Donald Clancy | Texas Tech University (original) (raw)

Papers by Donald Clancy

Research paper thumbnail of Predicting the Temperature Evolution during Nanomilling of Drug Suspensions via a Semi-Theoretical Lumped-Parameter Model

Pharmaceutics, Dec 18, 2022

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of An Enthalpy-Balance Model for Timewise Evolution of Temperature during Wet Stirred Media Milling of Drug Suspensions

Research paper thumbnail of RESEARCH ARTICLE Quality by Design Methodology for Development and Scale-up of Batch Mixing Processes

# International Society for Pharmaceutical Engineering 2008 Abstract In this study, a quality by ... more # International Society for Pharmaceutical Engineering 2008 Abstract In this study, a quality by design approach was applied to the design and scale-up of a batch mixing process. Mixtures of acetaminophen and lactose were sampled at different mixing times using a groove sampler. Samples were subsequently analyzed using NIR reflection spectroscopy. The effects of four processing parameters on the empirical mixing rate in a bin blender were examined. Blender rotation rate (two levels), powder fill level (two levels), powder cohesion (two levels), and blender size (three levels) represent the four parameters studied. Blender geometry and blender loading method were treated as constant parameters. Statistical analysis was used to assess the impact each parameter had on the mixing rate. Blender size (p=0.02), powder cohesion (p=0.05), and rotation rate (p=0.07) all significantly affected the mixing rate. The least significant parameter was the vessel fill level (p=0.18), indicating mixing performance is not strongly affected by fill level, given the range studied.

Research paper thumbnail of Accelerated Stability Modeling: Desolvation of a Solvate Drug Product

Accelerated Predictive Stability, 2018

Abstract An APS study conducted on API was used to accurately predict the long-term stability of ... more Abstract An APS study conducted on API was used to accurately predict the long-term stability of tablets packaged in HDPE bottles. The API solid form is a 1:1 crystalline solvate and the critical degradation process in this case study is the desolvation process. The representativeness of the API APS study to the long-term stability of the tablets is partly because the DMSO vapor pressures in both systems are maintained at very low levels: in the API APS studies, the presence of saturated salt solutions acts as a sink for the removal of free DMSO, whereas in the tablet long-term stability studies, the excipients, desiccant, and the semipermeable bottles provide the sink conditions for the removal of free DMSO. The desolvation kinetics of the API appear to be similar to those of the drug product and are apparently unaffected by factors such as drug load.

Research paper thumbnail of Accelerated Stability Modeling: Investigation of Disintegration Time of a Drug Product With Sodium Bicarbonate

Increasing disintegration times observed during stability testing of an immediate-release drug pr... more Increasing disintegration times observed during stability testing of an immediate-release drug product containing sodium bicarbonate were investigated and modeled using an accelerated stability modeling approach. The activation energy and humidity sensitivity of the increase in disintegration times were inconsistent with the decomposition of sodium bicarbonate via the formation of water and carbon dioxide, and X-ray analysis found no evidence of the formation of “Trona” (a different crystalline form of sodium bicarbonate and sodium carbonate created by the reaction of water). Increasing disintegration times appeared to be associated with the formation of rod-like particles observed using scanning electron microscopy. A predictive model for disintegration times was developed, based on an exponential effect of relative humidity; this model indicates that control of the product's starting moisture content or use of a desiccant is key to achieving a 2-year shelf life for the disinte...

Research paper thumbnail of Accelerated Stability Modeling: An Ionic Liquid Drug Product

Accelerated predictive stability (APS) approaches were used to predict the growth of degradation ... more Accelerated predictive stability (APS) approaches were used to predict the growth of degradation products and loss of assay of a drug product made from ionic liquids. Two formulations, one based on glutaric acid and the other based on lactic acid, were compared using APS methodology. The stability behavior was modeled using GSK's Accelerated Stability Modeling software, which predicted that the glutaric acid formulation would need to be stored in a freezer to achieve a 2-year shelf life, whereas the lactic acid formulation was predicted to have a shelf life in excess of 4 years when stored refrigerated. Two degradation products were found to be critical, and these were found to have opposite moisture sensitivities; thus, an optimum humidity was found for storage.

