such a microtoroid [32]. And then, the focused ion beam (FIB) method [33], [34] is applied to the microtoroid structure to fabricate truncated microtoroid with different height. A PNJ with an enhanced intensity of 55.21 times to the incident light, ultralong length up to 46.47 , narrow FWHM of 0.77 and high quality factor of 3308.68 generated by the semi-microtoroid. ...
A photonic nanojet (PNJ) is a highly confined light beam that focuses from the shadow side of microparticles. In this work, we propose a PNJ with ultrahigh quality factor formed by dielectric truncated-microdoughnut. The key properties of PNJ, such as the maximum intensity, the length of PNJ, the full-width at half maximum (FWHM), are studied in detail using finite-difference time-domain (FDTD) analysis. The results show that a PNJ with an enhanced intensity of 55.21 times to the incident light, superlong length of and subwavelength FWHM of is formed by semi-microdoughnut, thus, an ultrahigh quality factor of 3308.68 is achieved. More importantly, the properties of the PNJ are tunable by changing the truncated proportions of the microdoughnut. The structure we proposed has the advantages of compact structure and simple experimental operation, which is expected to apply in many research fields, including optical detection, optical data storage, super-resolution image, nanopattern, nanolithography, and so on.
... The time dependent simulation of a microparticle's motion to the traps was confirmed by experimental data (Fig. 9). Similarly, Zhang et al. used FIB-SEM to study the effects of drug distribution and micro-porosity on controlled release characteristics [180]. PBM was implemented to study mass transport, controlling the size, and stability of microspheres. ...
Polymeric microparticles are preferred over the non-polymeric one based on the market trends and diverse conventional methods have been used to fabricate the polymeric microparticles. However, poor encapsulation, unpredictable drug release, non-uniform particle size, difficulties of removing the residual solvent, and tedious scale-up procedures associated with the traditional techniques affected the overall quality attributes of the formulation. This might lead to the development of novel approaches (droplet-microfluidics/microchips, membrane emulsification, ultra-fine particle processing system, self-healing encapsulation) for microparticles preparation. These novel methods are capable of delivering desired quality products by eliminating the quality and manufacturing issues. This review systematically outlines various quality attributes of microparticles along with innovative methods to overcome the manufacturing-related limitations of the conventional preparations. Furthermore, this review discusses in vitro-in vivo correlation concerning the parenteral microparticles as an essential quality parameter in formulation development. Moreover, different simulation models like population balance model, computational fluid dynamics, finite element model, and fine element analysis are elaborated to define polymer erosion, degradation, burst release, injectability, and drug release profiles, which will affect overall quality of microparticles.
... Such approaches could potentially improve drug-development efficiencies with respect to time and material costs, as well as reduce the burden of animal and/or clinical screening studies. Image-based characterization data were also used to correlate formulation parameters with drug release performance through numerical simulations of effective diffusivity coefficients, disintegration patterns, and various designed release behaviors [4]. Geoscience. ...
Management, Analysis, and Simulation of Micrographs with Cloud Computing - Volume 27 Issue 2 - Shawn Zhang, Alan P. Byrnes, Jasna Jankovic, Joseph Neilly
The microstructures of pharmaceutical preparations play a pivotal role in determining their critical quality attributes, such as drug release, content uniformity, and stability, which greatly impact the safety and efficacy of drugs. Unlike the inherent molecular structures of active pharmaceutical ingredients and excipients, the microstructures of pharmaceutical preparations are developed during the formulation process, presenting unique analytical challenges. In this review, we primarily focus on presenting the research methods used to elucidate the microstructures of pharmaceutical preparations, including X-ray imaging, scanning electron microscopy, atomic force microscopy, Raman spectroscopy, infrared spectroscopy, and rheometer technology. Subsequently, we highlight the applications, advantages, and limitations of these methods. Finally, we discuss the current challenges and future perspectives in this field. This review aims to provide a comprehensive reference for understanding the microstructures of pharmaceutical preparations, offering new insights and potential advancements in their development.
