Raafat Fahmy - Academia.edu (original) (raw)

Papers by Raafat Fahmy

Research paper thumbnail of Comparing a Statistical Model and Bayesian Approach to Establish the Design Space for the Coating of Ciprofloxacin HCl Beads at Different Scales of Production

AAPS PharmSciTech, 2018

The primary objective of this study was to compare two methods for establishing a design space fo... more The primary objective of this study was to compare two methods for establishing a design space for critical process parameters that affect ethylcellulose film coating of multiparticulate beads and assess this design space validity across manufacturing scales. While there are many factors that can affect film coating, this study will focus on the effects processing conditions have on the quality and extent of film formation, as evaluated by their impact coating yield and drug release. Ciprofloxacin HCl layered beads were utilized as an active substrate core, ethylcellulose aqueous dispersion as a controlled release polymer, and triethyl citrate as a plasticizer. Thirty experiments were conducted using a central composite design to optimize the coating process and map the response surface to build a design space using either statistical least squares or a Bayesian approach. The response surface was fitted using a linear two-factor interaction model with spraying temperature, curing temperature, and curing time as significant model terms. The design spaces established by the two approaches were in close agreement with the statistical least squares approach being more conservative than the Bayesian approach. The design space established for the critical process parameters using small-scale batches was tested using scale-up batches and found to be scale-independent. The robustness of the design space was confirmed across scales and was successfully utilized to establish process signature for the coating process.

Research paper thumbnail of Quality-by-Design II: Application of Quantitative Risk Analysis to the Formulation of Ciprofloxacin Tablets

AAPS PharmSciTech, 2015

Qualitative risk assessment methods are often used as the first step to determining design space ... more Qualitative risk assessment methods are often used as the first step to determining design space boundaries; however, quantitative assessments of risk with respect to the design space, i.e., calculating the probability of failure for a given severity, are needed to fully characterize design space boundaries. Quantitative risk assessment methods in design and operational spaces are a significant aid to evaluating proposed design space boundaries. The goal of this paper is to demonstrate a relatively simple strategy for design space definition using a simplified Bayesian Monte Carlo simulation. This paper builds on a previous paper that used failure mode and effects analysis (FMEA) qualitative risk assessment and Plackett-Burman design of experiments to identity the critical quality attributes. The results show that the sequential use of qualitative and quantitative risk assessments can focus the design of experiments on a reduced set of critical material and process parameters that determine a robust design space under conditions of limited laboratory experimentation. This approach provides a strategy by which the degree of risk associated with each known parameter can be calculated and allocates resources in a manner that manages risk to an acceptable level.

Research paper thumbnail of Enhancing Dissolution Rate of Carbamazepine via Solvent Casting with a Novel Polymeric Solubilizer (Soluplus ® )

Purpose: To increase dissolution rate of Carbamazepine (CBZ) by forming solid dispersions (SD) wi... more Purpose: To increase dissolution rate of Carbamazepine (CBZ) by forming solid dispersions (SD) with a novel polymeric solubilizer (Soluplus ®) via solvent casting technique. This study also attempted to investigate the solid state within the SD and its potential in enhancing the dissolution rate of CBZ. Methods: SD of CBZ-Soluplus ® at different weight ratios (1:9, 1:4, 1:3, 3:7, 1:1) were prepared by solvent casting technique. The SD samples were dried in an oven at 50 C until the loss on drying is greater than 78%. The SD is then cooled at -20 C for 1 hour. The SDs were gently grounded in a mortar and the resulting granules were sieved and the 106-500 μm particle size fraction was obtained. The dissolution profile of CBZ was performed in a USP II dissolution apparatus (paddle method) with 900 mL of 0.1N HCl (adjusted to pH 1.2) at 100 rpm and 37 C 0.5 C. The solution was filtered and continuously pumped into a Shimadzu UV 160U spectrophotometer and the absorbance values were recor...

Research paper thumbnail of Excipient Manufacturing and Good Manufacturing Practices

Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems, 2006

Research paper thumbnail of Comparison of bovine in vivo bioavailability of two sulfamethazine oral boluses exhibiting different in vitro dissolution profiles

Journal of Veterinary Pharmacology and Therapeutics, 2006

Comparison of bovine in vivo bioavailability of two sulfamethazine oral boluses exhibiting differ... more Comparison of bovine in vivo bioavailability of two sulfamethazine oral boluses exhibiting different in vitro dissolution profiles. J. vet. Pharmacol. Therap. 29, 459-467. The bolus (or oblet) is a dosage form that can be used for the oral administration of pharmaceutical compounds to ruminating species. Unlike traditional tablets, oral boluses may contain quantities of drug on the order of grams rather than milligrams. Due to its size, it is only recently that USP-like in vitro dissolution methods have been developed for this dosage form. However, whether or not these dissolution tests can predict product in vivo performance has yet to be determined. The importance of this issue is apparent when the U.S. Food and Drug Administration Center for Veterinary Medicine is faced with the decision of whether to require additional in vivo bioequivalence study data to support the approval of changes in product chemistry or manufacturing method. The current study was undertaken to determine whether an in vivo/ in vitro correlation can be established for bovine sulfamethazine oral boluses and to acquire insight into the magnitude of changes in in vitro product performance that can occur before corresponding changes are seen in in vivo blood level profiles. Based upon the results of this investigation, it is concluded that marked changes in in vitro sulfamethazine bolus performance can be tolerated before resulting in altered in vivo blood level profiles. However, the data also suggest that rumenal absorption may occur for some compounds. Therefore the degree to which variation in product in vitro dissolution profiles can be tolerated may be compound specific.