Research paper thumbnail of Hydrothermal BaTiO3-based aqueous slurries

American Ceramic Society Bulletin, 1999

Aqueous, hydrothermal barium titanate-based submicron dielectric slurries have demonstrated sever... more Aqueous, hydrothermal barium titanate-based submicron dielectric slurries have demonstrated several benefits in the fabrication of high-quality thin green-ceramic sheets with <5 μm thickness.

Research paper thumbnail of Development and Scale-Up of Diversion Strategy for Twin Screw Granulation in Continuous Manufacturing

Journal of Pharmaceutical Sciences, 2020

This paper explores the impact of the definition of the bounds of the limiter proposed by Michala... more This paper explores the impact of the definition of the bounds of the limiter proposed by Michalak and Ollivier-Gooch in [56] (2009), for higher-order Monotone-Upstream Central Scheme for Conservation Laws (MUSCL) numerical schemes on unstructured meshes in the finite-volume (FV) framework. A new modification of the limiter is proposed where the bounds are redefined by utilising all the spatial information provided by all the elements in the reconstruction stencil. Numerical results obtained on smooth and discontinuous test problems of the Euler equations on unstructured meshes, highlight that the newly proposed extended bounds limiter exhibits superior performance in terms of accuracy and mesh sensitivity compared to the cell-based or vertex-based bounds implementations.

Research paper thumbnail of Characterization of NIR interfaces for the feeding and in-line monitoring of a continuous granulation process

International Journal of Pharmaceutics, 2019

This work describes the characterization of three NIR interfaces intended to monitor a continuous... more This work describes the characterization of three NIR interfaces intended to monitor a continuous granulation process. Two interfaces (i.e. a barrel interface and a rotating paddle interface) were evaluated in order to monitor the API concentration at the entrance of the granulator, and a third interface (i.e. an outlet interface), was evaluated to monitor the quality of the resulting outlet granules. The barrel interface provided an assessment of the API concentration during the feeding process by scanning the material conveyed by the screws of the loss-in-weight feeder. The rotating paddle interface analyzed discrete amounts of powder upon exiting the feeder via the accumulation of material on the paddles. Partial Least Squares (PLS) calibration models were constructed using the same powder blends for the two inlet interfaces and using the outlet granules for the outlet interface. Five independent batches were used to evaluate the prediction performance of each inlet calibration model. The outlet interface produced the lowest error of prediction due to the homogeneity of the granules. The barrel interface produced lower errors of prediction than the rotating paddle interface. However, powder density affected only the barrel interface, producing deviations in the predicted values. Therefore, powder density is a factor that should be considered in the calibration sample design for spectroscopic measurements when using this type of interface. A variographic analysis demonstrated that the continuous 1-dimensional motion in the barrel and outlet interfaces produced representative measurements of each batch during calibration and test experiments, generating a low minimum practical error (MPE).

Research paper thumbnail of Theory and Fundamentals of Accelerated Predictive Stability (APS) Studies

Accelerated Predictive Stability, 2018

Abstract The aim of accelerated predictive stability (APS) studies is to predict long-term stabil... more Abstract The aim of accelerated predictive stability (APS) studies is to predict long-term stability behavior on the basis of short-term stability assessments that comprise multiple different accelerated conditions. The effects of temperature and humidity on the rate of degradation are modeled using a humidity-modified Arrhenius equation. APS methods require that an expression for the rate of degradation (k) be obtained for each stability condition; this chapter outlines various methods used to calculate “k” if the degradation profile is not linear. Finally, various methods for data processing and assessing the goodness of fit of the model are discussed.

