Ecevit Bilgili | New Jersey Institute of Technology (original) (raw)

Papers by Ecevit Bilgili

Research paper thumbnail of Nanoseeded Desupersaturation and Dissolution Tests for Elucidating Supersaturation Maintenance in Amorphous Solid Dispersions

Pharmaceutics

The impact of residual drug crystals that are formed during the production and storage of amorpho... more The impact of residual drug crystals that are formed during the production and storage of amorphous solid dispersions (ASDs) has been studied using micron-sized seed crystals in solvent-shift (desupersaturation) and dissolution tests. This study examines the impacts of the seed size loading on the solution-mediated precipitation from griseofulvin ASDs. Nanoparticle crystals (nanoseeds) were used as a more realistic surrogate for residual crystals compared with conventional micron-sized seeds. ASDs of griseofulvin with Soluplus (Sol), Kollidon VA64 (VA64), and hydroxypropyl methyl cellulose (HPMC) were prepared by spray-drying. Nanoseeds produced by wet media milling were used in the dissolution and desupersaturation experiments. DLS, SEM, XRPD, and DSC were used for characterization. The results from the solvent-shift tests suggest that the drug nanoseeds led to a faster and higher extent of desupersaturation than the as-received micron-sized crystals and that the higher seed loadin...

Research paper thumbnail of CHE 626-101: Math Methods in Chemical Engineering

Research paper thumbnail of A Combined Isolation and Formulation Approach to Convert Nanomilled Suspensions into High Drug-Loaded Composite Particles That Readily Reconstitute

Powders

The advantage of nanoparticles to improve bioavailability of poorly soluble drugs is well known. ... more The advantage of nanoparticles to improve bioavailability of poorly soluble drugs is well known. However, the higher-energy state of nanoparticles beneficial for bioavailability presents challenges for both the stability of nanosuspensions and preventing irreversible aggregation if isolated as dry solids. The aim of this study is to explore the feasibility of an evaporation isolation route for converting wet media milled nanosuspensions into high drug-loaded nanocomposites that exhibit fast redispersion in aqueous media, ideally fully restoring the particle size distribution of the starting suspension. Optimization of this approach is presented, starting from nanomilling conditions and formulation composition to achieve physical stability post milling, followed by novel evaporative drying conditions coupled with various dispersant types/loadings. Ultimately, isolated nanocomposite particles reaching 55–75% drug load were achieved, which delivered fast redispersion and immediate rele...

Research paper thumbnail of A Predictive Transport Model for Convective Drying of Polymer Strip Films Loaded with a BCS Class II Drug

European Journal of Pharmaceutics and Biopharmaceutics, 2019

Research paper thumbnail of A pseudo-coupled DEM–non-linear PBM approach for simulating the evolution of particle size during dry milling

Research paper thumbnail of A microhydrodynamic rationale for selection of bead size in preparation of drug nanosuspensions via wet stirred media milling

International journal of pharmaceutics, Jan 2, 2017

Although wet stirred media milling has proven to be a robust process for producing nanoparticle s... more Although wet stirred media milling has proven to be a robust process for producing nanoparticle suspensions of poorly water-soluble drugs and thereby enhancing their bioavailability, selection of bead size has been largely empirical, lacking fundamental rationale. This study aims to establish such rationale by investigating the impact of bead size at various stirrer speeds on the drug breakage kinetics via a microhydrodynamic model. To this end, stable suspensions of griseofulvin, a model BCS Class II drug, were prepared using hydroxypropyl cellulose and sodium dodecyl sulfate. The suspensions were milled at four different stirrer speeds (1000-4000rpm) using various sizes (50-1500μm) of zirconia beads. Laser diffraction, SEM, and XRPD were used for characterization. Our results suggest that there is an optimal bead size that achieves fastest breakage at each stirrer speed and that it shifts to a smaller size at higher speed. Calculated microhydrodynamic parameters reveal two counter...

