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Papers by fernando muzzio

Continuous processing is widely used in bulk solids manufacturing, especially for processing larg... more Continuous processing is widely used in bulk solids manufacturing, especially for processing large material volumes in industries such as minerals, foods, detergents, and construction materials. Few studies have been published on continuous bulk solids mixing, but in recent years, continuous mixing has attracted increasing interest, particularly in pharmaceutical solid oral dose manufacturing, t rad i t iona l ly a batch-based industry.

La presente invention concerne un film en bande ameliore a base de produits pharmaceutiques (par ... more La presente invention concerne un film en bande ameliore a base de produits pharmaceutiques (par exemple, permettant d'ameliorer la dissolution et la biodisponibilite). Plus particulierement, la presente invention concerne des systemes/procedes de fabrication d'un film en bande a base de produits pharmaceutiques par l'utilisation de precurseurs filmogenes a viscosite superieure et des procedes de sechage qui realisent un sechage ameliore/accelere et offrent une uniformite de contenu ameliore/excellent de principes actifs pharmaceutiques dans les produits pharmaceutiques a base de film en bande. Des exemples de systemes/procedes utilisent avantageusement des precurseurs polymeriques biocompatibles de haute viscosite (utilisation facultative de poudres de medicaments a modification de surface) et un sechage convectif pour la fabrication de films minces charges de particules de taille nanometrique et/ou micrometrique de principes actifs pharmaceutiques (API) faiblement hydr...

International Journal of Pharmaceutics, 2021

A better understanding of a pharmaceutical tablet's microstructure has the potential to unloc... more A better understanding of a pharmaceutical tablet's microstructure has the potential to unlock the black box between material attributes, process parameters and the critical quality attributes. Microstructure determination requires measuring the spatial-, particle size-distributions (absolute and relative) of the ingredients, and the void space, which is the overt goal of chemical Imaging (CI). Reliable quantitative results can be obtained by imaging multiple layers per tablet, with each layer having a minimal surface roughness. This study utilized scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDX) and Raman chemical imaging (RCI) to provide a comparative discussion of results obtained when determining the microstructure of commercial zinc sulfate tablets, using three methods of tablet surface preparation: scoring & hand-fracturing, microtoming, and grating. A description of the working principles of the measurement and surface preparation methods is followed by a comparison of microstructure (particle size distribution and homogeneity of distribution) using chemical images. A comparison of the general advantages and disadvantages of SEM/EDX and RCI and the common errors in analyzing microstructure are also discussed. The results indicate that in addition to selecting the correct tablet surface preparation method, chemical imaging method, and the subsequent microstructural analyses method, correct problem formulation is also critical.

OF THE DISSERTATION Quality by Design for Continuous Powder Mixing By PATRICIA MARIBEL PORTILLO D... more OF THE DISSERTATION Quality by Design for Continuous Powder Mixing By PATRICIA MARIBEL PORTILLO Dissertation Directors: Marianthi G. Ierapetritou and Fernando J. Muzzio The main target of our research is to investigate powder mixing, particularly continuous mixing. Continuous mixing is considered as an efficient alternative to batch mixing processes that in principle allows for easier on-line control and optimization of mixing performance. In order to illustrate the benefits of this process we have demonstrated the effectiveness of continuous mixing for powders. A number of operating and design parameters including processing angle, rotation rate, fill level, convective design, APAP concentration, and residence time have been investigated to consider their effects on mixing performance and on the content uniformity. Statistical analysis has been applied to examine the significance of the effects of processing parameters and material properties on the mixing rate. In addition to mixi...

After 50 years of near-stagnation, pharmaceutical manufacturing is experiencing unprecedented sci... more After 50 years of near-stagnation, pharmaceutical manufacturing is experiencing unprecedented scientific and technological innovation. There is a paradigm shift from testing product quality using lengthy off-line (and after-the-fact) assays to quality being tested during the process using online/ at-line measurements. This ability to evaluate and I have worked on this thesis. I would like to extend my deepest gratitude to my thesis advisor, Fernando Muzzio, for his valuable guidance, meaningful insight into my research, and for providing me with wonderful and challenging opportunities throughout the course of my PhD. Fernando, thank you for helping me improve my presentation, communication, and writing skills. I would like to thank my committee members, Alberto Cuitino, Gerardo Callegari, and Ron Snee, for their valuable suggestions and feedback. A special thanks to Alberto Cuitino who guided me through various interesting projects. I would like to thank German Drazer for revising my manuscript in detail. I would also like to thank National Science Foundation's Engineering Research Center for Structured Organic Particulate Systems (ERC-SOPS) for providing me with opportunities to interact with industry mentors, and help discuss and exchange ideas.