Research paper thumbnail of Application of Near-Infrared Spectroscopy (NIRS) as a Tool for Quality Control in Traditional Chinese Medicine (TCM)

Current Bioactive Compounds, 2011

ABSTRACT Traditional Chinese Medicine (TCM) is becoming more and more popular all over the world.... more ABSTRACT Traditional Chinese Medicine (TCM) is becoming more and more popular all over the world. Novel analytical tools for quality control are highly demanded enabling analysis starting at breeding and ending at biological fluids including urine or serum. Compared to analytical separation methods (chromatography, electrophoresis) near-infrared spectroscopy (NIRS) allows analyzing matter of interest non-invasively, fast and physical/chemical parameters simultaneously. It can be used for the quantitative control of certain (active) ingredients. In many cases identification can only be achieved by pattern recognition. Therefore, NIRS combined with cluster analysis offers huge potential to identify e.g. species, geographic origin, special medicinal formula etc. In the present contribution the fundamentals, possibilities of NIR applied in quality control of TCM are pointed out and its ad- and disadvantages are discussed in detail by several practical examples.

Research paper thumbnail of Impact of gastrointestinal differences in veterinary species on the oral drug solubility, in vivo dissolution, and formulation of veterinary therapeutics

ADMET and DMPK, 2022

Many gaps exist in our understanding of species differences in gastrointestinal (GI) fluid compos... more Many gaps exist in our understanding of species differences in gastrointestinal (GI) fluid composition and the associated impact of food intake and dietary composition on in vivo drug solubilization. This information gap can lead to uncertainties with regard to how best to formulate pharmaceuticals for veterinary use or the in vitro test conditions that will be most predictive of species-specific in vivo oral product performance. To address these challenges, this overview explores species-specific factors that can influence oral drug solubility and the formulation approaches that can be employed to overcome solubility-associated bioavailability difficulties. These discussions are framed around some of the basic principles associated with drug solubilization, reported species differences in GI fluid composition, types of oral dosage forms typically given for the various animal species, and the effect of prandial state in dogs and cats. This basic information is integrated into a ques...

Research paper thumbnail of Veterinary Pharmaceuticals: Factors Influencing Their Development and Use

Encyclopedia of pharmaceutical …, 2006

Research paper thumbnail of Workshop Report: USP Workshop on Exploring the Science of Drug Absorption

Dissolution Technologies

In October 2018, the United States Pharmacopeia (USP) hosted a two-day workshop to explore the sc... more In October 2018, the United States Pharmacopeia (USP) hosted a two-day workshop to explore the science of drug absorption. Experts from around the globe presented some of the challenges associated with drug product development from the perspective of the physiological attributes of the patient (human or canine) and the body site for drug activity. Included in the discussions were methods and approaches for answering complex questions, providing insights into the strengths and challenges of methods available in our biopharmaceutical tool chest. The following is a synopsis of the presentations and the highlights of the discussions that ensued. Disclaimer: This article reflects the views of the authors and should not be construed as representing the views or policies of the United States Food and Drug Administration.

Research paper thumbnail of Prediction of Dissolution of Sustained Release Coated Ciprofloxacin Beads Using Near-infrared Spectroscopy and Process Parameters: a Data Fusion Approach

AAPS PharmSciTech

The aim of the work is to develop a data fusion model using near-infrared (NIR) and process param... more The aim of the work is to develop a data fusion model using near-infrared (NIR) and process parameters for the predictions of drug dissolution from controlled release multiparticulate beads. Using a design of experiments, ciprofloxacin-coated beads were manufactured and critical process parameters such as air volume, product temperature, curing temperature, and curing time were measured; environmental humidity was monitored using a Pyrobuttons®. The NIR spectra were decomposed using principal component analysis (PCA). The PCA scores were fused with process measurements and all variables were autoscaled. The autoscaled variables were regressed against measured dissolution data at 1 h and 2 h time points; the PLS regression used quadratic and cross terms. The NIR spectra only model using data collected at the end of bead curing generated a PLS model using 5 latent variables with R2 equal to 0.245 and 0.299 and RMSECV 13.23 and 13.12 for the 1 h and 2 h dissolution time points, respectively. The low R2 and high root mean square error of cross validation (RMSECV) values indicate that NIR spectra alone were insufficient to model the drug release. Similar results were obtained for NIR model using data collected at the end of spraying phase. Models with fused spectral and process data yielded better prediction with R2 above 0.88 and RMSECV less than 5% for the 1 h and 2 h dissolution time points. The data fusion model predicted dissolution profiles with an error less than 10%.

Research paper thumbnail of Primer on the Science of In Vitro Dissolution Testing of Oral Dosage Forms and Factors Influencing its Biological Relevance

Dissolution Technologies

In vitro dissolution testing can serve as an effective and efficient tool for evaluating the infl... more In vitro dissolution testing can serve as an effective and efficient tool for evaluating the influence of formulation and manufacturing variables on drug release characteristics. The targeted purpose will determine the method used and the implications of the test results. Regardless of its intended purpose, it is necessary to understand the factors influencing in vitro dissolution outcomes to avoid the introduction of error into the data interpretation. This will influence the selection of the in vitro test procedure, ensuring that the method can identify changes in the critical formulation and manufacturing variables. There is also a need to understand the rate limiting factors influencing in vivo product bioavailability both from a dissolution and an absorption perspective. Finally, to achieve in vivo biorelevance, it is necessary to understand how the selected in vitro dissolution test method reflects the variables impacting in vivo product dissolution behavior. This primer summarizes and integrates these diverse variables, fostering an appreciation of the strengths and potential pitfalls that may be encountered during the generation and analysis of in vitro dissolution profiles associated with oral dosage forms. This understanding is needed for developing a well-designed dissolution test procedure that is appropriately fit for purpose.