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 CHE 626-101: Mathematical Methods in Chemical Engineering

Research paper thumbnail of CHE 260-002: Fluid Flow (Revised for Remote Learning)

Research paper thumbnail of On the Similarity of Austin Model and Kotake–Kanda Model and Implications for Tumbling Ball Mill Scale-up

KONA Powder and Particle Journal

Research paper thumbnail of A semi-theoretical model for simulating the temporal evolution of moisture-temperature during industrial fluidized bed granulation

European Journal of Pharmaceutics and Biopharmaceutics, 2020

Research paper thumbnail of Statistical analysis of undergraduate chemical engineering curricula of United States of America universities: Trends and observations

Education for Chemical Engineers, 2017

Research paper thumbnail of Incorporation of Fenofibrate Nanoparticles Prepared by Melt Emulsification into Polymeric Films

Journal of Pharmaceutical Innovation, 2015

Research paper thumbnail of Engineered Particles Prepared Via Drying of Drug Nanosuspensions for Bioavailability Enhancement

Drug nanosuspensions of poorly water soluble drugs were prepared by wet stirred media milling in ... more Drug nanosuspensions of poorly water soluble drugs were prepared by wet stirred media milling in the Netzsch mill. Different polymers and surfactants were used to prevent the aggregation of these nanoparticles via adsorption of the stabilizers on the nanoparticle surfaces. The nanosuspensions were converted into powders by coating of these nanosuspensions on inert beads (Celphere) in a fluid bed coater for solid oral dosage forms. The redispersion of nanosuspensions after drying lead to increase in the particle size of drug nanoparticles as the stabilizers lose their functionality during the drying process. Therefore, the bioavailability improvement expected from nanoparticles was not realized. Hence the formulation and coating process parameters will be explored in this study as they affect the particle attributes leading to poor redispersibility. The preliminary results of the addition of matrix formers lactose, sucrose and mannitol in the formulation of nanosuspensions before coa...

Research paper thumbnail of Use of Convective Drying Technique for the Production of Strip-films Containing Poorly Water Soluble Drug Nanoparticles

Research paper thumbnail of Enhanced physical stabilization of fenofibrate nanosuspensions via wet co-milling with a superdisintegrant and an adsorbing polymer

European Journal of Pharmaceutics and Biopharmaceutics, 2015

Drug nanoparticles in suspensions can form aggregates leading to physical instability, which is t... more Drug nanoparticles in suspensions can form aggregates leading to physical instability, which is traditionally mitigated using soluble polymers and surfactants. The aim of this paper was to explore common superdisintegrants, i.e., sodium starch glycolate (SSG), croscarmellose sodium (CCS), and crospovidone (CP), as novel class of dispersants for enhanced stabilization of fenofibrate (FNB), a model BCS Class II drug, suspensions. FNB was wet-milled with superdisintegrants along with hydroxypropyl methylcellulose (HPMC), a soluble adsorbing polymer, in a stirred media mill. For comparison, FNB was also milled in the presence of HPMC and/or SDS (sodium dodecyl sulfate) without superdisintegrants. Laser diffraction, scanning electron microscopy, viscometry, differential scanning calorimetry, and powder X-ray diffraction were used to characterize the suspensions. The results show that 2% HPMC along with 1% SSG or 1% CCS mitigated the aggregation of FNB nanoparticles significantly similar to the use of either 5% HPMC or 1% HPMC-0.075% SDS, whereas CP was not effective due to its low swelling capacity. CCS/SSG enhanced steric-kinetic stabilization of the FNB suspensions owing to their high swelling capacity, viscosity enhancement, and physical barrier action. Overall, this study provides a mechanistic basis for a novel method of formulating surfactant-free drug nanosuspensions with co-milled superdisintegrants.

Research paper thumbnail of Spray drying of drug-swellable dispersant suspensions for preparation of fast-dissolving, high drug-loaded, surfactant-free nanocomposites

