Single Particle Optical Sensing Research Articles

(Sub)micron particles forming in aqueous dispersions of amorphous solid dispersions of the poorly soluble drug ABT-199: A combined particle optical counting and field-flow fractionation study

The dispersive behavior of three different amorphous solid dispersion (ASD) formulations of the poorly soluble ABT-199 (Venetoclax) were studied in aqueous and biomimetic media and spontaneously forming supramolecular associates and particles analysed. To this end, the aqueous dispersions were fractionated into a submicron (colloidal) and micrometer-sized particle-fraction by bench-top centrifugation. The submicron fraction was characterized by Asymmetric Flow Field-Flow Fractionation in conjunction with Multi-angle Laser Light Scattering (AF4-MALLS), Dynamic Light Scattering (DLS) and zeta potential analysis. The micron particle fraction was characterized by Single Particle Optical Sensing (SPOS) and light microscopy. Furthermore, drug contents were monitored in terms of total dispersed drug and apparently dissolved drug in the submicron fraction. Despite the fact, that all three formulations showed decent dispersive behavior with almost the complete drug content rapidly dispersed, substantial differences were identified between two of the formulations and the third one: ABT-199/12 and ABT-199/20 showed pronounced precipitation of the drug in form of micrometer particles, a phenomenon described as glass liquid phase separation (GLPS) and only a marginal fraction of the drug was found in the submicron-fraction, i.e. associated with 3 to 4 different supramolecular assemblies (micelles), irrespective whether buffer or fasted state simulated intestinal fluid (FaSSIF) were used as dispersion media. In contrast, ABT-199/40 showed pronounced formation of a wide variety of supramolecular assemblies (micelles) along with substantial association of the drug with all of these, but reduced glass liquid phase separation.

Study of Agglomeration Behavior of Chemical Mechanical Polishing Slurry under Controlled Shear Environments

The presence of large oversize particles (>0.5 μm) in the slurry is known to cause polishing defects during chemical mechanical planarization/polishing (CMP) process. One of the reasons for presence of large particles in the slurry is due to usage of pumps during slurry delivery. The shear rate of pumps is known to cause agglomeration problem in CMP slurries, with increasing shear rate leading to increase in agglomeration in the slurries. However, till now all the work on shear-induced agglomeration has been qualitative or at best semi-quantitative in nature. In the present work, a novel technique to study agglomeration behavior as a function of quantified shear rates has been developed. A rheometer was used as a means to subject slurry to different shear rates for various times. The resulting change in oversize particle distribution was measured using a single particle optical sensing (SPOS) system. It was observed that the behavior of silica slurry when subjected to different shear rates falls into three regions namely de-agglomeration, transition region and agglomeration region. This technique provides a deterministic way for slurry stability and can be used as a guide for design of slurry, slurry selection and design of slurry delivery systems.