Research paper thumbnail of Formulation characteristics and in vitro release testing of cyclosporine ophthalmic ointments

International journal of pharmaceutics, Jan 21, 2018

The aim of the present study was to investigate the relationship between formulation/process vari... more The aim of the present study was to investigate the relationship between formulation/process variables versus the critical quality attributes (CQAs) of cyclosporine ophthalmic ointments and to explore the feasibility of using an in vitro approach to assess product sameness. A definitive screening design (DSD) was used to evaluate the impact of formulation and process variables. The formulation variables included drug percentage, percentage of corn oil and lanolin alcohol. The process variables studied were mixing temperature, mixing time and the method of mixing. The quality and performance attributes examined included drug assay, content uniformity, image analysis, rheology (storage modulus, shear viscosity) and in vitro drug release. Of the formulation variables evaluated, the percentage of the drug substance and the percentage of corn oil in the matrix were the most influential factors with respect to in vitro drug release. Conversely, the process parameters tested were observed ...

Research paper thumbnail of A Systematic Approach of Employing Quality by Design Principles: Risk Assessment and Design of Experiments to Demonstrate Process Understanding and Identify the Critical Process Parameters for Coating of the Ethylcellulose Pseudolatex Dispersion Using Non-Conventional Fluid Bed Process

AAPS PharmSciTech, 2016

The goal of this study was to utilize risk assessment techniques and statistical design of experi... more The goal of this study was to utilize risk assessment techniques and statistical design of experiments (DoE) to gain process understanding and to identify critical process parameters for the manufacture of controlled release multiparticulate beads using a novel disk-jet fluid bed technology. The material attributes and process parameters were systematically assessed using the Ishikawa fish bone diagram and failure mode and effect analysis (FMEA) risk assessment methods. The high risk attributes identified by the FMEA analysis were further explored using resolution V fractional factorial design. To gain an understanding of the processing parameters, a resolution V fractional factorial study was conducted. Using knowledge gained from the resolution V study, a resolution IV fractional factorial study was conducted; the purpose of this IV study was to identify the critical process parameters (CPP) that impact the critical quality attributes and understand the influence of these parameters on film formation. For both studies, the microclimate, atomization pressure, inlet air volume, product temperature (during spraying and curing), curing time, and percent solids in the coating solutions were studied. The responses evaluated were percent agglomeration, percent fines, percent yield, bead aspect ratio, median particle size diameter (d50), assay, and drug release rate. Pyrobuttons® were used to record real-time temperature and humidity changes in the fluid bed. The risk assessment methods and process analytical tools helped to understand the novel disk-jet technology and to systematically develop models of the coating process parameters like process efficiency and the extent of curing during the coating process.

Research paper thumbnail of Erratum to: Use of Modeling and Simulation Tools for Understanding the Impact of Formulation on the Absorption of a Low Solubility Compound: Ciprofloxacin

The AAPS journal, Nov 23, 2016

Research paper thumbnail of Use of Modeling and Simulation Tools for Understanding the Impact of Formulation on the Absorption of a Low Solubility Compound: Ciprofloxacin

The AAPS journal, Jul 1, 2016

This study explored the utility of mechanistic absorption models to describe the in vivo performa... more This study explored the utility of mechanistic absorption models to describe the in vivo performance of a low solubility/low permeability compound in normal healthy subjects. Sixteen healthy human volunteers received three oral formulations and an intravenous infusion in a randomized crossover design. Plasma ciprofloxacin concentrations were estimated by HPLC. In vitro ciprofloxacin release from the oral tablets was tested under a variety of conditions. A mechanistic model was used to explore in vivo dissolution and intestinal absorption. Although dissolution rate influenced the location of drug release, absorption challenges appeared to be associated with permeability limitations in the lower small intestine and colon. The apparent relationship between drug solubilization within the upper small intestinal and formulation overall bioavailability suggested the presence of an intestinal absorption window in many individuals. Failure to absorb drug within this window appeared to be lin...

Research paper thumbnail of Eudragit ® RS PO/RL PO as rate-controlling matrix-formers via roller compaction: Influence of formulation and process variables on functional attributes of granules and tablets

Drug Development and Industrial Pharmacy, 2012

Research paper thumbnail of Near-infrared spectroscopic analysis of the breaking force of extended-release matrix tablets prepared by roller-compaction: influence of plasticizer levels and sintering temperature

Drug development and industrial pharmacy, Jan 2, 2014

The aim of this study was to investigate the feasibility of near-infrared (NIR) spectroscopy for ... more The aim of this study was to investigate the feasibility of near-infrared (NIR) spectroscopy for the determination of the influence of sintering temperature and plasticizer levels on the breaking force of extended-release matrix tablets prepared via roller-compaction. Six formulations using theophylline as a model drug, Eudragit® RL PO or Eudragit® RS PO as a matrix former and three levels of TEC (triethyl citrate) as a plasticizer were prepared. The powder blend was roller compacted using a fixed roll-gap of 1.5 mm, feed screw speed to roller speed ratio of 5:1 and roll pressure of 4 MPa. The granules, after removing fines, were compacted into tablets on a Stokes B2 rotary tablet press at a compression force of 7 kN. The tablets were thermally treated at different temperatures (Room Temperature, 50, 75 and 100 °C) for 5 h. These tablets were scanned in reflectance mode in the wavelength range of 400-2500 nm and were evaluated for breaking force. Tablet breaking force significantly ...