Research paper thumbnail of Predictive modeling of pharmaceutical unit operations

Predictive Modeling of Pharmaceutical Unit Operations, 2017

Research paper thumbnail of Method and Apparatus for Predicting Properties of Granulated Materials and Dosage Forms made Therefrom

Research paper thumbnail of Kinetic Model Development for Accelerated Stability Studies

AAPS PharmSciTech, 2016

Accelerated stability coupled with modeling to predict the stability of compounds, blends, and pr... more Accelerated stability coupled with modeling to predict the stability of compounds, blends, and products at long-term storage conditions provides significant benefits in science-based decision-making throughout drug substance and drug product development. The study can often be completed, including data analysis in the space of three working weeks, and the information gathered and learning made in this time period can rival years of traditional analysis. The speed of the studies allows an earlier assessment of risk to quality enabling appropriate risk mitigation strategies to be implemented in a timely manner. The scientific foundation is based upon Arrhenius kinetic equations that can be linear or nonlinear in time, and can be based upon water vapor pressure or liquid water activity (relative humidity). A variety of kinetic models are evaluated, and the best model is chosen based upon both Bayesian information criteria and an automated assessment of kinetic model parameters fitting within acceptable ranges. Confidence intervals are estimated based upon a bootstrapping approach. Moisture vapor transmission rate models are applied on top of the resulting kinetic models in order to simulate different packaging types and the use of desiccant. The kinetic models are integrated with the prediction of packaging humidity over time to create a long-term prediction of impurities and other phenomena. The resulting models have been shown to be useful for not only the prediction of drug product impurities in long-term storage but other physical phenomena as well such as hydrate development and solvate loss.

Research paper thumbnail of Dispersible dielectric particles and methods of forming the same

Research paper thumbnail of Real-Time Process Analytical Technology Assurance for Flow Synthesis of Oligonucleotides

Organic Process Research & Development, 2015

A feasibility study has been conducted using Process Analytical Technology (PAT) monitoring and c... more A feasibility study has been conducted using Process Analytical Technology (PAT) monitoring and chemometric modeling techniques to mitigate risks identified for the solid-phase synthesis of a model oligonucleotide compound in a flow reactor manifold. This paper will discuss three of the key risks identified for this automated process that are generally applicable to oligonucleotide manufacturing: (1) connection of an incorrect chemical solution to a designated input port of the synthesizer; (2) incorrect quantitative preparation of a chemical solution; and (3) errors that may come from mechanical or other unknown sources associated with the synthesizer. Mid-infrared and Raman spectroscopy were the key PAT techniques used to monitor the automated synthetic process in real time. Classification, quantitative (partial least-squares), and multivariate statistical process control (MSPC) modeling were then used to analyze the acquired data and detect the occurrence of the aforementioned failure modes. MSPC models were constructed and tested with intentionally induced key process deviations to explore their sensitivity and detection capability. Suggestions are proposed for more stringent validated processes that would be required to implement these techniques in a manufacturing environment.

Research paper thumbnail of Rigorous numerical simulation of gas separation by hollow-fiber membranes

Research paper thumbnail of Accelerated Stability Modeling: Assay Loss of Nicotine Lozenges

Analysis of nicotine assay loss from a drug product shows improved fit and predictive capability ... more Analysis of nicotine assay loss from a drug product shows improved fit and predictive capability when the stability data are first treated using a Prout-Tompkins’ data transformation. Prout-Tompkins kinetics are based on a degradation rate that initially increases exponentially, but then decelerates exponentially beyond 50% conversion, leading to a sigmoidal degradation profile. In scenarios where very different extents of degradation are obtained under different conditions, the limitations of the isoconversion approach and the benefit of using an appropriate data transform are demonstrated.