A Novel Light Scattering Analysis Method for Monitoring Undiluted CMP Slurry

Correlation of CMP slurry properties including large particle counts (LPC) to semiconductor manufacturing defect and yield metrics has long been a promise of proper implementation of undiluted slurry process monitoring [1]. Continuous, real-time metrology validating this correlation has now been in use in volume production for over three years in fabs in Asia and the US [2]. In addition to wafer defects, such metrology has also proven useful in identifying slurry lot and tank changes, filter changes, and other operational events in the fab [3]. Process monitoring metrology often shares many attributes with the laboratory analytical methods on which it is based. This is the case for slurry particle analysis using a variety of single-particle optical sensing (SPOS) technologies that have been available over the past 30 years. SPOS is a laboratory analysis technique that has been adapted to provide periodic monitoring of the particle size distribution in CMP slurry. Due to small sample volume, periodic sampling of the production slurry stream, delay time, and chemical and electrostatic disturbance of the suspension due to sample dilution, users can obtain only a gross record of slurry characteristics with low statistical inference power. Correlation of SPOS data with yield and defect events has proven to be unsatisfying, with consecutive data points exhibiting a high level of random variation that masks trends and slurry events. Nonetheless, because SPOS has been the only option available, there is a vast historical database and an adequate comfort level in the semiconductor industry despite known shortcomings. Recent advances in sample delivery and dilution methods have attempted to address these issues, but the underlying problem of statistical significance due to small sample volume [4] remains a major contributor to SPOS data inconsistency. To address these fundamental shortcomings of SPOS as a manufacturing process monitor, the Vantage SlurryScope™ system was designed from its inception to be a continuous, real-time, undiluted slurry process monitor. As such, a primary requirement is to detect changes in the characteristics of the CMP slurry for any reason as a function of time. Less importance is attributed to precise reporting of the characteristics of isolated particles, although this option is available under some conditions. An SPOS-like data conversion becomes physically untenable in flowing, undiluted slurry, where resolution of individual particles is confounded by massive particle coincidence, with concurrent light detection from thousands to millions of particles on each sensor element, and with the cumulative light scattering from small particles that are individually below the detection threshold. A solution which provides continuous, real-time process monitoring can be more effective without depending on individual particle resolution. To enable robust process monitoring under these constraints, a novel, computationally efficient method has been developed to extract meaningful information about CMP slurry characteristics from the large set of light scattering observations that SlurryScope produces. This method does not depend on the resolution of individual particles or on a preset minimum particle size resolution. While these parameters are crucial for analyzing and reporting particle size distributions, they are not essential for process monitoring. The new Vantage method presented here uses the entire distribution of light power scattered by the flowing slurry and integrated by SlurryScope sensors to detect changes in that distribution which correspond to physical changes in the slurry. More than 107 light scattering integrations per second are collected from a highly controlled sampling volume. This circumvents SPOS sampling limitations, and opens new directions in process monitoring of CMP slurries. An initial implementation of such monitoring metrics for high density ceria slurries, called “HD Mode,” is described in this paper. The SlurryScope system has demonstrated a high sensitivity to slurry properties due to lot-to-lot differences, tank changes, filter changes, dilution and mixing errors, mechanical failures, and violation of turnover limits. In one production fab study [2], the correlation of SlurryScope monitoring data to process yield and defects provided a 3x improvement over traditional SPOS methods. Evaluation of the new algorithm is continuing, with benefits including the use of a single hardware sensor and computational engine for all slurries from low refractive index silica to high refractive index ceria across a full range of fab production concentrations. The elimination of dependence on a minimum particle size detection limit and a continuous, real-time sensitivity to changes in slurry conditions allows the user to achieve process defect objectives in sub-10nm device technologies. REFERENCES [1] K.A. Barry, APC XXV Symposium, 2013. [2] J. Bennett, M.A. Fury, ICPT, 2014. [3] C.D. Aparece, M.A. Fury, Semicon West, 2013. [4] M.A. Fury, NCCAVS CMPUG, May, 2012.

Quantitative characterization of viscoelasticity of microbubbles in ultrasound contrast agent

Ultrasound contrast agent (UCA) microbubbles have been commonly used in clinic to enhance the acoustic backscattering signals in ultrasound imaging diagnosis. With increasing demand for the continuous improvement of imaging resolution and sensitivity, new type UCAs (e.g., targeted microbubbles and multifunctional microbubbles) have attracted growing interest in both medical and scientific communities. Many efforts have been made to modify microbubble shell properties, which can strongly affect microbubble dynamic behaviors, so as to enable to create some new functionalities of UCAs. However, accurate characterization of the shell mechanical properties of UCAs has been recognized to be rather challenging. In previous work, microbubble’s mechanical properties are normally estimated by fitting measured dynamic response signals with coated-microbubble models. Inevitable uncertainty will be introduced in fitting results because there are more than one unknown shell parameters are adopted in these dynamic models. In the present paper, a comprehensive approach is developed to quantitatively characterize the visco-elasticity of the encapsulated microbubbles. By combining the techniques of atomic force microscopy (AFM), single particle optical sensing (SPOS), acoustic attenuation measurement, and the coated-bubble dynamics simulation, the size distribution, shell thickness, shell elasticity and viscosity of UCA microbubbles are determined one by one in sequence. To examine the validity of this approach, a kind of albumin-shelled microbubbles with diameters ranging from 1 to 5 μm are fabricated in our lab. Based on AFM technology, the microbubble effective shell stiffness and bulk elasticity modulus are measured to be 0.149±0.012 N/m and 8.31±0.667 MPa, respectively. It is noteworthy that the shell elastic property is shown to be independent of the initial size of microbubbles. Furthermore, the size distribution and acoustic attenuation measurements are also performed of these bubbles. Then, combined with microbubble dynamic model simulations, the UCA shell viscosity is calculated to be 0.374±0.003 Pa·s. Compared with previous estimation method, the current technology can be used as an effective tool to assess UCA shell visco-elasticity with improved accuracy and certainty. It is also shown that the feasibility to optimize the design and fabrication of UCAs can satisfy different requirements in ultrasound diagnostic and therapeutic applications.