Research paper thumbnail of Near-infrared spectroscopic analysis of the breaking force of extended-release matrix tablets prepared by roller-compaction: influence of plasticizer levels and sintering temperature

Drug development and industrial pharmacy, Jan 2, 2014

The aim of this study was to investigate the feasibility of near-infrared (NIR) spectroscopy for ... more The aim of this study was to investigate the feasibility of near-infrared (NIR) spectroscopy for the determination of the influence of sintering temperature and plasticizer levels on the breaking force of extended-release matrix tablets prepared via roller-compaction. Six formulations using theophylline as a model drug, Eudragit® RL PO or Eudragit® RS PO as a matrix former and three levels of TEC (triethyl citrate) as a plasticizer were prepared. The powder blend was roller compacted using a fixed roll-gap of 1.5 mm, feed screw speed to roller speed ratio of 5:1 and roll pressure of 4 MPa. The granules, after removing fines, were compacted into tablets on a Stokes B2 rotary tablet press at a compression force of 7 kN. The tablets were thermally treated at different temperatures (Room Temperature, 50, 75 and 100 °C) for 5 h. These tablets were scanned in reflectance mode in the wavelength range of 400-2500 nm and were evaluated for breaking force. Tablet breaking force significantly ...

Research paper thumbnail of Investigation of the physical–mechanical properties of Eudragit ® RS PO/RL PO and their mixtures with common pharmaceutical excipients

Drug Development and Industrial Pharmacy, 2013

Ammonio methacrylate copolymers Eudragit ® RS PO and Eudragit ® RL PO have found widespread use a... more Ammonio methacrylate copolymers Eudragit ® RS PO and Eudragit ® RL PO have found widespread use as key components in various types of extended release solid dosage forms. The deformation behavior of neat polymers and binary mixes was evaluated using Heckel Analysis, strain rate sensitivity, work of compaction and elastic recovery index. Additionally, the compact forming ability of neat materials and binary mixes were evaluated by analyzing their tabletability, compressibility and compactibility profiles. The Heckel analysis of both polymers exhibited a speedsensitive deformation behavior typical to plastic materials. The yield values of the binary mixes of the polymers with microcrystalline cellulose revealed a linear relationship with the weight fractions of individual components. The yield values of binary mixes of both the polymers with dibasic calcium phosphate exhibited slight negative deviations from linearity. Both polymers exhibited axial relaxation after ejection typical of viscoelastic materials, as measured by the elastic recovery index values. The work of compaction and the elastic recovery index values of the binary mixtures were found to be linearly related to the weight fractions of the individual components thus, confirming ideal mixing behavior based on the composition. Addition of microcrystalline cellulose to both polymers significantly improved their tabletability and compactibility. The tensile strengths of the compacts prepared with neat materials and binary mixes with microcrystalline cellulose, dibasic calcium phosphate and lactose were the function of their solid fraction and independent of the tableting speeds tested; thus, validating compactibility as a reliable parameter in predicting acceptable tablet properties.

Research paper thumbnail of Near-infrared spectroscopic analysis of the breaking force of extended-release matrix tablets prepared by roller-compaction: influence of plasticizer levels and sintering temperature

Drug Development and Industrial Pharmacy, 2014

The aim of this study was to investigate the feasibility of near-infrared (NIR) spectroscopy for ... more The aim of this study was to investigate the feasibility of near-infrared (NIR) spectroscopy for the determination of the influence of sintering temperature and plasticizer levels on the breaking force of extended-release matrix tablets prepared via roller-compaction. Six formulations using theophylline as a model drug, Eudragit Õ RL PO or Eudragit Õ RS PO as a matrix former and three levels of TEC (triethyl citrate) as a plasticizer were prepared. The powder blend was roller compacted using a fixed roll-gap of 1.5 mm, feed screw speed to roller speed ratio of 5:1 and roll pressure of 4 MPa. The granules, after removing fines, were compacted into tablets on a Stokes B2 rotary tablet press at a compression force of 7 kN. The tablets were thermally treated at different temperatures (Room Temperature, 50, 75 and 100 C) for 5 h. These tablets were scanned in reflectance mode in the wavelength range of 400-2500 nm and were evaluated for breaking force. Tablet breaking force significantly increased with increasing plasticizer levels and with increases in the sintering temperature. An increase in tablet hardness produced an upward shift (increase in absorbance) in the NIR spectra. The principle component analysis (PCA) of the spectra was able to distinguish samples with different plasticizer levels and sintering temperatures. In addition, a 9-factor partial least squares (PLS) regression model for tablets containing Eudragit Õ RL PO had an r 2 of 0.9797, a standard error of calibration of 0.6255 and a standard error of cross validation (SECV) of 0.7594. Similar analysis of tablets containing Eudragit Õ RS PO showed an r 2 of 0.9831, a standard error of calibration of 0.9711 and an SECV of 1.192.