Langmuir, 2016

We present a method to characterize the wettability of powders, based on the penetration dynamics... more We present a method to characterize the wettability of powders, based on the penetration dynamics of a sessile drop deposited on a slightly compressed powder bed. First, we show that a direct comparison of the wetting properties of different liquids is possible without having to solve the three-dimensional liquid penetration problem, by considering the appropriate dimensionless variables. We show that the contact area between the sessile drop and the powder bed remains constant during the penetration process and demonstrate that, as a result, the evolution of the dimensionless penetration volume is given by a universal function of the dimensionless time, with no dimensionless parameters. Then, using a reference liquid that completely wets the powder it is possible to obtain an effective contact angle for a test liquid of interest, independent of other properties of the powder bed, such as permeability and characteristic pore size. We apply the proposed method to estimate the contact angle of water 1 Page 1 of 33 ACS Paragon Plus Environment Langmuir with different powder blends, by using silicone oil as the reference liquid. Finally, to highlight the potential of the proposed method to characterize pharmaceutical powders we consider a blend of Lactose, Acetaminophen and a small amount of lubricant (Magnesium Stearate). The proposed method adequately captures a large increase in hydrophobicity that results from exposing the blend to excessive mixing, a well known effect in pharmaceutical industry.

Powder Technology, 2016

Purpose: The shear cell test has been widely used to characterize flow properties of powders and ... more Purpose: The shear cell test has been widely used to characterize flow properties of powders and granular materials. The purpose of this study is to address the gap between the extensive usage of the test and the limited methods available to analyze the data, and to introduce methodologies for comparing results for different initial consolidation stresses, materials, and testing devices. Method: A library of shear cell data was established. Forty-one powders were included, and each material was tested under four different initial consolidation stresses. For each initial consolidation stress, 3 sampling replicates were performed. Results: A dimensionless cohesion, C*, was defined as the cohesion divided by the initial consolidation stress. By identifying a correlation between the flow function coefficient (ffc) and C*, the effects of the initial consolidation stress and the testing device were separated. In addition, by identifying a mathematical correlation between the unconfined yield strength and the cohesion, the yield loci from different initial consolidation stresses could be collapsed into a single material characteristic line, enabling one to characterize each material by a single number (the characteristic slope). This approach can be used to economically compare different materials, or different testing devices. Conclusion: The proposed method augments shear cell data analysis and significantly reduces the complexity of the shear cell data.

International Journal of Pharmaceutics, 2016

Near infrared spectroscopic (NIRS) calibration models for real time prediction of powder density ... more Near infrared spectroscopic (NIRS) calibration models for real time prediction of powder density (tap, bulk and consolidated) were developed for a pharmaceutical formulation. Powder density is a critical property in the manufacturing of solid oral dosages, related to critical quality attributes such as tablet mass, hardness and dissolution. The establishment of calibration techniques for powder density is highly desired towards the development of control strategies. Three techniques were evaluated to obtain the required variation in powder density for calibration sets: 1) different tap density levels (for a single component), 2) generating different strain levels in powders blends (and as consequence powder density), through a modified shear Couette Cell, and 3) applying normal forces during a compressibility test with a powder rheometer to a pharmaceutical blend. For each variation in powder density, near infrared spectra were acquired to develop partial least squares (PLS) calibration models. Test samples were predicted with a relative standard error of prediction of 0.38 %, 7.65 % and 0.9 3% for tap density (single component), shear and rheometer respectively. Spectra obtained in real time in a continuous manufacturing (CM) plant were compared to the spectra from the three approaches used to vary powder density. The calibration based on the application of different strain levels showed the greatest similarity with the blends produced in the CM plant.