Research paper thumbnail of Closing the gap in series scale up of high shear wet granulation process using impeller power and blade design

Powder Technology, 2011

This paper investigates the use of impeller work combined with an understanding of the significan... more This paper investigates the use of impeller work combined with an understanding of the significance of the impeller power inflection point during granulation to monitor, control, and scale up high shear wet granulation processes in the pharmaceutical industry. High shear wet granulations were carried out in a series of PMA Fielder granulators (25, 65, 150, and 300-L) with a geometric similar bowl at conditions of constant water addition time and constant tip speed. The results suggested that the granulation process can be effectively scaled up using a linear relationship between the impeller power inflection point (percent of water added at the point where the impeller load starts rising) and the Froude number in PMA Fielder granulator. To close the gap in the series scale up of wet granulation processes, it is desirable to design a granulator at small scale that performs similarly to a full scale commercial granulator such that no variables have to be significantly changed during scale up. A customized 6-L granulator (Fluid Air, Inc.) was designed with a similar bowl geometry as the 300-L Fielder granulator with a specialized blade of lower angle. It is illustrated in this paper that a 6-L granulator can be directly scaled up to a 300-L granulator using constant tip speed and percentage water addition, with the same impeller work and drug product performance. Granulation scale up using the impeller power as the endpoint measurement, combined with a proper impeller blade design can significantly reduce expenditure and time and accelerate the progression of drug product to market, by eliminating stepwise series scale up, and minimizing drug substance requirements.

Research paper thumbnail of Dehydrogenation as an aid to the mass spectrometric analysis of naphthenes

Analytical Chemistry, 1961

Research paper thumbnail of Quality by Design Methodology for Development and Scale-up of Batch Mixing Processes

Journal of Pharmaceutical Innovation, 2008

In this study, a quality by design approach was applied to the design and scale-up of a batch mix... more In this study, a quality by design approach was applied to the design and scale-up of a batch mixing process. Mixtures of acetaminophen and lactose were sampled at different mixing times using a groove sampler. Samples were subsequently analyzed using NIR reflection spectroscopy. The effects of four processing parameters on the empirical mixing rate in a bin blender were examined. Blender rotation rate (two levels), powder fill level (two levels), powder cohesion (two levels), and blender size (three levels) represent the four parameters studied. Blender geometry and blender loading method were treated as constant parameters. Statistical analysis was used to assess the impact each parameter had on the mixing rate. Blender size (p=0.02), powder cohesion (p=0.05), and rotation rate (p=0.07) all significantly affected the mixing rate. The least significant parameter was the vessel fill level (p=0.18), indicating mixing performance is not strongly affected by fill level, given the range studied.

Research paper thumbnail of Predicting the Temperature Evolution during Nanomilling of Drug Suspensions via a Semi-Theoretical Lumped-Parameter Model

Pharmaceutics, Dec 18, 2022

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of An Enthalpy-Balance Model for Timewise Evolution of Temperature during Wet Stirred Media Milling of Drug Suspensions

Research paper thumbnail of RESEARCH ARTICLE Quality by Design Methodology for Development and Scale-up of Batch Mixing Processes

# International Society for Pharmaceutical Engineering 2008 Abstract In this study, a quality by ... more # International Society for Pharmaceutical Engineering 2008 Abstract In this study, a quality by design approach was applied to the design and scale-up of a batch mixing process. Mixtures of acetaminophen and lactose were sampled at different mixing times using a groove sampler. Samples were subsequently analyzed using NIR reflection spectroscopy. The effects of four processing parameters on the empirical mixing rate in a bin blender were examined. Blender rotation rate (two levels), powder fill level (two levels), powder cohesion (two levels), and blender size (three levels) represent the four parameters studied. Blender geometry and blender loading method were treated as constant parameters. Statistical analysis was used to assess the impact each parameter had on the mixing rate. Blender size (p=0.02), powder cohesion (p=0.05), and rotation rate (p=0.07) all significantly affected the mixing rate. The least significant parameter was the vessel fill level (p=0.18), indicating mixing performance is not strongly affected by fill level, given the range studied.

Research paper thumbnail of Accelerated Stability Modeling: Desolvation of a Solvate Drug Product

Accelerated Predictive Stability, 2018

Abstract An APS study conducted on API was used to accurately predict the long-term stability of ... more Abstract An APS study conducted on API was used to accurately predict the long-term stability of tablets packaged in HDPE bottles. The API solid form is a 1:1 crystalline solvate and the critical degradation process in this case study is the desolvation process. The representativeness of the API APS study to the long-term stability of the tablets is partly because the DMSO vapor pressures in both systems are maintained at very low levels: in the API APS studies, the presence of saturated salt solutions acts as a sink for the removal of free DMSO, whereas in the tablet long-term stability studies, the excipients, desiccant, and the semipermeable bottles provide the sink conditions for the removal of free DMSO. The desolvation kinetics of the API appear to be similar to those of the drug product and are apparently unaffected by factors such as drug load.