Research paper thumbnail of Comparing a Statistical Model and Bayesian Approach to Establish the Design Space for the Coating of Ciprofloxacin HCl Beads at Different Scales of Production

AAPS PharmSciTech, 2018

The primary objective of this study was to compare two methods for establishing a design space fo... more The primary objective of this study was to compare two methods for establishing a design space for critical process parameters that affect ethylcellulose film coating of multiparticulate beads and assess this design space validity across manufacturing scales. While there are many factors that can affect film coating, this study will focus on the effects processing conditions have on the quality and extent of film formation, as evaluated by their impact coating yield and drug release. Ciprofloxacin HCl layered beads were utilized as an active substrate core, ethylcellulose aqueous dispersion as a controlled release polymer, and triethyl citrate as a plasticizer. Thirty experiments were conducted using a central composite design to optimize the coating process and map the response surface to build a design space using either statistical least squares or a Bayesian approach. The response surface was fitted using a linear two-factor interaction model with spraying temperature, curing temperature, and curing time as significant model terms. The design spaces established by the two approaches were in close agreement with the statistical least squares approach being more conservative than the Bayesian approach. The design space established for the critical process parameters using small-scale batches was tested using scale-up batches and found to be scale-independent. The robustness of the design space was confirmed across scales and was successfully utilized to establish process signature for the coating process.

Research paper thumbnail of Quality-by-Design II: Application of Quantitative Risk Analysis to the Formulation of Ciprofloxacin Tablets

AAPS PharmSciTech, 2015

Qualitative risk assessment methods are often used as the first step to determining design space ... more Qualitative risk assessment methods are often used as the first step to determining design space boundaries; however, quantitative assessments of risk with respect to the design space, i.e., calculating the probability of failure for a given severity, are needed to fully characterize design space boundaries. Quantitative risk assessment methods in design and operational spaces are a significant aid to evaluating proposed design space boundaries. The goal of this paper is to demonstrate a relatively simple strategy for design space definition using a simplified Bayesian Monte Carlo simulation. This paper builds on a previous paper that used failure mode and effects analysis (FMEA) qualitative risk assessment and Plackett-Burman design of experiments to identity the critical quality attributes. The results show that the sequential use of qualitative and quantitative risk assessments can focus the design of experiments on a reduced set of critical material and process parameters that determine a robust design space under conditions of limited laboratory experimentation. This approach provides a strategy by which the degree of risk associated with each known parameter can be calculated and allocates resources in a manner that manages risk to an acceptable level.

Research paper thumbnail of Enhancing Dissolution Rate of Carbamazepine via Solvent Casting with a Novel Polymeric Solubilizer (Soluplus ® )

Purpose: To increase dissolution rate of Carbamazepine (CBZ) by forming solid dispersions (SD) wi... more Purpose: To increase dissolution rate of Carbamazepine (CBZ) by forming solid dispersions (SD) with a novel polymeric solubilizer (Soluplus ®) via solvent casting technique. This study also attempted to investigate the solid state within the SD and its potential in enhancing the dissolution rate of CBZ. Methods: SD of CBZ-Soluplus ® at different weight ratios (1:9, 1:4, 1:3, 3:7, 1:1) were prepared by solvent casting technique. The SD samples were dried in an oven at 50 C until the loss on drying is greater than 78%. The SD is then cooled at -20 C for 1 hour. The SDs were gently grounded in a mortar and the resulting granules were sieved and the 106-500 μm particle size fraction was obtained. The dissolution profile of CBZ was performed in a USP II dissolution apparatus (paddle method) with 900 mL of 0.1N HCl (adjusted to pH 1.2) at 100 rpm and 37 C 0.5 C. The solution was filtered and continuously pumped into a Shimadzu UV 160U spectrophotometer and the absorbance values were recor...

Research paper thumbnail of Excipient Manufacturing and Good Manufacturing Practices

Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems, 2006

Research paper thumbnail of Comparison of bovine in vivo bioavailability of two sulfamethazine oral boluses exhibiting different in vitro dissolution profiles

Journal of Veterinary Pharmacology and Therapeutics, 2006

Comparison of bovine in vivo bioavailability of two sulfamethazine oral boluses exhibiting differ... more Comparison of bovine in vivo bioavailability of two sulfamethazine oral boluses exhibiting different in vitro dissolution profiles. J. vet. Pharmacol. Therap. 29, 459-467. The bolus (or oblet) is a dosage form that can be used for the oral administration of pharmaceutical compounds to ruminating species. Unlike traditional tablets, oral boluses may contain quantities of drug on the order of grams rather than milligrams. Due to its size, it is only recently that USP-like in vitro dissolution methods have been developed for this dosage form. However, whether or not these dissolution tests can predict product in vivo performance has yet to be determined. The importance of this issue is apparent when the U.S. Food and Drug Administration Center for Veterinary Medicine is faced with the decision of whether to require additional in vivo bioequivalence study data to support the approval of changes in product chemistry or manufacturing method. The current study was undertaken to determine whether an in vivo/ in vitro correlation can be established for bovine sulfamethazine oral boluses and to acquire insight into the magnitude of changes in in vitro product performance that can occur before corresponding changes are seen in in vivo blood level profiles. Based upon the results of this investigation, it is concluded that marked changes in in vitro sulfamethazine bolus performance can be tolerated before resulting in altered in vivo blood level profiles. However, the data also suggest that rumenal absorption may occur for some compounds. Therefore the degree to which variation in product in vitro dissolution profiles can be tolerated may be compound specific.