Drug Development and Industrial Pharmacy, 2014

Abstract Bioavailability of a poorly soluble drug can be improved by preparing a drug nanosuspens... more Abstract Bioavailability of a poorly soluble drug can be improved by preparing a drug nanosuspension and subsequently drying it into nanocomposite microparticles (NCMPs). Unfortunately, drug nanoparticles aggregate during milling and drying, causing incomplete recovery and slow dissolution. The aim of this study is to investigate the impact of various classes of dispersants on drug dissolution from drug NCMPs, with the ultimate goal of enhancing the bioavailability of poorly water-soluble drugs via high drug nanoparticle loaded, surfactant-free NCMPs. Precursor suspensions of griseofulvin (GF, model drug) nanoparticles in the presence of various dispersants were prepared via wet stirred media milling and spray dried to form the NCMPs. Hydroxypropyl cellulose (HPC, polymer) alone and with sodium dodecyl sulfate (SDS, surfactant) was used as a base-line stabilizer/dispersant during milling. Two swellable crosslinked polymers, croscarmellose sodium (CCS) and sodium starch glycolate (SSG), and a conventional soluble matrix former, Mannitol, were used in addition to HPC. Besides being used as-received, CCS was also wet co-milled with GF for two different durations to examine the impact of CCS particle size. Laser diffraction, scanning electron microscopy, powder X-ray diffraction (XRD), UV spectroscopy, NCMP redispersion and dissolution tests were used for characterization. The results show that incorporation of CCS/SSG, preferably wet-milled to a wide particle size distribution, into the spray-dried NCMPs resulted in fast release and dispersion of drug nanoparticle clusters. The swellable dispersants were superior to Mannitol in dissolution enhancement, and could achieve fast release comparable to SDS, demonstrating the feasibility of spray drying to prepare high drug-loaded, surfactant-free nanocomposites.

Research paper thumbnail of Redispersible fast dissolving nanocomposite microparticles of poorly water-soluble drugs

International Journal of Pharmaceutics, 2014

Research paper thumbnail of Kinetic and Microhydrodynamic Modeling of Fenofibrate Nanosuspension Production in a Wet Stirred Media Mill

Pharmaceutics

This study examined the impact of stirrer speed and bead material loading on fenofibrate particle... more This study examined the impact of stirrer speed and bead material loading on fenofibrate particle breakage during wet stirred media milling (WSMM) via three kinetic models and a microhydrodynamic model. Evolution of median particle size was tracked via laser diffraction during WSMM operating at 3000–4000 rpm with 35–50% (v/v) concentration of polystyrene or zirconia beads. Additional experiments were performed at the center points of the above conditions, as well as outside the range of these conditions, in order to test the predictive capability of the models. First-order, nth-order, and warped-time kinetic models were fitted to the data. Main effects plots helped to visualize the influence of the milling variables on the breakage kinetics and microhydrodynamic parameters. A subset selection algorithm was used along with a multiple linear regression model (MLRM) to delineate how the breakage rate constant k was affected by the microhydrodynamic parameters. As a comparison, a purely...

Research paper thumbnail of Use of Bead Mixtures as a Novel Process Optimization Approach to Nanomilling of Drug Suspensions

Pharmaceutical Research

PURPOSE We aimed to evaluate the feasibility of cross-linked polystyrene (CPS)-yttrium-stabilized... more PURPOSE We aimed to evaluate the feasibility of cross-linked polystyrene (CPS)-yttrium-stabilized zirconia (YSZ) bead mixtures as a novel optimization approach for fast, effective production of drug nanosuspensions during wet stirred media milling (WSMM). METHODS Aqueous suspensions of 10% fenofibrate (FNB, drug), 7.5% HPC-L, and 0.05% SDS were wet-milled at 3000-4000 rpm and 35%-50% volumetric loading of CPS:YSZ bead mixtures (CPS:YSZ 0:1-1:0 v:v). Laser diffraction, SEM, viscometry, DSC, and XRPD were used for characterization. An nth-order model described the breakage kinetics, while a microhydrodynamic model allowed us to gain insights into the impact of bead materials. RESULTS CPS beads achieved the lowest specific power consumption, whereas YSZ beads led to the fastest breakage. Breakage followed second-order kinetics. Optimum conditions were identified as 3000 rpm and 50% loading of 0.5:0.5 v/v CPS:YSZ mixture from energy-cycle time-heat dissipation perspectives. The microhydrodynamic model suggests that YSZ beads experienced more energetic/forceful collisions with smaller contact area as compared with CPS beads owing to the higher density-elastic modulus of the former. CONCLUSIONS We demonstrated the feasibility of CPS-YSZ bead mixtures and rationalized its optimal use in WSMM through their modulation of breakage kinetics, energy utilization, and heat dissipation.