Research paper thumbnail of Accelerated Stability Modeling: Investigation of Disintegration Time of a Drug Product With Sodium Bicarbonate

Increasing disintegration times observed during stability testing of an immediate-release drug pr... more Increasing disintegration times observed during stability testing of an immediate-release drug product containing sodium bicarbonate were investigated and modeled using an accelerated stability modeling approach. The activation energy and humidity sensitivity of the increase in disintegration times were inconsistent with the decomposition of sodium bicarbonate via the formation of water and carbon dioxide, and X-ray analysis found no evidence of the formation of “Trona” (a different crystalline form of sodium bicarbonate and sodium carbonate created by the reaction of water). Increasing disintegration times appeared to be associated with the formation of rod-like particles observed using scanning electron microscopy. A predictive model for disintegration times was developed, based on an exponential effect of relative humidity; this model indicates that control of the product's starting moisture content or use of a desiccant is key to achieving a 2-year shelf life for the disinte...

Research paper thumbnail of Accelerated Stability Modeling: An Ionic Liquid Drug Product

Accelerated predictive stability (APS) approaches were used to predict the growth of degradation ... more Accelerated predictive stability (APS) approaches were used to predict the growth of degradation products and loss of assay of a drug product made from ionic liquids. Two formulations, one based on glutaric acid and the other based on lactic acid, were compared using APS methodology. The stability behavior was modeled using GSK's Accelerated Stability Modeling software, which predicted that the glutaric acid formulation would need to be stored in a freezer to achieve a 2-year shelf life, whereas the lactic acid formulation was predicted to have a shelf life in excess of 4 years when stored refrigerated. Two degradation products were found to be critical, and these were found to have opposite moisture sensitivities; thus, an optimum humidity was found for storage.

Research paper thumbnail of Hydrothermal BaTiO3-based aqueous slurries

American Ceramic Society Bulletin, 1999

Aqueous, hydrothermal barium titanate-based submicron dielectric slurries have demonstrated sever... more Aqueous, hydrothermal barium titanate-based submicron dielectric slurries have demonstrated several benefits in the fabrication of high-quality thin green-ceramic sheets with <5 μm thickness.

Research paper thumbnail of Development and Scale-Up of Diversion Strategy for Twin Screw Granulation in Continuous Manufacturing

Journal of Pharmaceutical Sciences, 2020

This paper explores the impact of the definition of the bounds of the limiter proposed by Michala... more This paper explores the impact of the definition of the bounds of the limiter proposed by Michalak and Ollivier-Gooch in [56] (2009), for higher-order Monotone-Upstream Central Scheme for Conservation Laws (MUSCL) numerical schemes on unstructured meshes in the finite-volume (FV) framework. A new modification of the limiter is proposed where the bounds are redefined by utilising all the spatial information provided by all the elements in the reconstruction stencil. Numerical results obtained on smooth and discontinuous test problems of the Euler equations on unstructured meshes, highlight that the newly proposed extended bounds limiter exhibits superior performance in terms of accuracy and mesh sensitivity compared to the cell-based or vertex-based bounds implementations.