Research paper thumbnail of Application of Near-Infrared Spectroscopy (NIRS) as a Tool for Quality Control in Traditional Chinese Medicine (TCM)

Current Bioactive Compounds, 2011

ABSTRACT Traditional Chinese Medicine (TCM) is becoming more and more popular all over the world.... more ABSTRACT Traditional Chinese Medicine (TCM) is becoming more and more popular all over the world. Novel analytical tools for quality control are highly demanded enabling analysis starting at breeding and ending at biological fluids including urine or serum. Compared to analytical separation methods (chromatography, electrophoresis) near-infrared spectroscopy (NIRS) allows analyzing matter of interest non-invasively, fast and physical/chemical parameters simultaneously. It can be used for the quantitative control of certain (active) ingredients. In many cases identification can only be achieved by pattern recognition. Therefore, NIRS combined with cluster analysis offers huge potential to identify e.g. species, geographic origin, special medicinal formula etc. In the present contribution the fundamentals, possibilities of NIR applied in quality control of TCM are pointed out and its ad- and disadvantages are discussed in detail by several practical examples.

Research paper thumbnail of Impact of gastrointestinal differences in veterinary species on the oral drug solubility, in vivo dissolution, and formulation of veterinary therapeutics

ADMET and DMPK, 2022

Many gaps exist in our understanding of species differences in gastrointestinal (GI) fluid compos... more Many gaps exist in our understanding of species differences in gastrointestinal (GI) fluid composition and the associated impact of food intake and dietary composition on in vivo drug solubilization. This information gap can lead to uncertainties with regard to how best to formulate pharmaceuticals for veterinary use or the in vitro test conditions that will be most predictive of species-specific in vivo oral product performance. To address these challenges, this overview explores species-specific factors that can influence oral drug solubility and the formulation approaches that can be employed to overcome solubility-associated bioavailability difficulties. These discussions are framed around some of the basic principles associated with drug solubilization, reported species differences in GI fluid composition, types of oral dosage forms typically given for the various animal species, and the effect of prandial state in dogs and cats. This basic information is integrated into a ques...

Research paper thumbnail of Veterinary Pharmaceuticals: Factors Influencing Their Development and Use

Encyclopedia of pharmaceutical …, 2006

Research paper thumbnail of Workshop Report: USP Workshop on Exploring the Science of Drug Absorption

Dissolution Technologies

In October 2018, the United States Pharmacopeia (USP) hosted a two-day workshop to explore the sc... more In October 2018, the United States Pharmacopeia (USP) hosted a two-day workshop to explore the science of drug absorption. Experts from around the globe presented some of the challenges associated with drug product development from the perspective of the physiological attributes of the patient (human or canine) and the body site for drug activity. Included in the discussions were methods and approaches for answering complex questions, providing insights into the strengths and challenges of methods available in our biopharmaceutical tool chest. The following is a synopsis of the presentations and the highlights of the discussions that ensued. Disclaimer: This article reflects the views of the authors and should not be construed as representing the views or policies of the United States Food and Drug Administration.

Research paper thumbnail of Prediction of Dissolution of Sustained Release Coated Ciprofloxacin Beads Using Near-infrared Spectroscopy and Process Parameters: a Data Fusion Approach

AAPS PharmSciTech

The aim of the work is to develop a data fusion model using near-infrared (NIR) and process param... more The aim of the work is to develop a data fusion model using near-infrared (NIR) and process parameters for the predictions of drug dissolution from controlled release multiparticulate beads. Using a design of experiments, ciprofloxacin-coated beads were manufactured and critical process parameters such as air volume, product temperature, curing temperature, and curing time were measured; environmental humidity was monitored using a Pyrobuttons®. The NIR spectra were decomposed using principal component analysis (PCA). The PCA scores were fused with process measurements and all variables were autoscaled. The autoscaled variables were regressed against measured dissolution data at 1 h and 2 h time points; the PLS regression used quadratic and cross terms. The NIR spectra only model using data collected at the end of bead curing generated a PLS model using 5 latent variables with R2 equal to 0.245 and 0.299 and RMSECV 13.23 and 13.12 for the 1 h and 2 h dissolution time points, respectively. The low R2 and high root mean square error of cross validation (RMSECV) values indicate that NIR spectra alone were insufficient to model the drug release. Similar results were obtained for NIR model using data collected at the end of spraying phase. Models with fused spectral and process data yielded better prediction with R2 above 0.88 and RMSECV less than 5% for the 1 h and 2 h dissolution time points. The data fusion model predicted dissolution profiles with an error less than 10%.

Research paper thumbnail of Primer on the Science of In Vitro Dissolution Testing of Oral Dosage Forms and Factors Influencing its Biological Relevance

Dissolution Technologies

In vitro dissolution testing can serve as an effective and efficient tool for evaluating the infl... more In vitro dissolution testing can serve as an effective and efficient tool for evaluating the influence of formulation and manufacturing variables on drug release characteristics. The targeted purpose will determine the method used and the implications of the test results. Regardless of its intended purpose, it is necessary to understand the factors influencing in vitro dissolution outcomes to avoid the introduction of error into the data interpretation. This will influence the selection of the in vitro test procedure, ensuring that the method can identify changes in the critical formulation and manufacturing variables. There is also a need to understand the rate limiting factors influencing in vivo product bioavailability both from a dissolution and an absorption perspective. Finally, to achieve in vivo biorelevance, it is necessary to understand how the selected in vitro dissolution test method reflects the variables impacting in vivo product dissolution behavior. This primer summarizes and integrates these diverse variables, fostering an appreciation of the strengths and potential pitfalls that may be encountered during the generation and analysis of in vitro dissolution profiles associated with oral dosage forms. This understanding is needed for developing a well-designed dissolution test procedure that is appropriately fit for purpose.