Biotechnology and Bioengineering, Oct 20, 2000

Powder Technology, 2016

A full factorial design of experiments was used to study the effect of blend shear strain on the ... more A full factorial design of experiments was used to study the effect of blend shear strain on the compaction process, relative density and strength of pharmaceutical tablets. The powder blends were subjected to different shear strain levels (integral of shear rate with respect to time) using an ad hoc Couette shear cell. Tablets were compressed at different compaction forces using an instrumented compactor simulator, and compaction curves showing the force-displacement profiles during compaction were obtained. Although the die-fill blend porosity (initial porosity) and the minimum in-die tablet porosity (at maximum compaction) decreased significantly with shear strain, the final tablet porosity was surprisingly independent of shear strain. The increase in the in-die maximum compaction with shear strain was, in fact, compensated during postcompaction relaxation of the tables, which also increased significantly with shear strain. Therefore, tablet porosity alone was not sufficient to predict tablet tensile strength. A decrease in the 'work of compaction' as a function of shear strain, and an increase in the recovered elastic work was observed, which suggested weaker particle-particle bonding as the shear strain increased. For each shear strain level, the Ryskewitch Duckworth equation was a good fit to the tensile strength as a function of tablet porosity, and the obtained asymptotic tensile strength at zero porosity exhibited a 60% reduction as a function of shear strain. This was consistent with a reduced bonding efficiency as the shear strain increased.

Physica A: Statistical Mechanics and its Applications, 1998

This article shows the existence of a non-uniform stationary measure (referred to as the w-invari... more This article shows the existence of a non-uniform stationary measure (referred to as the w-invariant measure) associated with the space-ÿlling properties of the unstable manifold and characterizing some statistical properties of chaotic two-dimensional area-preserving systems. The w-invariant measure, which di ers from the ergodic measure and is non-uniform in general, plays a central role in the statistical characterization of chaotic uid mixing systems, since several properties of partially mixed structures can be expressed as ensemble averages over the w-invariant measure. A closed-form expression for the w-invariant density is obtained for a class of mixing systems topologically conjugate with the linear toral automorphism. The physical implications in the theory of uid mixing, and in the statistical characterization of chaotic Hamiltonian systems, are discussed.

Physical Review E, 1998

This article derives an analytic expression for the short-or intermediate-time behavior of the mo... more This article derives an analytic expression for the short-or intermediate-time behavior of the moment hierarchy of finite-time Liapunov exponents ͑stretching exponents͒ for two-dimensional periodically forced Hamiltonian systems and incompressible time-periodic fluid flows. As a result, the exponent characterizing the apparent short-time exponential growth of the intermaterial contact perimeter for two-dimensional systems can be predicted from the statistical properties of the invariant stretching distribution. The analysis as a whole is in fact grounded on an analytic expression for the high stretching tail of the invariant distribution of the finitetime Liapunov exponents. The asymptotic behavior of the moment hierarchy of the stretching field is also addressed in order to highlight the role of the dynamic heterogeneity accounted for by the variance of the stretching exponents. ͓S1063-651X͑98͒02807-4͔

Cohesive powders can be loosely defined as systems where the attractive forced between particles ... more Cohesive powders can be loosely defined as systems where the attractive forced between particles exceed the average particle weight. Cohesive powder flow is interesting from a wide range of reasons. Their main characteristic, intermittence, is evidenced both in the interruption of flow out of hoppers (a mundane issue causing great annoyance to industrial practitioners) and in the sudden avalanching of

International Journal of Pharmaceutics, 2005

The USP tablet dissolution test is an analytical tool used for the verification of drug release p... more The USP tablet dissolution test is an analytical tool used for the verification of drug release processes and formulation selection within the pharmaceutical industry. Given the strong impact of this test, it is surprising that operating conditions and testing devices have been selected empirically. In fact, the flow phenomena in the USP test have received little attention in the past. An examination of the hydrodynamics in the USP apparatus II shows that the device is highly vulnerable to mixing problems that can affect testing performance and consistency. Experimental and computational techniques reveal that the flow field within the device is not uniform, and dissolution results can vary dramatically with the position of the tablet within the vessel. Specifically, computations predict sharp variations in the shear along the bottom of the vessel where the tablet is most likely to settle. Experiments in which the tablet location was carefully controlled reveal that the variation of shear within the testing device can affect the measured dissolution rate.