Research paper thumbnail of Characterization of NIR interfaces for the feeding and in-line monitoring of a continuous granulation process

International Journal of Pharmaceutics, 2019

This work describes the characterization of three NIR interfaces intended to monitor a continuous... more This work describes the characterization of three NIR interfaces intended to monitor a continuous granulation process. Two interfaces (i.e. a barrel interface and a rotating paddle interface) were evaluated in order to monitor the API concentration at the entrance of the granulator, and a third interface (i.e. an outlet interface), was evaluated to monitor the quality of the resulting outlet granules. The barrel interface provided an assessment of the API concentration during the feeding process by scanning the material conveyed by the screws of the loss-in-weight feeder. The rotating paddle interface analyzed discrete amounts of powder upon exiting the feeder via the accumulation of material on the paddles. Partial Least Squares (PLS) calibration models were constructed using the same powder blends for the two inlet interfaces and using the outlet granules for the outlet interface. Five independent batches were used to evaluate the prediction performance of each inlet calibration model. The outlet interface produced the lowest error of prediction due to the homogeneity of the granules. The barrel interface produced lower errors of prediction than the rotating paddle interface. However, powder density affected only the barrel interface, producing deviations in the predicted values. Therefore, powder density is a factor that should be considered in the calibration sample design for spectroscopic measurements when using this type of interface. A variographic analysis demonstrated that the continuous 1-dimensional motion in the barrel and outlet interfaces produced representative measurements of each batch during calibration and test experiments, generating a low minimum practical error (MPE).

Research paper thumbnail of Theory and Fundamentals of Accelerated Predictive Stability (APS) Studies

Accelerated Predictive Stability, 2018

Abstract The aim of accelerated predictive stability (APS) studies is to predict long-term stabil... more Abstract The aim of accelerated predictive stability (APS) studies is to predict long-term stability behavior on the basis of short-term stability assessments that comprise multiple different accelerated conditions. The effects of temperature and humidity on the rate of degradation are modeled using a humidity-modified Arrhenius equation. APS methods require that an expression for the rate of degradation (k) be obtained for each stability condition; this chapter outlines various methods used to calculate “k” if the degradation profile is not linear. Finally, various methods for data processing and assessing the goodness of fit of the model are discussed.

Research paper thumbnail of Predictive modeling of pharmaceutical unit operations

Predictive Modeling of Pharmaceutical Unit Operations, 2017

Research paper thumbnail of Method and Apparatus for Predicting Properties of Granulated Materials and Dosage Forms made Therefrom

Research paper thumbnail of Kinetic Model Development for Accelerated Stability Studies

AAPS PharmSciTech, 2016

Accelerated stability coupled with modeling to predict the stability of compounds, blends, and pr... more Accelerated stability coupled with modeling to predict the stability of compounds, blends, and products at long-term storage conditions provides significant benefits in science-based decision-making throughout drug substance and drug product development. The study can often be completed, including data analysis in the space of three working weeks, and the information gathered and learning made in this time period can rival years of traditional analysis. The speed of the studies allows an earlier assessment of risk to quality enabling appropriate risk mitigation strategies to be implemented in a timely manner. The scientific foundation is based upon Arrhenius kinetic equations that can be linear or nonlinear in time, and can be based upon water vapor pressure or liquid water activity (relative humidity). A variety of kinetic models are evaluated, and the best model is chosen based upon both Bayesian information criteria and an automated assessment of kinetic model parameters fitting within acceptable ranges. Confidence intervals are estimated based upon a bootstrapping approach. Moisture vapor transmission rate models are applied on top of the resulting kinetic models in order to simulate different packaging types and the use of desiccant. The kinetic models are integrated with the prediction of packaging humidity over time to create a long-term prediction of impurities and other phenomena. The resulting models have been shown to be useful for not only the prediction of drug product impurities in long-term storage but other physical phenomena as well such as hydrate development and solvate loss.

Research paper thumbnail of Dispersible dielectric particles and methods of forming the same

Research paper thumbnail of Real-Time Process Analytical Technology Assurance for Flow Synthesis of Oligonucleotides