Research paper thumbnail of Nanoseeded Desupersaturation and Dissolution Tests for Elucidating Supersaturation Maintenance in Amorphous Solid Dispersions

Pharmaceutics

The impact of residual drug crystals that are formed during the production and storage of amorpho... more The impact of residual drug crystals that are formed during the production and storage of amorphous solid dispersions (ASDs) has been studied using micron-sized seed crystals in solvent-shift (desupersaturation) and dissolution tests. This study examines the impacts of the seed size loading on the solution-mediated precipitation from griseofulvin ASDs. Nanoparticle crystals (nanoseeds) were used as a more realistic surrogate for residual crystals compared with conventional micron-sized seeds. ASDs of griseofulvin with Soluplus (Sol), Kollidon VA64 (VA64), and hydroxypropyl methyl cellulose (HPMC) were prepared by spray-drying. Nanoseeds produced by wet media milling were used in the dissolution and desupersaturation experiments. DLS, SEM, XRPD, and DSC were used for characterization. The results from the solvent-shift tests suggest that the drug nanoseeds led to a faster and higher extent of desupersaturation than the as-received micron-sized crystals and that the higher seed loadin...

Research paper thumbnail of CHE 626-101: Math Methods in Chemical Engineering

Research paper thumbnail of A Combined Isolation and Formulation Approach to Convert Nanomilled Suspensions into High Drug-Loaded Composite Particles That Readily Reconstitute

Powders

The advantage of nanoparticles to improve bioavailability of poorly soluble drugs is well known. ... more The advantage of nanoparticles to improve bioavailability of poorly soluble drugs is well known. However, the higher-energy state of nanoparticles beneficial for bioavailability presents challenges for both the stability of nanosuspensions and preventing irreversible aggregation if isolated as dry solids. The aim of this study is to explore the feasibility of an evaporation isolation route for converting wet media milled nanosuspensions into high drug-loaded nanocomposites that exhibit fast redispersion in aqueous media, ideally fully restoring the particle size distribution of the starting suspension. Optimization of this approach is presented, starting from nanomilling conditions and formulation composition to achieve physical stability post milling, followed by novel evaporative drying conditions coupled with various dispersant types/loadings. Ultimately, isolated nanocomposite particles reaching 55–75% drug load were achieved, which delivered fast redispersion and immediate rele...

Research paper thumbnail of A Predictive Transport Model for Convective Drying of Polymer Strip Films Loaded with a BCS Class II Drug

European Journal of Pharmaceutics and Biopharmaceutics, 2019

Research paper thumbnail of A pseudo-coupled DEM–non-linear PBM approach for simulating the evolution of particle size during dry milling

Research paper thumbnail of A microhydrodynamic rationale for selection of bead size in preparation of drug nanosuspensions via wet stirred media milling

International journal of pharmaceutics, Jan 2, 2017

Although wet stirred media milling has proven to be a robust process for producing nanoparticle s... more Although wet stirred media milling has proven to be a robust process for producing nanoparticle suspensions of poorly water-soluble drugs and thereby enhancing their bioavailability, selection of bead size has been largely empirical, lacking fundamental rationale. This study aims to establish such rationale by investigating the impact of bead size at various stirrer speeds on the drug breakage kinetics via a microhydrodynamic model. To this end, stable suspensions of griseofulvin, a model BCS Class II drug, were prepared using hydroxypropyl cellulose and sodium dodecyl sulfate. The suspensions were milled at four different stirrer speeds (1000-4000rpm) using various sizes (50-1500μm) of zirconia beads. Laser diffraction, SEM, and XRPD were used for characterization. Our results suggest that there is an optimal bead size that achieves fastest breakage at each stirrer speed and that it shifts to a smaller size at higher speed. Calculated microhydrodynamic parameters reveal two counter...