Fractals in Engineering, 1997

This paper focuses on the evolution of material filaments in chaotic flows. This evolution is num... more This paper focuses on the evolution of material filaments in chaotic flows. This evolution is numerically calculated for three cases of the sine flow corresponding to a mainly regular, a mainly chaotic, and a globally chaotic case without discernible islands. In all cases, the stretched filament has an extremely non-uniform spatial distribution, with densities spanning several orders of magnitude and being the largest in the neighborhood of hyperbolic periodic points. Such spatial non-uniformity is a permanent property of time-periodic flows. As expected, the length of the filament increases exponentially in time, but due to the spatial non-uniformities in filament density, its growth is much faster than predicted by the Lyapunov exponent. The stretched filaments are self-similar in time, as revealed by their spatial structure and by the frequency distribution of the logarithm of the striation thickness, which is described by a family of curves that have an invariant shape and that can be collapsed onto a single curve by means of a simple scaling.

Scientia Pharmaceutica, 2010

International Journal of Pharmaceutics, 2011

The main objective of the present work was to study the effect of mixing order of Cab-O-Sil (CS) ... more The main objective of the present work was to study the effect of mixing order of Cab-O-Sil (CS) and magnesium stearate (MgSt) and microlayers during mixing on blend and tablet properties. A first set of pharmaceutical blend containing Avicel PH200, Pharmatose and micronized acetaminophen was prepared with three mixing orders (mixing order-1: CS added first; mixing order-2: MgSt added first; mixing order-3: CS and MgSt added together). All the blends were subjected to a shear rate of 80 rpm and strain of 40, 160 and 640 revolutions in a controlled shear environment resulting in nine different blends. A second set of nine blends was prepared by replacing Avicel PH200 with Avicel PH102. A total of eighteen blends thus prepared were tested for powder hydrophobicity, powder flow, tablet weight, tablet hardness and tablet dissolution. Results indicated that powder hydrophobicity increased significantly for mixing order-1. Intermediate hydrophobic behavior was found for mixing order-3. Additionally, mixing order 1 resulted in improved powder flow properties, low weight variability, higher average tablet weight and slow drug release rates. Dissolution profiles obtained were found to be strongly dependent not only on the mixing order of flowing agents, but also on the strain and the resulting hydrophobicity.

Continuous processing is widely used in bulk solids manufacturing, especially for processing larg... more Continuous processing is widely used in bulk solids manufacturing, especially for processing large material volumes in industries such as minerals, foods, detergents, and construction materials. Few studies have been published on continuous bulk solids mixing, but in recent years, continuous mixing has attracted increasing interest, particularly in pharmaceutical solid oral dose manufacturing, t rad i t iona l ly a batch-based industry.

La presente invention concerne un film en bande ameliore a base de produits pharmaceutiques (par ... more La presente invention concerne un film en bande ameliore a base de produits pharmaceutiques (par exemple, permettant d'ameliorer la dissolution et la biodisponibilite). Plus particulierement, la presente invention concerne des systemes/procedes de fabrication d'un film en bande a base de produits pharmaceutiques par l'utilisation de precurseurs filmogenes a viscosite superieure et des procedes de sechage qui realisent un sechage ameliore/accelere et offrent une uniformite de contenu ameliore/excellent de principes actifs pharmaceutiques dans les produits pharmaceutiques a base de film en bande. Des exemples de systemes/procedes utilisent avantageusement des precurseurs polymeriques biocompatibles de haute viscosite (utilisation facultative de poudres de medicaments a modification de surface) et un sechage convectif pour la fabrication de films minces charges de particules de taille nanometrique et/ou micrometrique de principes actifs pharmaceutiques (API) faiblement hydr...

International Journal of Pharmaceutics, 2021

A better understanding of a pharmaceutical tablet's microstructure has the potential to unloc... more A better understanding of a pharmaceutical tablet's microstructure has the potential to unlock the black box between material attributes, process parameters and the critical quality attributes. Microstructure determination requires measuring the spatial-, particle size-distributions (absolute and relative) of the ingredients, and the void space, which is the overt goal of chemical Imaging (CI). Reliable quantitative results can be obtained by imaging multiple layers per tablet, with each layer having a minimal surface roughness. This study utilized scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDX) and Raman chemical imaging (RCI) to provide a comparative discussion of results obtained when determining the microstructure of commercial zinc sulfate tablets, using three methods of tablet surface preparation: scoring & hand-fracturing, microtoming, and grating. A description of the working principles of the measurement and surface preparation methods is followed by a comparison of microstructure (particle size distribution and homogeneity of distribution) using chemical images. A comparison of the general advantages and disadvantages of SEM/EDX and RCI and the common errors in analyzing microstructure are also discussed. The results indicate that in addition to selecting the correct tablet surface preparation method, chemical imaging method, and the subsequent microstructural analyses method, correct problem formulation is also critical.