Droplet-size distribution and stability of commercial injectable lipid emulsions containing fish oil

The droplet size of commercial fish oil-containing injectable lipid emulsions, including conformance to United States Pharmacopeia (USP) standards on fat-globule size, was investigated. A total of 18 batches of three multichamber parenteral products containing the emulsion SMOFlipid as a component were analyzed. Samples from multiple lots of the products were evaluated to determine compliance with standards on the volume-weighted percentage of fat exceeding 0.05% (PFAT(5)) specified in USP chapter 729 to ensure the physical stability of i.v. lipid emulsions. The products were also analyzed to determine the effects of various storage times (3, 6, 9, and 12 months) and storage temperatures (25, 30, and 40 °C) on product stability. Larger-size lipid particles were quantified via single-particle optical sensing (SPOS). The emulsion's droplet-size distribution was determined via laser light scattering. SPOS and light-scattering analysis demonstrated mean PFAT(5) values well below USP-specified globule-size limits for all the tested products under all study conditions. In addition, emulsion aging at any storage temperature in the range studied did not result in a significant increase of PFAT(5) values, and mean droplet-size values did not change significantly during storage of up to 12 months at temperatures of 25-40 °C. PFAT(5) values were below the USP upper limits in SMOFlipid samples from multiple lots of three multichamber products after up to 12 months of storage at 25 or 30 °C or 6 months of storage at 40 °C.

Distortion of Single‐Particle Optical Sensing (SPOS) Particle Count by Sub‐Countable Particles

AbstractSingle particle optical sensing (SPOS) is a highly sensitive particle characterization technique for the measurement of the large particle (> 0.5 μm) tail of a submicron particle size distribution. We have examined the SPOS technique for fumed silica dispersions which have a mass mean particle size of ~140 nm. The reported large particle population varies as a highly non‐linear function of sample concentration and is accompanied by the distortion of the particle size distribution. A similar response is also demonstrated for monodisperse polystyrene latex spheres. The source of spurious particle counts and the distortion of the particle size distribution is shown to be secondary coincidence. Model calculations indicate that the primary contributors to spurious counts are particles near the peak of the size distribution. These particles are substantially smaller than the nominal minimum 0.5 μm diameter. These findings establish the limited range of reliability for SPOS measurements when used to measure a small fraction of the total particle size distribution and establish the need for new particle characterization metrologies.

New insights into the pore structure of poly( d, l-lactide-co-glycolide) microspheres

The objective of this work was to develop a fast and significant method for the determination of the intraparticulate pore size distribution of microspheres. Poly(lactide-co-glycolide) (PLGA) microspheres prepared with a solvent extraction/evaporation process were studied. From the envelope and the skeletal volume of the microspheres the porosity was calculated. The skeletal volume was determined with nitrogen and helium pycnometry and mercury intrusion porosimetry. Based on single particle optical sensing (SPOS) a novel method was developed by which the envelope volume is calculated from the particle size distribution (PSD), provided that all particles have a spherical shape. The penetration capacity of the applied intrusion media is limited by their atomic or molecular diameter or by the surface tension and the pressure in case of mercury. A classification of the pore structure was obtained by comparing these different skeletal values with the values for the envelope volume. Two well separated pore fractions were found, a nanoporous fraction smaller than 0.36 nm and a macroporous fraction larger than 3.9 μm. The total porosity and the ratio between both fractions is controlled by the preparation process and was shown to depend on the solvent extraction temperature.