Research paper thumbnail of Formulation characteristics and in vitro release testing of cyclosporine ophthalmic ointments

International journal of pharmaceutics, Jan 21, 2018

The aim of the present study was to investigate the relationship between formulation/process vari... more The aim of the present study was to investigate the relationship between formulation/process variables versus the critical quality attributes (CQAs) of cyclosporine ophthalmic ointments and to explore the feasibility of using an in vitro approach to assess product sameness. A definitive screening design (DSD) was used to evaluate the impact of formulation and process variables. The formulation variables included drug percentage, percentage of corn oil and lanolin alcohol. The process variables studied were mixing temperature, mixing time and the method of mixing. The quality and performance attributes examined included drug assay, content uniformity, image analysis, rheology (storage modulus, shear viscosity) and in vitro drug release. Of the formulation variables evaluated, the percentage of the drug substance and the percentage of corn oil in the matrix were the most influential factors with respect to in vitro drug release. Conversely, the process parameters tested were observed ...

Research paper thumbnail of A Systematic Approach of Employing Quality by Design Principles: Risk Assessment and Design of Experiments to Demonstrate Process Understanding and Identify the Critical Process Parameters for Coating of the Ethylcellulose Pseudolatex Dispersion Using Non-Conventional Fluid Bed Process

AAPS PharmSciTech, 2016

The goal of this study was to utilize risk assessment techniques and statistical design of experi... more The goal of this study was to utilize risk assessment techniques and statistical design of experiments (DoE) to gain process understanding and to identify critical process parameters for the manufacture of controlled release multiparticulate beads using a novel disk-jet fluid bed technology. The material attributes and process parameters were systematically assessed using the Ishikawa fish bone diagram and failure mode and effect analysis (FMEA) risk assessment methods. The high risk attributes identified by the FMEA analysis were further explored using resolution V fractional factorial design. To gain an understanding of the processing parameters, a resolution V fractional factorial study was conducted. Using knowledge gained from the resolution V study, a resolution IV fractional factorial study was conducted; the purpose of this IV study was to identify the critical process parameters (CPP) that impact the critical quality attributes and understand the influence of these parameters on film formation. For both studies, the microclimate, atomization pressure, inlet air volume, product temperature (during spraying and curing), curing time, and percent solids in the coating solutions were studied. The responses evaluated were percent agglomeration, percent fines, percent yield, bead aspect ratio, median particle size diameter (d50), assay, and drug release rate. Pyrobuttons® were used to record real-time temperature and humidity changes in the fluid bed. The risk assessment methods and process analytical tools helped to understand the novel disk-jet technology and to systematically develop models of the coating process parameters like process efficiency and the extent of curing during the coating process.

Research paper thumbnail of Erratum to: Use of Modeling and Simulation Tools for Understanding the Impact of Formulation on the Absorption of a Low Solubility Compound: Ciprofloxacin

The AAPS journal, Nov 23, 2016

Research paper thumbnail of Use of Modeling and Simulation Tools for Understanding the Impact of Formulation on the Absorption of a Low Solubility Compound: Ciprofloxacin

The AAPS journal, Jul 1, 2016

This study explored the utility of mechanistic absorption models to describe the in vivo performa... more This study explored the utility of mechanistic absorption models to describe the in vivo performance of a low solubility/low permeability compound in normal healthy subjects. Sixteen healthy human volunteers received three oral formulations and an intravenous infusion in a randomized crossover design. Plasma ciprofloxacin concentrations were estimated by HPLC. In vitro ciprofloxacin release from the oral tablets was tested under a variety of conditions. A mechanistic model was used to explore in vivo dissolution and intestinal absorption. Although dissolution rate influenced the location of drug release, absorption challenges appeared to be associated with permeability limitations in the lower small intestine and colon. The apparent relationship between drug solubilization within the upper small intestinal and formulation overall bioavailability suggested the presence of an intestinal absorption window in many individuals. Failure to absorb drug within this window appeared to be lin...

Research paper thumbnail of Eudragit ® RS PO/RL PO as rate-controlling matrix-formers via roller compaction: Influence of formulation and process variables on functional attributes of granules and tablets

Drug Development and Industrial Pharmacy, 2012

Research paper thumbnail of Near-infrared spectroscopic analysis of the breaking force of extended-release matrix tablets prepared by roller-compaction: influence of plasticizer levels and sintering temperature

Drug development and industrial pharmacy, Jan 2, 2014

The aim of this study was to investigate the feasibility of near-infrared (NIR) spectroscopy for ... more The aim of this study was to investigate the feasibility of near-infrared (NIR) spectroscopy for the determination of the influence of sintering temperature and plasticizer levels on the breaking force of extended-release matrix tablets prepared via roller-compaction. Six formulations using theophylline as a model drug, Eudragit® RL PO or Eudragit® RS PO as a matrix former and three levels of TEC (triethyl citrate) as a plasticizer were prepared. The powder blend was roller compacted using a fixed roll-gap of 1.5 mm, feed screw speed to roller speed ratio of 5:1 and roll pressure of 4 MPa. The granules, after removing fines, were compacted into tablets on a Stokes B2 rotary tablet press at a compression force of 7 kN. The tablets were thermally treated at different temperatures (Room Temperature, 50, 75 and 100 °C) for 5 h. These tablets were scanned in reflectance mode in the wavelength range of 400-2500 nm and were evaluated for breaking force. Tablet breaking force significantly ...