OF THE DISSERTATION Quality by Design for Continuous Powder Mixing By PATRICIA MARIBEL PORTILLO D... more OF THE DISSERTATION Quality by Design for Continuous Powder Mixing By PATRICIA MARIBEL PORTILLO Dissertation Directors: Marianthi G. Ierapetritou and Fernando J. Muzzio The main target of our research is to investigate powder mixing, particularly continuous mixing. Continuous mixing is considered as an efficient alternative to batch mixing processes that in principle allows for easier on-line control and optimization of mixing performance. In order to illustrate the benefits of this process we have demonstrated the effectiveness of continuous mixing for powders. A number of operating and design parameters including processing angle, rotation rate, fill level, convective design, APAP concentration, and residence time have been investigated to consider their effects on mixing performance and on the content uniformity. Statistical analysis has been applied to examine the significance of the effects of processing parameters and material properties on the mixing rate. In addition to mixi...

After 50 years of near-stagnation, pharmaceutical manufacturing is experiencing unprecedented sci... more After 50 years of near-stagnation, pharmaceutical manufacturing is experiencing unprecedented scientific and technological innovation. There is a paradigm shift from testing product quality using lengthy off-line (and after-the-fact) assays to quality being tested during the process using online/ at-line measurements. This ability to evaluate and I have worked on this thesis. I would like to extend my deepest gratitude to my thesis advisor, Fernando Muzzio, for his valuable guidance, meaningful insight into my research, and for providing me with wonderful and challenging opportunities throughout the course of my PhD. Fernando, thank you for helping me improve my presentation, communication, and writing skills. I would like to thank my committee members, Alberto Cuitino, Gerardo Callegari, and Ron Snee, for their valuable suggestions and feedback. A special thanks to Alberto Cuitino who guided me through various interesting projects. I would like to thank German Drazer for revising my manuscript in detail. I would also like to thank National Science Foundation's Engineering Research Center for Structured Organic Particulate Systems (ERC-SOPS) for providing me with opportunities to interact with industry mentors, and help discuss and exchange ideas.

Langmuir, 2016

We present a method to characterize the wettability of powders, based on the penetration dynamics... more We present a method to characterize the wettability of powders, based on the penetration dynamics of a sessile drop deposited on a slightly compressed powder bed. First, we show that a direct comparison of the wetting properties of different liquids is possible without having to solve the three-dimensional liquid penetration problem, by considering the appropriate dimensionless variables. We show that the contact area between the sessile drop and the powder bed remains constant during the penetration process and demonstrate that, as a result, the evolution of the dimensionless penetration volume is given by a universal function of the dimensionless time, with no dimensionless parameters. Then, using a reference liquid that completely wets the powder it is possible to obtain an effective contact angle for a test liquid of interest, independent of other properties of the powder bed, such as permeability and characteristic pore size. We apply the proposed method to estimate the contact angle of water 1 Page 1 of 33 ACS Paragon Plus Environment Langmuir with different powder blends, by using silicone oil as the reference liquid. Finally, to highlight the potential of the proposed method to characterize pharmaceutical powders we consider a blend of Lactose, Acetaminophen and a small amount of lubricant (Magnesium Stearate). The proposed method adequately captures a large increase in hydrophobicity that results from exposing the blend to excessive mixing, a well known effect in pharmaceutical industry.