Physicochemical stability of lipid injectable emulsions: Correlating changes in large globule distributions with phase separation behavior

Single particle optical sensing (SPOS) and visual inspection were used to characterize a series of lipid injectable emulsions ( n = 21) featuring three lipid types, two electrolyte conditions, and three pH levels (7.0, 4.75, and 2.5). Seven of the twenty-one sample conditions exhibited phase separation instability by visual inspection within 98 h of emulsion preparation. The phase instability was driven by electrolyte type and pH, and “cracking” phenomena were independent of lipid type despite the base lipids ranging almost two orders of magnitude in PFAT 5 levels. Logistic regression analysis showed that the PFAT 5 level determined 1 h after admixture preparation was not correlated with phase separation behavior. However, PFAT 5 measured at later times showed much improved correlations with emulsion instability. PFAT 5 was highly correlated with neighboring cumulative distributions termed PFAT X where X = 2–10 μm. Although the admixtures studied were not clinically relevant, the data demonstrate some limitations of developing empirical correlations between single-point SPOS measurements and emulsion instability. An alternative limit test for emulsion stability based on the rate of change in the large globule counts is proposed to mitigate inherent deficiencies in the current USP Chapter 〈729〉 limit test based on single-point determination of PFAT 5 values.

New Particle Metrology for CMP Slurries

ABSTRACTA new particle sizing and counting method based on the coupling of flow field-flow fractionation (FFF) with dual-sensor, single particle optical sensing (SPOS) detection is reported. The integration of FFF and SPOS systems was accomplished by means of a dilution interface that preserved the resolution of FFF-separated particles. Analysis of a model mixture of polystyrene latex standards of different diameters established that the FFF-SPOS system can resolve particles into discrete peaks for subsequent particle counting. Application of this method for the analysis of a colloidal silica standard demonstrated its use for materials commonly employed as CMP abrasives. Further development and refinement of the technique will enable compositional and structural analyses of heterogeneous large particle populations constituting commercial CMP slurries.

Analysis of Large Particle Count in Fumed Silica Slurries and Its Correlation with Scratch Defects Generated by CMP

The large particle count (LPC) of fumed silica slurries was evaluated and correlated with scratch counts created on films by table-top, chemical-mechanical planarization (CMP). Particle sizing results obtained by static light scattering, capillary hydrodynamic fractionation, and dual-sensor single particle optical sensing (SPOS) pointed to the latter as the superior method for quantitative analyses of the LPC. Dual-sensor SPOS is a new technique that determines the LPC on a silica sphere-equivalent, light-scattering diameter scale for particles as small as . LPC measurements used in combination with dark-field optical microscopy for scratch metrology afforded linear correlations between scratch counts and the LPC. Particles producing scratches had silica sphere-equivalent, light-scattering diameters exceeding . Inclusion of these particles in the LPC produced a two-fold increase in the number of scratch-forming particles in the correlation relative to correlations generated via single-sensor SPOS measurements of LPC. Experimental uncertainty in scratch counts limited the correlation as a scratch predictor. Slurries differing in LPC by a minimum of had statistically different predicted scratch counts at the 95% confidence level. Additional method development is needed to extend LPC-based scratch prediction to other CMP processes producing scratch defects.

Stability of Nonaqueous Ink Jet Inks as Studied by Single Particle Optical Sensing

Nonaqueous ink jet inks and their long-time stability at different temperatures were studied using single particle optical sensing (SPOS). Samples ground for the same period but having different amphiphilic polymer additives used for steric stabilization were prepared. SPOS characterizes the particle size distribution at the high end of the particle diameter (>0.5 μm.). In the aging at different temperatures, the high-end size distribution exhibited changes ascribed to sedimentation and aggregation. In the absence of aggregation, the decrease of the particle volume was identified as originating from sedimentation; the dependence on particle diameter and solvent viscosity agreed with theoretical prediction. The aggregation appeared as a hump in the tail of the main peak in the size distribution. The hump was apparent for inks aged at a higher temperature and having more loosely adsorbed polymer additives.