Introduction: Kartogenin, a potent inducer of chondrogenic differentiation in mesenchymal stem cells and a key agent in cartilage regeneration, presents a viable therapeutic strategy for osteoarthritis management. Despite the abundance of literature on therapeutic potential of kartogenin, there is a paucity of studies characterizing the formulation specifics in microsphere fabrication. This exploration is pivotal to advances in regenerative medicine, particularly in the domain of cartilage regeneration, to assure clinical efficacy and safety.
Methods: In this work, we fabricated kartogenin-loaded PLGA microspheres with diverse formulations and their particle size, size distribution, encapsulation efficiency, drug loading and release profiles were characterized. Ratio of polymer, drug, and solvent and the use of surfactant was used as variables, and in particular, the effect of surfactant on particles was investigated.
Results: The average diameter of the spheres was 16.0–31.7 μm. Morphological variations from solid to porous surface structures depending on surfactant incorporation during the emulsification process was observed. Cumulative kartogenin release from microspheres ranged from 53.8% to 80.9% on day 28, and release profiles conform predominantly to the Korsmeyer-Peppas kinetics model.
Discussion: This study provides a foundational framework for modulating kartogenin release dynamics, a critical consideration for optimizing therapeutic efficacy and minimizing adverse effects in cartilage tissue engineering applications.
Poly(lactic-co-glycolic acid) (PLGA) microspheres are a sustained-release drug delivery system with several successful commercial products used for the treatment of a variety of diseases. By utilizing PLGA polymers with different compositions, therapeutic agents can be released over durations varying from several weeks to several months. However, precise quality control of PLGA polymers and a fundamental understanding of all the factors associated with the performance of PLGA microsphere formulations remains challenging. This knowledge gap can hinder product development of both innovator and generic products. In this review, variability of the key release controlling excipient (PLGA), as well as advanced physicochemical characterization techniques for the PLGA polymer and PLGA microspheres are discussed. The relative merits and challenges of different in vitro release testing methods, in vivo pharmacokinetic studies, and in vitro-in vivo correlation development are also summarized. This review is intended to provide an in-depth understanding of long-acting microsphere products and consequently facilitate the development of these complex products.
Poly (lactic-co-glycolic acid) (PLGA) microspheres have been one of the most successful products for slow drug release. While distribution of drugs in microspheres might be a fundamental factor affecting drug release, it has been often overlooked. Indeed, very few studies are available on the distribution of drugs in microspheres with complex morphology, like e.g. golf ball-shaped microspheres. In this paper, the distribution of rotigotine in golf ball-shaped microspheres (GSRM) was investigated by argon ion milling, combined with scanning electron microscopy and energy dispersive X-ray spectroscopy (AIM-SEM-EDS). Rotigotine in GSRM was clearly observed in two forms, respectively in an aggregated state and as a molecular dispersion. The distribution of palmitic acid in the microspheres (used as an additive to reduce burst release) was also demonstrated: 10% was found on the microspheres' surface while 90% separated from the polymer to form small particles inside the microspheres onto which rotigotine aggregated through hydrogen bonding interactions. In in-vitro release studies we observed that first the phase-separated palmitic acid/rotigotine particles dissolved and released the drug, followed by the release of the molecularly dispersed rotigotines by osmosis. We also found that rotigotine accelerated the degradation and reduced the glass transition temperature of PLGA, which played an important role as well in the release of the drug from GSRM. Finally, two linear Level A in vitro-in vivo correlations were established and validated, indicating that the in vitro release testing could be a meaningful predictor for the in vivo performance of GSRM. Our work demonstrates the importance of studying drug distribution in complex microspheres to understand drug release.
Introduction:
Long acting Injectable PLGA microspheres have gained more and more interest and attention in the field of life cycle management of pharmaceutical products due to their biocompatibility and biodegradability. So far, a multitude of trial-and-error experiments at lab scale have been used for establishing the correlation relationship between critical process parameters, critical material attributes and critical quality attributes. However, few published studies have elaborated on the development of PLGA microspheres from an industrial perspective.