Powder Technology, 2016

Purpose: The shear cell test has been widely used to characterize flow properties of powders and ... more Purpose: The shear cell test has been widely used to characterize flow properties of powders and granular materials. The purpose of this study is to address the gap between the extensive usage of the test and the limited methods available to analyze the data, and to introduce methodologies for comparing results for different initial consolidation stresses, materials, and testing devices. Method: A library of shear cell data was established. Forty-one powders were included, and each material was tested under four different initial consolidation stresses. For each initial consolidation stress, 3 sampling replicates were performed. Results: A dimensionless cohesion, C*, was defined as the cohesion divided by the initial consolidation stress. By identifying a correlation between the flow function coefficient (ffc) and C*, the effects of the initial consolidation stress and the testing device were separated. In addition, by identifying a mathematical correlation between the unconfined yield strength and the cohesion, the yield loci from different initial consolidation stresses could be collapsed into a single material characteristic line, enabling one to characterize each material by a single number (the characteristic slope). This approach can be used to economically compare different materials, or different testing devices. Conclusion: The proposed method augments shear cell data analysis and significantly reduces the complexity of the shear cell data.

International Journal of Pharmaceutics, 2016

Near infrared spectroscopic (NIRS) calibration models for real time prediction of powder density ... more Near infrared spectroscopic (NIRS) calibration models for real time prediction of powder density (tap, bulk and consolidated) were developed for a pharmaceutical formulation. Powder density is a critical property in the manufacturing of solid oral dosages, related to critical quality attributes such as tablet mass, hardness and dissolution. The establishment of calibration techniques for powder density is highly desired towards the development of control strategies. Three techniques were evaluated to obtain the required variation in powder density for calibration sets: 1) different tap density levels (for a single component), 2) generating different strain levels in powders blends (and as consequence powder density), through a modified shear Couette Cell, and 3) applying normal forces during a compressibility test with a powder rheometer to a pharmaceutical blend. For each variation in powder density, near infrared spectra were acquired to develop partial least squares (PLS) calibration models. Test samples were predicted with a relative standard error of prediction of 0.38 %, 7.65 % and 0.9 3% for tap density (single component), shear and rheometer respectively. Spectra obtained in real time in a continuous manufacturing (CM) plant were compared to the spectra from the three approaches used to vary powder density. The calibration based on the application of different strain levels showed the greatest similarity with the blends produced in the CM plant.

Biotechnology and Bioengineering, Oct 20, 2000

Powder Technology, 2016

A full factorial design of experiments was used to study the effect of blend shear strain on the ... more A full factorial design of experiments was used to study the effect of blend shear strain on the compaction process, relative density and strength of pharmaceutical tablets. The powder blends were subjected to different shear strain levels (integral of shear rate with respect to time) using an ad hoc Couette shear cell. Tablets were compressed at different compaction forces using an instrumented compactor simulator, and compaction curves showing the force-displacement profiles during compaction were obtained. Although the die-fill blend porosity (initial porosity) and the minimum in-die tablet porosity (at maximum compaction) decreased significantly with shear strain, the final tablet porosity was surprisingly independent of shear strain. The increase in the in-die maximum compaction with shear strain was, in fact, compensated during postcompaction relaxation of the tables, which also increased significantly with shear strain. Therefore, tablet porosity alone was not sufficient to predict tablet tensile strength. A decrease in the 'work of compaction' as a function of shear strain, and an increase in the recovered elastic work was observed, which suggested weaker particle-particle bonding as the shear strain increased. For each shear strain level, the Ryskewitch Duckworth equation was a good fit to the tensile strength as a function of tablet porosity, and the obtained asymptotic tensile strength at zero porosity exhibited a 60% reduction as a function of shear strain. This was consistent with a reduced bonding efficiency as the shear strain increased.

Physica A: Statistical Mechanics and its Applications, 1998

This article shows the existence of a non-uniform stationary measure (referred to as the w-invari... more This article shows the existence of a non-uniform stationary measure (referred to as the w-invariant measure) associated with the space-ÿlling properties of the unstable manifold and characterizing some statistical properties of chaotic two-dimensional area-preserving systems. The w-invariant measure, which di ers from the ergodic measure and is non-uniform in general, plays a central role in the statistical characterization of chaotic uid mixing systems, since several properties of partially mixed structures can be expressed as ensemble averages over the w-invariant measure. A closed-form expression for the w-invariant density is obtained for a class of mixing systems topologically conjugate with the linear toral automorphism. The physical implications in the theory of uid mixing, and in the statistical characterization of chaotic Hamiltonian systems, are discussed.