Investigating the Effects of Diluting Solutions and Trace Metal Contamination on Aggregation Characteristics of Silica-Based ILD CMP Slurries

AbstractOne of the major drawbacks to CMP is the tendency for abrasive particles in slurries to form aggregates, which have the potential to cause defects on wafer surfaces. Therefore, it is crucial to understand the mechanisms by which aggregates are formed so appropriate metrology can be implemented that will identify defect-causing slurries before they are used in the fab. Single particle optical sensing (SPOS) techniques are commonly used to obtain large particle counts (LPC) for slurries. The SPOS technique requires slurry dilution before measuring and the instrument continues to dilute the sample during a measurement. Other techniques that can be used to characterize slurries are particle size distribution by static light scattering (SLS), mean particle size (MPS) by dynamic light scattering (DLS), and zeta potential (ZP) measurements. Like SPOS, all of these techniques require that slurry be diluted prior to measuring and the current method for doing so is with UPW. Diluted slurry demonstrates significantly different ionic strength than the undiluted slurry, and electrolyte concentration has been shown to affect aggregation and electric double layer characteristics of silica particles 2–6. An alternative diluting solution was formulated that simulates the conductivity and pH of the original slurry to mimic the conditions to which particles are actually exposed. It is crucial to identify the metrology that is compatible with high pH solutions and the impact of these solutions on measurements. A second objective of the study is to examine aluminum contamination in slurries. To date, the aluminum content of silica-based CMP slurries and effects on performance have not been well studied. Aluminum is known as a potential contaminant during abrasive and/or slurry manufacturing processes. Known defect free slurries were doped with aluminum and effects on particle aggregation were observed. Specifically, it is of interest to identify the metrology and techniques that may be useful (and those that are not) in monitoring aluminum induced aggregation.

Correlation of Defects on Dielectric Surfaces with Large Particle Counts in Chemical-Mechanical Planarization (CMP) Slurries Using a New Single Particle Optical Sensing (SPOS) Technique

AbstractA dual-sensor single particle optical sensing method (SPOS) is described for the measurement of the large particle count (LPC) in fumed silica polishing slurries. LPC values were expressed on a silica sphere-equivalent diameter scale rather than a polystyrene latex-equivalent size basis. Linear correlations between LPC and scratch counts on SiO2 surface films for wafers polished under clean room and table-top CMP conditions are demonstrated. However, these correlations were obtained for a limited set of model slurries; and further investigation will be needed to assess the general applicability of dual-sensor SPOS for oxide scratch defect prediction in CMP slurries.

Stability of Nonaqueous Ink-jet Inks as Studied by Single-Particle Optical Sensing

Stability of Nonaqueous Ink-jet Inks as Studied by Single-Particle Optical Sensing

A Multi-tool Approach to Colloid Stability: SPOS and Separation Analysis

ABSTRACT The stability of a colloidal suspension is dependent upon many factors. Often the presence of larger than normal particles in a given suspension is indicative of the commencement of destabilization. Single Particle Optical Sensing (SPOS) has been proven to be a highly accurate and reproducible particle characterization technique. By measuring each and every particle within a sample, SPOS precisely reports incidences of coarse particles found in the tail of the particle size distribution. To complement particle size distributions reported by SPOS, the stability of a sample can also be classified using a separation analyzer. This separation analysis is based on a microprocessor controlled analytical centrifuge that directly measures the stability and de-mixing rates of emulsions and concentrated suspensions. Theory and experimental results from the two methods for samples of emulsions, coatings, and CMP (chemical mechanical polishing) slurries are presented and discussed.

Analysis of Size Distribution of Inclusions in Metal by Using Single-particle Optical Sensing Method.

The spatial size distributions of oxide and/or nitride inclusions on a film filter after chemical or electrolytic extraction have been measured using single-particle optical sensing (SPOS) method in an Fe-10mass%Ni-0.2mass%M (M=Ti and Al) and an Fe-10mass%Ni-0.025mass%Al-0.1 mass%Ti-0.02mass%N alloys. The size distributions obtained from the SPOS method are compared with those obtained from the three-dimensional observation of particles on a film filter using scanning electron microscope (SEM) with electron probe microanalysis. The volume fractions of particles calculated from the size distributions by the SPOS method and SEM observation have been compared with those calculated from chemical analysis. It is found that in the size distribution measurement the SPOS method is superior to the SEM observation, particularly, in the range of d v >5 μm.