Areas covered:
In this review, the scale-up feasibility of translational technologies of PLGA microspheres manufacturing have been evaluated. Additionally, state-of-the-art of technologies and facilities in PLGA development have been summarized. Meanwhile, the industrial knowledge matrix of PLGA microspheres development and research are establishing which provide comprehensive insight for understanding properties of PLGA microspheres as controlled/sustained release vehicle.
Expert opinion:
There is still big gap between fundamental research in academic institute and product development in pharmaceuticals. Therefore, the difference and connection between them should be identified gradually for better understanding of PLGA microspheres development.
The development of long-acting drug formulations requires efficient characterization technique as the designed 6-12 months release duration renders real-time in vitro and in vivo experiments cost and time prohibitive. Using a novel image-based release modeling method, release profiles were predicted from X-Ray Microscopy (XRM) of T0 samples. A validation study with the in vitro release test shows good prediction accuracy of the initial burst release. Through fast T0 image-based release prediction, the impact of formulation and process parameters on burst release rate was investigated. Recognizing the limitations of XRM, correlative imaging with Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) was introduced. A water stress test was designed to directly elucidate the formation of pores through polymer-drug-water interplay. Through an iterative correction method that considers poly(lactic-co-glycolic acid) (PLGA) polymer degradation, good agreement was achieved between release predictions using FIB-SEM images acquired from T0 samples and in vitro testing data. Furthermore, using image-based release simulations, a practical percolation threshold was identified that has profound influence on the implant performance. It is proposed as an important critical quality attribute for biodegradable long-acting delivery system, that needs to be investigated and quantified.
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.
Long-acting implants are typically formulated using carrier(s) with specific physical and chemical properties, along with the active pharmaceutical ingredient (API), to achieve the desired daily exposure for the target duration of action. In characterizing such formulations, real-time in-vitro and in-vivo experiments that are typically used to characterize implants are lengthy, costly, and labor intensive as these implants are designed to be long acting. A novel characterization technique, combining high resolution three-dimensional X-Ray microscopy imaging, image-based quantification, and transport simulation, has been employed to provide a mechanistic understanding of formulation and process impact on the microstructures and performance of a polymer-based implant. Artificial intelligence-based image segmentation and image data analytics were used to convert morphological features visualized at high resolution into numerical microstructure models. These digital models were then used to calculate key physical parameters governing drug transport in a polymer matrix, including API uniformity, API domain size, and permeability. This powerful new tool has the potential to advance the mechanistic understanding of the interplay between drug-microstructure and performance and accelerate the therapeutic development long-acting implants.
Mass transport mechanisms of drug release inside a pellet formulation through polymer membrane were investigated with focused ion beam scanning electron microscopy (FIB-SEM). Through careful control of imaging conditions, sub-surface cross sectional images were acquired on two controlled release membrane samples. Image analysis of porosity, pore size distribution, and pore connectivity in 3D provided a matrix of parameters to quantitatively compare samples from different formulations and processing conditions. Image-based computational fluid dynamics simulations were employed to correlate membrane microporosity with flow permeability. Through high resolution FIB-SEM characterization, quantitative microporosity analysis, and mechanistic investigations of flow via image-based simulations, it was found that a 10% difference in the water content of the mixed aqueous-organic solvent used to dissolve polymers had a significant impact on the controlled release performance. This approach provides an analytical avenue to evaluate effects of permeation enhancers, solvents, and other process conditions on controlled release formulations.