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 CHE 626-101: Mathematical Methods in Chemical Engineering

Research paper thumbnail of CHE 260-002: Fluid Flow (Revised for Remote Learning)

Research paper thumbnail of On the Similarity of Austin Model and Kotake–Kanda Model and Implications for Tumbling Ball Mill Scale-up

KONA Powder and Particle Journal

Research paper thumbnail of A semi-theoretical model for simulating the temporal evolution of moisture-temperature during industrial fluidized bed granulation

European Journal of Pharmaceutics and Biopharmaceutics, 2020

Research paper thumbnail of Statistical analysis of undergraduate chemical engineering curricula of United States of America universities: Trends and observations

Education for Chemical Engineers, 2017

Research paper thumbnail of Incorporation of Fenofibrate Nanoparticles Prepared by Melt Emulsification into Polymeric Films

Journal of Pharmaceutical Innovation, 2015

Research paper thumbnail of Engineered Particles Prepared Via Drying of Drug Nanosuspensions for Bioavailability Enhancement

Drug nanosuspensions of poorly water soluble drugs were prepared by wet stirred media milling in ... more Drug nanosuspensions of poorly water soluble drugs were prepared by wet stirred media milling in the Netzsch mill. Different polymers and surfactants were used to prevent the aggregation of these nanoparticles via adsorption of the stabilizers on the nanoparticle surfaces. The nanosuspensions were converted into powders by coating of these nanosuspensions on inert beads (Celphere) in a fluid bed coater for solid oral dosage forms. The redispersion of nanosuspensions after drying lead to increase in the particle size of drug nanoparticles as the stabilizers lose their functionality during the drying process. Therefore, the bioavailability improvement expected from nanoparticles was not realized. Hence the formulation and coating process parameters will be explored in this study as they affect the particle attributes leading to poor redispersibility. The preliminary results of the addition of matrix formers lactose, sucrose and mannitol in the formulation of nanosuspensions before coa...

Research paper thumbnail of Use of Convective Drying Technique for the Production of Strip-films Containing Poorly Water Soluble Drug Nanoparticles

Research paper thumbnail of Enhanced physical stabilization of fenofibrate nanosuspensions via wet co-milling with a superdisintegrant and an adsorbing polymer

European Journal of Pharmaceutics and Biopharmaceutics, 2015

Drug nanoparticles in suspensions can form aggregates leading to physical instability, which is t... more Drug nanoparticles in suspensions can form aggregates leading to physical instability, which is traditionally mitigated using soluble polymers and surfactants. The aim of this paper was to explore common superdisintegrants, i.e., sodium starch glycolate (SSG), croscarmellose sodium (CCS), and crospovidone (CP), as novel class of dispersants for enhanced stabilization of fenofibrate (FNB), a model BCS Class II drug, suspensions. FNB was wet-milled with superdisintegrants along with hydroxypropyl methylcellulose (HPMC), a soluble adsorbing polymer, in a stirred media mill. For comparison, FNB was also milled in the presence of HPMC and/or SDS (sodium dodecyl sulfate) without superdisintegrants. Laser diffraction, scanning electron microscopy, viscometry, differential scanning calorimetry, and powder X-ray diffraction were used to characterize the suspensions. The results show that 2% HPMC along with 1% SSG or 1% CCS mitigated the aggregation of FNB nanoparticles significantly similar to the use of either 5% HPMC or 1% HPMC-0.075% SDS, whereas CP was not effective due to its low swelling capacity. CCS/SSG enhanced steric-kinetic stabilization of the FNB suspensions owing to their high swelling capacity, viscosity enhancement, and physical barrier action. Overall, this study provides a mechanistic basis for a novel method of formulating surfactant-free drug nanosuspensions with co-milled superdisintegrants.

Research paper thumbnail of Spray drying of drug-swellable dispersant suspensions for preparation of fast-dissolving, high drug-loaded, surfactant-free nanocomposites