Physical Review E, 1998

This article derives an analytic expression for the short-or intermediate-time behavior of the mo... more This article derives an analytic expression for the short-or intermediate-time behavior of the moment hierarchy of finite-time Liapunov exponents ͑stretching exponents͒ for two-dimensional periodically forced Hamiltonian systems and incompressible time-periodic fluid flows. As a result, the exponent characterizing the apparent short-time exponential growth of the intermaterial contact perimeter for two-dimensional systems can be predicted from the statistical properties of the invariant stretching distribution. The analysis as a whole is in fact grounded on an analytic expression for the high stretching tail of the invariant distribution of the finitetime Liapunov exponents. The asymptotic behavior of the moment hierarchy of the stretching field is also addressed in order to highlight the role of the dynamic heterogeneity accounted for by the variance of the stretching exponents. ͓S1063-651X͑98͒02807-4͔

Cohesive powders can be loosely defined as systems where the attractive forced between particles ... more Cohesive powders can be loosely defined as systems where the attractive forced between particles exceed the average particle weight. Cohesive powder flow is interesting from a wide range of reasons. Their main characteristic, intermittence, is evidenced both in the interruption of flow out of hoppers (a mundane issue causing great annoyance to industrial practitioners) and in the sudden avalanching of

International Journal of Pharmaceutics, 2005

The USP tablet dissolution test is an analytical tool used for the verification of drug release p... more The USP tablet dissolution test is an analytical tool used for the verification of drug release processes and formulation selection within the pharmaceutical industry. Given the strong impact of this test, it is surprising that operating conditions and testing devices have been selected empirically. In fact, the flow phenomena in the USP test have received little attention in the past. An examination of the hydrodynamics in the USP apparatus II shows that the device is highly vulnerable to mixing problems that can affect testing performance and consistency. Experimental and computational techniques reveal that the flow field within the device is not uniform, and dissolution results can vary dramatically with the position of the tablet within the vessel. Specifically, computations predict sharp variations in the shear along the bottom of the vessel where the tablet is most likely to settle. Experiments in which the tablet location was carefully controlled reveal that the variation of shear within the testing device can affect the measured dissolution rate.

Fractals in Engineering, 1997

This paper focuses on the evolution of material filaments in chaotic flows. This evolution is num... more This paper focuses on the evolution of material filaments in chaotic flows. This evolution is numerically calculated for three cases of the sine flow corresponding to a mainly regular, a mainly chaotic, and a globally chaotic case without discernible islands. In all cases, the stretched filament has an extremely non-uniform spatial distribution, with densities spanning several orders of magnitude and being the largest in the neighborhood of hyperbolic periodic points. Such spatial non-uniformity is a permanent property of time-periodic flows. As expected, the length of the filament increases exponentially in time, but due to the spatial non-uniformities in filament density, its growth is much faster than predicted by the Lyapunov exponent. The stretched filaments are self-similar in time, as revealed by their spatial structure and by the frequency distribution of the logarithm of the striation thickness, which is described by a family of curves that have an invariant shape and that can be collapsed onto a single curve by means of a simple scaling.

Scientia Pharmaceutica, 2010

International Journal of Pharmaceutics, 2011

The main objective of the present work was to study the effect of mixing order of Cab-O-Sil (CS) ... more The main objective of the present work was to study the effect of mixing order of Cab-O-Sil (CS) and magnesium stearate (MgSt) and microlayers during mixing on blend and tablet properties. A first set of pharmaceutical blend containing Avicel PH200, Pharmatose and micronized acetaminophen was prepared with three mixing orders (mixing order-1: CS added first; mixing order-2: MgSt added first; mixing order-3: CS and MgSt added together). All the blends were subjected to a shear rate of 80 rpm and strain of 40, 160 and 640 revolutions in a controlled shear environment resulting in nine different blends. A second set of nine blends was prepared by replacing Avicel PH200 with Avicel PH102. A total of eighteen blends thus prepared were tested for powder hydrophobicity, powder flow, tablet weight, tablet hardness and tablet dissolution. Results indicated that powder hydrophobicity increased significantly for mixing order-1. Intermediate hydrophobic behavior was found for mixing order-3. Additionally, mixing order 1 resulted in improved powder flow properties, low weight variability, higher average tablet weight and slow drug release rates. Dissolution profiles obtained were found to be strongly dependent not only on the mixing order of flowing agents, but also on the strain and the resulting hydrophobicity.