Management, Analysis, and Simulation of Micrographs with Cloud Computing - Volume 27 Issue 2 - Shawn Zhang, Alan P. Byrnes, Jasna Jankovic, Joseph Neilly
Poly(lactic-co-glycolic acid) (PLGA) is the most widely used biomaterial for microencapsulation and prolonged delivery of therapeutic drugs, proteins and antigens. PLGA has excellent biodegradability and biocompatibility and is generally recognized as safe by international regulatory agencies including the United States Food and Drug Administration and the European Medicines Agency. The physicochemical properties of PLGA may be varied systematically by changing the ratio of lactic acid to glycolic acid. This in turn alters the release rate of microencapsulated therapeutic molecules from PLGA microparticle formulations. The obstacles hindering more widespread use of PLGA for producing sustained-release formulations for clinical use include low drug loading, particularly of hydrophilic small molecules, high initial burst release and/or poor formulation stability. In this review, we address strategies aimed at overcoming these challenges. These include use of low-temperature double-emulsion methods to increase drug-loading by producing PLGA particles with a small volume for the inner water phase and a suitable pH of the external phase. Newer strategies for producing PLGA particles with high drug loading and the desired sustained-release profiles include fabrication of multi-layered microparticles, nanoparticles-in-microparticles, use of hydrogel templates, as well as coaxial electrospray, microfluidics, and supercritical carbon dioxide methods. Another recent strategy with promise for producing particles with well-controlled and reproducible sustained-release profiles involves complexation of PLGA with additives such as polyethylene glycol, poly(ortho esters), chitosan, alginate, caffeic acid, hyaluronic acid, and silicon dioxide.
In-vitro degradation of 50/50 PLGA for programmed drug release has been systematically investigated from the drug eluting stents. Mass loss, molecular weight reduction, thermal changes and surface morphology of the drug eluting stents were analyzed as a function of degradation time. It was observed that degradation of 50/50 PLGA occurs in two phases. Quick decrease in molecular weight but little mass loss took place during first phase whereas in second phase, molecular weight reduction is slow with significant mass loss. This phenomenon supports heterogeneous degradation mechanism of PLGA. Drug release was attributed to diffusion rather then polymer degradation.
In past two decades poly lactic-co-glycolic acid (PLGA) has been among the most attractive polymeric candidates used to fabricate devices for drug delivery and tissue engineering applications. PLGA is biocompatible and biodegradable, exhibits a wide range of erosion times, has tunable mechanical properties and most importantly, is a FDA approved polymer. In particular, PLGA has been extensively studied for the development of devices for controlled delivery of small molecule drugs, proteins and other macromolecules in commercial use and in research. This manuscript describes the various fabrication techniques for these devices and the factors affecting their degradation and drug release.
Understanding the degradation behavior of polymeric microspheres is crucial for the successful application of such devices in controlled drug delivery. The degradation mechanism of poly(lactic-co-glycolic acid) (PLGA) microspheres inside phagocytic cells is not known, but different models for degradation in aqueous solution have been proposed. We have used confocal Raman spectroscopy and imaging to study the intracellular degradation of PLGA microspheres inside individual macrophages. Our results show that ingested microspheres degrade in a heterogeneous manner, with a more rapid degradation in the center. Comparison of Raman spectra from degrading beads with those of uningested beads reveals that ester hydrolysis occurs throughout the phagocytosed microspheres, with a selective loss of glycolic acid units. Furthermore, we show that PLGA degradation is a cell-mediated process, possibly caused by the low pH of the phagosome and/or the presence of hydrolytic enzymes. In conclusion, we have demonstrated that the chemical composition of degrading polymers inside cells can be probed by Raman spectral imaging. This technique will expand the capabilities of investigating biomaterial degradation in vivo.
Particle size analysis in the pharmaceutical industry has long been a source of debate regarding how best to define measurement accuracy; the degree to which the result of a measurement or calculation conforms to the true value. Defining a “true” value for the size of a particle can be challenging as the output of its measurement will differ because of variations in measurement approaches, instrumental differences and calculation methods. Consequently, for “real” particles, a universal “true” value does not exist and accuracy is therefore not a definable characteristic. Accordingly, precision is then a measure of the ability to reproducibly achieve a measurement of unknown relevance.
This article proposes, in place of accuracy, a means to define the “appropriateness” of a measurement in line with the critical quality attributes (CQA) of the material being characterized. The decision as to whether the measurement is correct should involve a link to the CQA; that is, correlation should be demonstrated, without which the measured particle size cannot be defined as a critical material attribute.