Drug Development and Industrial Pharmacy, 2014

Abstract Bioavailability of a poorly soluble drug can be improved by preparing a drug nanosuspens... more Abstract Bioavailability of a poorly soluble drug can be improved by preparing a drug nanosuspension and subsequently drying it into nanocomposite microparticles (NCMPs). Unfortunately, drug nanoparticles aggregate during milling and drying, causing incomplete recovery and slow dissolution. The aim of this study is to investigate the impact of various classes of dispersants on drug dissolution from drug NCMPs, with the ultimate goal of enhancing the bioavailability of poorly water-soluble drugs via high drug nanoparticle loaded, surfactant-free NCMPs. Precursor suspensions of griseofulvin (GF, model drug) nanoparticles in the presence of various dispersants were prepared via wet stirred media milling and spray dried to form the NCMPs. Hydroxypropyl cellulose (HPC, polymer) alone and with sodium dodecyl sulfate (SDS, surfactant) was used as a base-line stabilizer/dispersant during milling. Two swellable crosslinked polymers, croscarmellose sodium (CCS) and sodium starch glycolate (SSG), and a conventional soluble matrix former, Mannitol, were used in addition to HPC. Besides being used as-received, CCS was also wet co-milled with GF for two different durations to examine the impact of CCS particle size. Laser diffraction, scanning electron microscopy, powder X-ray diffraction (XRD), UV spectroscopy, NCMP redispersion and dissolution tests were used for characterization. The results show that incorporation of CCS/SSG, preferably wet-milled to a wide particle size distribution, into the spray-dried NCMPs resulted in fast release and dispersion of drug nanoparticle clusters. The swellable dispersants were superior to Mannitol in dissolution enhancement, and could achieve fast release comparable to SDS, demonstrating the feasibility of spray drying to prepare high drug-loaded, surfactant-free nanocomposites.

Research paper thumbnail of Redispersible fast dissolving nanocomposite microparticles of poorly water-soluble drugs

International Journal of Pharmaceutics, 2014

Research paper thumbnail of Kinetic and Microhydrodynamic Modeling of Fenofibrate Nanosuspension Production in a Wet Stirred Media Mill

Pharmaceutics

This study examined the impact of stirrer speed and bead material loading on fenofibrate particle... more This study examined the impact of stirrer speed and bead material loading on fenofibrate particle breakage during wet stirred media milling (WSMM) via three kinetic models and a microhydrodynamic model. Evolution of median particle size was tracked via laser diffraction during WSMM operating at 3000–4000 rpm with 35–50% (v/v) concentration of polystyrene or zirconia beads. Additional experiments were performed at the center points of the above conditions, as well as outside the range of these conditions, in order to test the predictive capability of the models. First-order, nth-order, and warped-time kinetic models were fitted to the data. Main effects plots helped to visualize the influence of the milling variables on the breakage kinetics and microhydrodynamic parameters. A subset selection algorithm was used along with a multiple linear regression model (MLRM) to delineate how the breakage rate constant k was affected by the microhydrodynamic parameters. As a comparison, a purely...

Research paper thumbnail of Use of Bead Mixtures as a Novel Process Optimization Approach to Nanomilling of Drug Suspensions

Pharmaceutical Research

PURPOSE We aimed to evaluate the feasibility of cross-linked polystyrene (CPS)-yttrium-stabilized... more PURPOSE We aimed to evaluate the feasibility of cross-linked polystyrene (CPS)-yttrium-stabilized zirconia (YSZ) bead mixtures as a novel optimization approach for fast, effective production of drug nanosuspensions during wet stirred media milling (WSMM). METHODS Aqueous suspensions of 10% fenofibrate (FNB, drug), 7.5% HPC-L, and 0.05% SDS were wet-milled at 3000-4000 rpm and 35%-50% volumetric loading of CPS:YSZ bead mixtures (CPS:YSZ 0:1-1:0 v:v). Laser diffraction, SEM, viscometry, DSC, and XRPD were used for characterization. An nth-order model described the breakage kinetics, while a microhydrodynamic model allowed us to gain insights into the impact of bead materials. RESULTS CPS beads achieved the lowest specific power consumption, whereas YSZ beads led to the fastest breakage. Breakage followed second-order kinetics. Optimum conditions were identified as 3000 rpm and 50% loading of 0.5:0.5 v/v CPS:YSZ mixture from energy-cycle time-heat dissipation perspectives. The microhydrodynamic model suggests that YSZ beads experienced more energetic/forceful collisions with smaller contact area as compared with CPS beads owing to the higher density-elastic modulus of the former. CONCLUSIONS We demonstrated the feasibility of CPS-YSZ bead mixtures and rationalized its optimal use in WSMM through their modulation of breakage kinetics, energy utilization, and heat dissipation.