Organic Process Research & Development, 2015

A feasibility study has been conducted using Process Analytical Technology (PAT) monitoring and c... more A feasibility study has been conducted using Process Analytical Technology (PAT) monitoring and chemometric modeling techniques to mitigate risks identified for the solid-phase synthesis of a model oligonucleotide compound in a flow reactor manifold. This paper will discuss three of the key risks identified for this automated process that are generally applicable to oligonucleotide manufacturing: (1) connection of an incorrect chemical solution to a designated input port of the synthesizer; (2) incorrect quantitative preparation of a chemical solution; and (3) errors that may come from mechanical or other unknown sources associated with the synthesizer. Mid-infrared and Raman spectroscopy were the key PAT techniques used to monitor the automated synthetic process in real time. Classification, quantitative (partial least-squares), and multivariate statistical process control (MSPC) modeling were then used to analyze the acquired data and detect the occurrence of the aforementioned failure modes. MSPC models were constructed and tested with intentionally induced key process deviations to explore their sensitivity and detection capability. Suggestions are proposed for more stringent validated processes that would be required to implement these techniques in a manufacturing environment.

Research paper thumbnail of Rigorous numerical simulation of gas separation by hollow-fiber membranes

Research paper thumbnail of Accelerated Stability Modeling: Assay Loss of Nicotine Lozenges

Analysis of nicotine assay loss from a drug product shows improved fit and predictive capability ... more Analysis of nicotine assay loss from a drug product shows improved fit and predictive capability when the stability data are first treated using a Prout-Tompkins’ data transformation. Prout-Tompkins kinetics are based on a degradation rate that initially increases exponentially, but then decelerates exponentially beyond 50% conversion, leading to a sigmoidal degradation profile. In scenarios where very different extents of degradation are obtained under different conditions, the limitations of the isoconversion approach and the benefit of using an appropriate data transform are demonstrated.

Research paper thumbnail of Closing the gap in series scale up of high shear wet granulation process using impeller power and blade design

Powder Technology, 2011

This paper investigates the use of impeller work combined with an understanding of the significan... more This paper investigates the use of impeller work combined with an understanding of the significance of the impeller power inflection point during granulation to monitor, control, and scale up high shear wet granulation processes in the pharmaceutical industry. High shear wet granulations were carried out in a series of PMA Fielder granulators (25, 65, 150, and 300-L) with a geometric similar bowl at conditions of constant water addition time and constant tip speed. The results suggested that the granulation process can be effectively scaled up using a linear relationship between the impeller power inflection point (percent of water added at the point where the impeller load starts rising) and the Froude number in PMA Fielder granulator. To close the gap in the series scale up of wet granulation processes, it is desirable to design a granulator at small scale that performs similarly to a full scale commercial granulator such that no variables have to be significantly changed during scale up. A customized 6-L granulator (Fluid Air, Inc.) was designed with a similar bowl geometry as the 300-L Fielder granulator with a specialized blade of lower angle. It is illustrated in this paper that a 6-L granulator can be directly scaled up to a 300-L granulator using constant tip speed and percentage water addition, with the same impeller work and drug product performance. Granulation scale up using the impeller power as the endpoint measurement, combined with a proper impeller blade design can significantly reduce expenditure and time and accelerate the progression of drug product to market, by eliminating stepwise series scale up, and minimizing drug substance requirements.

Research paper thumbnail of Dehydrogenation as an aid to the mass spectrometric analysis of naphthenes

Analytical Chemistry, 1961

Research paper thumbnail of Quality by Design Methodology for Development and Scale-up of Batch Mixing Processes

Journal of Pharmaceutical Innovation, 2008

In this study, a quality by design approach was applied to the design and scale-up of a batch mix... more In this study, a quality by design approach was applied to the design and scale-up of a batch mixing process. Mixtures of acetaminophen and lactose were sampled at different mixing times using a groove sampler. Samples were subsequently analyzed using NIR reflection spectroscopy. The effects of four processing parameters on the empirical mixing rate in a bin blender were examined. Blender rotation rate (two levels), powder fill level (two levels), powder cohesion (two levels), and blender size (three levels) represent the four parameters studied. Blender geometry and blender loading method were treated as constant parameters. Statistical analysis was used to assess the impact each parameter had on the mixing rate. Blender size (p=0.02), powder cohesion (p=0.05), and rotation rate (p=0.07) all significantly affected the mixing rate. The least significant parameter was the vessel fill level (p=0.18), indicating mixing performance is not strongly affected by fill level, given the range studied.