Correspondingly, methods should also be able to provide sufficient precision to demonstrate discrimination relating to variation in the CQA. The benefits and challenges of this approach are discussed.
Physical tablet defects are related to internal structural defects that are not easily assessed by the traditional methods, such as dusting, laminating, or fracturing during appearance, friability, or hardness testing. Also, these methods do not allow objective and quantitative investigation of the role of formulation and process variables, which is essential for quality-by-design drug product development. In this study, an X-ray microcomputed tomography (XμCT) method to analyze internal tablet defects is developed using tablets from a quality-by-design design-of-experiment study. The design of experiment investigated the effect of roller compaction roll force, filler composition, and the amount of magnesium stearate on tablet quality attributes. Average contiguous void volume by optical image processing and fracture size distribution and direction by artificial intelligence–based image processing quantified the internal tablet fracture severity. XμCT increased formulation and process knowledge in support of scale-up manufacturing. We demonstrated how XμCT can be incorporated as a part of a holistic approach to quantitatively identify and mechanistically assess the risks of internal tablet defects. Furthermore, expanding the use of XμCT with an artificial intelligence–based quantitative analysis can deepen our tableting knowledge from an empirical understanding to a mechanistic understanding of compaction phenomenon.
This book approaches the subject from a mechanistic perspective that pitches the language at a level that is understandable to those entering the field and who are not familiar with its common phrases or complex terms. It provides a simple encapsulation of concepts and expands on them. In each chapter the basic concept is explained as simply and clearly as possible without a great deal of detail, then in subsequent sections additional material, exceptions to the general rule, examples, etc., is introduced and built up. Such material was generously supplemented with diagrams; conceptually elegant line diagrams in two or three colors. The artwork was well thought out and able to condense the scientific principles into a novel and visually exciting form. The diagrams encourage browsing or draw the reader to salient points. In addition, the technique of highlighting key concepts in a separate box is used throughout each chapter.
A complete description of the particle formation process can only be realized with techniques that enable the measurement of the composition and structural dependence of individual particles.
The purpose of this publication is to highlight the utility of one such high resolution imaging technique; focused-ion scanning electron microscopy (FIB-SEM). As a model system, amorphous dispersion particles of felodipine and polyvinylpyrrolidone (PVP) were prepared by spray drying and used to interrogate single particles. Further, FIB-SEM was coupled with energy dispersive X-ray analysis (EDX) to characterize spatial chemical distributions in spray dried amorphous solid dispersion particles. Within a single spray drying batch, individual particles exhibited different phase behavior as a function of particle size. Larger particles showed notable amorphous-amorphous phase separation while smaller particles showed uniform composition. The morphology of particles was also found to be a function of particle size. Larger particles were consistently more porous in nature compared to smaller particles. The observed differences in compositional heterogeneity of different spray dried particles as a function of size are interpreted via theoretical arguments based on the Peclet number, the ratio of the evaporative flux of the solvent to the diffusive flux of the drug and the polymer within the droplet. Phase behavior may also be interpreted in terms of equilibrium ternary phase diagrams. Regardless, commonly used bulk physical and chemical characterization techniques may be used to establish correlations between the nature of the dispersion and the processing parameters. However, these techniques lack the resolution to provide a scientific link between the processing conditions and the nature of individual particles. The current paper highlights the utility of high resolution morphological and compositional measurements of individual particles.