Research paper thumbnail of Near-infrared spectroscopic analysis of the breaking force of extended-release matrix tablets prepared by roller-compaction: influence of plasticizer levels and sintering temperature

Drug development and industrial pharmacy, Jan 2, 2014

The aim of this study was to investigate the feasibility of near-infrared (NIR) spectroscopy for ... more The aim of this study was to investigate the feasibility of near-infrared (NIR) spectroscopy for the determination of the influence of sintering temperature and plasticizer levels on the breaking force of extended-release matrix tablets prepared via roller-compaction. Six formulations using theophylline as a model drug, Eudragit® RL PO or Eudragit® RS PO as a matrix former and three levels of TEC (triethyl citrate) as a plasticizer were prepared. The powder blend was roller compacted using a fixed roll-gap of 1.5 mm, feed screw speed to roller speed ratio of 5:1 and roll pressure of 4 MPa. The granules, after removing fines, were compacted into tablets on a Stokes B2 rotary tablet press at a compression force of 7 kN. The tablets were thermally treated at different temperatures (Room Temperature, 50, 75 and 100 °C) for 5 h. These tablets were scanned in reflectance mode in the wavelength range of 400-2500 nm and were evaluated for breaking force. Tablet breaking force significantly ...

Research paper thumbnail of Investigation of the physical–mechanical properties of Eudragit ® RS PO/RL PO and their mixtures with common pharmaceutical excipients

Drug Development and Industrial Pharmacy, 2013

Ammonio methacrylate copolymers Eudragit ® RS PO and Eudragit ® RL PO have found widespread use a... more Ammonio methacrylate copolymers Eudragit ® RS PO and Eudragit ® RL PO have found widespread use as key components in various types of extended release solid dosage forms. The deformation behavior of neat polymers and binary mixes was evaluated using Heckel Analysis, strain rate sensitivity, work of compaction and elastic recovery index. Additionally, the compact forming ability of neat materials and binary mixes were evaluated by analyzing their tabletability, compressibility and compactibility profiles. The Heckel analysis of both polymers exhibited a speedsensitive deformation behavior typical to plastic materials. The yield values of the binary mixes of the polymers with microcrystalline cellulose revealed a linear relationship with the weight fractions of individual components. The yield values of binary mixes of both the polymers with dibasic calcium phosphate exhibited slight negative deviations from linearity. Both polymers exhibited axial relaxation after ejection typical of viscoelastic materials, as measured by the elastic recovery index values. The work of compaction and the elastic recovery index values of the binary mixtures were found to be linearly related to the weight fractions of the individual components thus, confirming ideal mixing behavior based on the composition. Addition of microcrystalline cellulose to both polymers significantly improved their tabletability and compactibility. The tensile strengths of the compacts prepared with neat materials and binary mixes with microcrystalline cellulose, dibasic calcium phosphate and lactose were the function of their solid fraction and independent of the tableting speeds tested; thus, validating compactibility as a reliable parameter in predicting acceptable tablet properties.

Research paper thumbnail of Near-infrared spectroscopic analysis of the breaking force of extended-release matrix tablets prepared by roller-compaction: influence of plasticizer levels and sintering temperature

Drug Development and Industrial Pharmacy, 2014

The aim of this study was to investigate the feasibility of near-infrared (NIR) spectroscopy for ... more The aim of this study was to investigate the feasibility of near-infrared (NIR) spectroscopy for the determination of the influence of sintering temperature and plasticizer levels on the breaking force of extended-release matrix tablets prepared via roller-compaction. Six formulations using theophylline as a model drug, Eudragit Õ RL PO or Eudragit Õ RS PO as a matrix former and three levels of TEC (triethyl citrate) as a plasticizer were prepared. The powder blend was roller compacted using a fixed roll-gap of 1.5 mm, feed screw speed to roller speed ratio of 5:1 and roll pressure of 4 MPa. The granules, after removing fines, were compacted into tablets on a Stokes B2 rotary tablet press at a compression force of 7 kN. The tablets were thermally treated at different temperatures (Room Temperature, 50, 75 and 100 C) for 5 h. These tablets were scanned in reflectance mode in the wavelength range of 400-2500 nm and were evaluated for breaking force. Tablet breaking force significantly increased with increasing plasticizer levels and with increases in the sintering temperature. An increase in tablet hardness produced an upward shift (increase in absorbance) in the NIR spectra. The principle component analysis (PCA) of the spectra was able to distinguish samples with different plasticizer levels and sintering temperatures. In addition, a 9-factor partial least squares (PLS) regression model for tablets containing Eudragit Õ RL PO had an r 2 of 0.9797, a standard error of calibration of 0.6255 and a standard error of cross validation (SECV) of 0.7594. Similar analysis of tablets containing Eudragit Õ RS PO showed an r 2 of 0.9831, a standard error of calibration of 0.9711 and an SECV of 1.192.