The objective of the present study was to develop a discriminatory and reproducible accelerated release testing method for naltrexone loaded parenteral polymeric microspheres. The commercially available naltrexone microsphere product (Vivitrol®) was used as the testing formulation in the in vitro release method development, and both sample-and-separate and USP apparatus 4 methods were investigated. Following an in vitro drug stability study, frequent media replacement and addition of anti-oxidant in the release medium were used to prevent degradation of naltrexone during release testing at “real-time” (37 °C) and “accelerated” (45 °C), respectively. The USP apparatus 4 method was more reproducible than the sample-and-separate method. In addition, the accelerated release profile obtained using USP apparatus 4 had a shortened release duration (within seven days), and good correlation with the “real-time” release profile. Lastly, the discriminatory ability of the developed accelerated release method was assessed using compositionally equivalent naltrexone microspheres with different release characteristics. The developed accelerated USP apparatus 4 release method was able to detect differences in the release characteristics of the prepared naltrexone microspheres. Moreover, a linear correlation was observed between the “real-time” and accelerated release profiles of all the formulations investigated, suggesting that the release mechanism(s) may be similar under both conditions. These results indicate that the developed accelerated USP apparatus 4 method has the potential to be an appropriate fast quality control tool for long-acting naltrexone PLGA microspheres.
Approaches to characterizing and developing understanding around the mechanisms that control the release of drugs from hydrophilic matrix tablets are reviewed. While historical context is provided and direct physical characterization methods are described, recent advances including the role of percolation thresholds, the application on magnetic resonance and other spectroscopic imaging techniques are considered. The influence of polymer and dosage form characteristics are reviewed. The utility of mathematical modeling is described. Finally, how all the information derived from applying the developed mechanistic understanding from all of these tools can be brought together to develop a robust and reliable hydrophilic matrix extended-release tablet formulation is proposed.
The aim of this study was to understand the polymer degradation and drug release mechanism from PLGA microspheres embedded in a PVA hydrogel. Two types of microspheres were prepared with different molecular weight PLGA polymers (approximately 25 and 7 kDa) to achieve different drug release profiles, with a 9-day lag phase and without a lag phase, respectively. The kinetics of water uptake into the microspheres coincided with the drug release profiles for both formulations. For the 25 kDa microspheres, minimal water uptake was observed in the early part of the lag phase followed by substantial water uptake at the later stages and in the drug release phase. For the 7 kDa microspheres, water uptake occurred simultaneously with drug release. Water uptake was approximately 2-3 times that of the initial microsphere weight for both formulations. The internal structure of the PLGA microspheres was evaluated using low temperature scanning electron microscopy (cryo-SEM). Burst drug release occurred followed by pore forming from the exterior to the core of both microspheres. A well-defined hydrogel/microsphere interface was observed. For the 25 kDa microspheres, internal pore formation and swelling occurred before the second drug release phase. The surface layer of the microspheres remained intact whereas swelling, and degradation of the core continued throughout the drug release period. In addition, microsphere swelling reduced glucose transport through the coatings in PBS media and this was considered to be a as a consequence of the increased thickness of the coatings. The combination of the swelling and microdialysis results provides a fresh understanding on the competing processes affecting molecular transport of bioanalytes (i.e. glucose) through these composite coatings during prolonged exposure in PBS.
The objective is to acquaint the microscopist with the crystallographic and contrast effects of electron channeling. The initial emphasis is on channeling experiments which can be performed on any conventional scanning electron microscope: large area channeling patterns of single crystals and channeling contrast images to reveal the crystalline microstructure of polycrystalline materials. The optional advanced experiments on covering area electron channeling patterns can only be carried out on an SEM which is equipped with special scanning and/or electron optical modifications. More detail on this topic may be found in ASEMXM, Chapter 3.
We develop and analyze a novel, quasi-static, pore-scale approach for modeling drainage in a porous medium system. The approach uses: (1) a synthetic, non-overlapping packing of a set of spheres, (2) a discrete representation of the sphere packing, and (3) concepts from pore morphology and local pore-scale physics to simulate the drainage process. The grain-size distribution and porosity of two well-characterized porous media were used as input into the drainage simulator, and the simulated results showed good agreement with experimental observations. We further comment on the use of this simulator for determining the size of a representative elementary volume needed to characterize the drainage process.
PLGA microspheres are widely studied for controlled release drug delivery applications, and many models have been proposed to describe PLGA degradation and erosion and drug release from the bulk polymer. Autocatalysis is known to have a complex role in the dynamics of PLGA erosion and drug transport and can lead to size-dependent heterogeneities in otherwise uniformly bulk-eroding polymer microspheres. The aim of this review is to highlight mechanistic, mathematical models for drug release from PLGA microspheres that specifically address interactions between phenomena generally attributed to autocatalytic hydrolysis and mass transfer limitation effects. Predictions of drug release profiles with mechanistic models are useful for understanding mechanisms and designing drug release particles.
Mathematical modeling of drug release can be very helpful to speed up product development and to better understand the mechanisms controlling drug release from advanced delivery systems. Ideally, in silico simulations can quantitatively predict the impact of formulation and processing parameters on the resulting drug release kinetics. The aim of this article is to give an overview on the current state of the art of modeling drug release from delivery systems, which are predominantly controlled by diffusional mass transport. The inner structure of the device, the ratio "initial drug concentration:drug solubility" as well as the device geometry determine which type of mathematical equation must be applied. A straightforward "road map" is given, explaining how to identify the appropriate equation for a particular type of drug delivery system. The respective equations for a broad range of devices are indicated, including reservoir and matrix systems, exhibiting or not an initial excess of drug and the geometry of slabs, spheres and cylinders. The assumptions the models are based on as well as their limitations are pointed out. Practical examples illustrate the usefulness of mathematical modeling of diffusion controlled drug delivery. Due to the advances in information technology the importance of in silico optimization of advanced drug delivery systems can be expected to significantly increase in the future.
Micro-computed tomography (micro-CT) has not to date been fully exploited in the area of controlled drug delivery despite its capability for providing detailed, 3-D images of morphology and the opportunity this presents for exploring the relationships between delivery device formulation, structure and performance. Micro-CT was used to characterize the internal structure of polycaprolactone (PCL) matrix-type devices incorporating soluble particulates (lactose Mw 342.30, gelatin Mw 20-25kDa) as models of hydrophilic bioactives or pore-forming excipients. Micro-CT images confirmed that the lactose and gelatin particles were uniformly dispersed throughout the PCL phase and that efficient delivery of 95-100% of each species in 9days involved transport from the matrix core. Quantitative analysis of micro-CT images provided values for matrix macroporosity, which were within 15% of the theoretical value and revealed uniform porosity throughout the samples. Total release of protein occurred in 9days (PBS, 37 degrees C) from matrices containing a high protein load (44%w/w) and was independent of particle size. Measurements of equivalent pore diameter and frequency distribution identified a large population of sub-40microm pores in each material, indicative of a high density of connecting channels between particles which facilitates protein transport through the matrices.
In the development of tunable PLGA microparticles as vaccine delivery vehicles, it is important to understand the drug distribution within the microparticle over time as well as the long-term release of the drug during polymer degradation. This study addresses the transient 3-D drug distribution in PLGA microparticles during in vitro degradation. Specifically, poly (lactide-co-glycolide) (PLGA 75:25) microparticles containing ovalbumin (OVA) as a model protein were fabricated by double-emulsion (w/o/w) method. The microparticles were incubated at 37 degrees C and 250 rpm in PBS buffer (pH 7.4) over a 100-day period. The in vitro polymer erosion, transient protein distribution profiles and protein release behaviors were investigated. Protein release profiles were determined via spectrophotometry using a BCA assay for the solution. Transmission electron microscopy (TEM) images were obtained for the OVA-loaded microparticles before and during degradation (0 day, 30 days and 60 days), and the corresponding 3-D constructions were developed. From the 3-D constructions, the overall protein distribution of the entire microparticle was vividly reflected. Pixel number analysis of the TEM images was used to quantify transient protein distribution. The transient protein release obtained from the TEM analysis was in good agreement with the BCA analysis. This technique provides an additional tool in helping develop polymer matrices for tunable delivery vehicles in vaccination and other drug delivery scenarios.
Sustained-release injectable drug delivery: a review of current and future systems
- Y S Phee
- C W Park
- P P Deluca
- H M Mansour
System and method for computing drug controlled release performance using images
- S Zhang