Adam Procopio - Academia.edu (original) (raw)
Papers by Adam Procopio
Metallurgical and Materials Transactions A-physical Metallurgy and Materials Science, Feb 1, 2000
Recently, the authors have shown that the ternary originally thought to be Ti{sub 3}Al{sub 2}N{su... more Recently, the authors have shown that the ternary originally thought to be Ti{sub 3}Al{sub 2}N{sub 2} was Ti{sub 4}AlN{sub 3}. In this work, polycrystalline, fully dense, predominantly single-phase bulk samples of Ti{sub 4}AlN{sub 3{minus}x} were fabricated by reactive hot isostatic pressing (hipping) of AlN, TiN, and Ti or TiH{sub 2} powders at 1,275 C for 24 hours at 70 MPa. The pressed samples were further annealed under Ar for 168 hours at 1,598 K, to obtain predominantly single-phase samples. The current Ti-Al-N isothermal (1,598 K) phase diagram, based on Ti{sub 3}Al{sub 2}N{sub 2}, has been revised to take into account the presence of Ti{sub 4}AlN{sub 3{minus}x} instead and to reflect the fact that Ti{sub 2}AlN is in equilibrium with all the binary and ternary phases in the Ti-Al-N system except AlN.
ABSTRACT Includes abstract and vita. Thesis (Ph.D.)--Drexel University, 2006. Includes bibliograp... more ABSTRACT Includes abstract and vita. Thesis (Ph.D.)--Drexel University, 2006. Includes bibliographical references.
Chemical Engineering Science, Mar 1, 2018
Here we present the microfluidic approach to engineer polymeric Janus particles using solvent dis... more Here we present the microfluidic approach to engineer polymeric Janus particles using solvent dissolution for potential drug delivery applications. Unlike the polymerization based particle generation techniques, this method does not suffer from potential toxicity concerns for drug delivery. This technique is based on dissolving away the solvent in the solution droplets containing designed concentration distribution of drug and polymer while preserving the concentration distribution during the transition of the droplet into a particle. We investigated the kinetics of solidification and concentration evolution in the droplets under different operational conditions. Our investigation demonstrated that the designed biphasic concentration of a drug surrogate introduced into two hemispheres of the droplets can be preserved in solidified particles. We conclude with practical guidelines for generating polymeric Janus particles using the dissolution technique. Highlights Monodisperse droplet generation regime for partially miscible liquids containing surfactants was experimentally evaluated. Experimental master curve for dissolution rate of solvent from a solidifying droplet in a rectangular channel was obtained. Micro Janus particle generation was achieved using microfluidic dissolution technique. The method is suitable for targeted drug delivery since it overcomes the liability of polymerization based techniquesnamely potential toxicity of residual monomers and degradation of the active drug
3D printing in medicine, Feb 4, 2019
Purpose: Microneedle patches are arrays of tiny needles that painlessly pierce the skin to delive... more Purpose: Microneedle patches are arrays of tiny needles that painlessly pierce the skin to deliver medication into the body. Biocompatible microneedles are usually fabricated via molding of a master structure. Microfabrication techniques used for fabricating these master structures are costly, time intensive, and require extensive expertise to control the structure's geometry of the structure, despite evidence that microneedle geometry is a key design parameter. Here, a commercially available 3D printer is utilized, for the first time, to quickly and easily manufacture microneedle masters. Design/methodology/approach: Because commercially available 3D printers are not typically used for micron-scale fabrication, the influence of three different sources of error-stair-stepping, aliasing, and light abberations-on the resulting structure is investigated. A custom Matlab code is written to control the light intensity projected off of each individual micromirror (through grayscale) at a given time. The effect of the layer height, the number of layers, and grayscale on the sharpness, surface texture, and dimensional fidelity of the final structure is described. Findings: The Autodesk Ember is successfully utilized to fabricate sharp microneedles with a tip radius of approximately 15 μm in less than 30 min per patch (as compared to weeks to months for existing approaches). Utilization of grayscale improves surface texture and sharpness, and dimensional fidelity within ±5% of desired dimensions is achieved. Originality/value: The described 3D printing technique enables investigators to accurately fabricate microneedles within minutes at low cost. Rapid, iterative optimization of microneedle geometry through 3D printing will accelerate microneedle research through improved understanding of the relationship between microneedle structure and function.
Abstract This section covers the source material properties general founded in polymers to 3D pri... more Abstract This section covers the source material properties general founded in polymers to 3D printing technologies and applications to drug delivery. Several published examples are used to highlight the advantages of certain technologies along with the disadvantages of others. In addition, because of the novelty of this technology, a brief discussion on the regulatory impact and implementation of 3D printing in a clinical and commercial setting is also included.
International Journal of Pharmaceutics, Sep 1, 2016
Journal of Pharmaceutical and Biomedical Analysis, Dec 1, 2003
The Tris(hydroxymethyl)aminomethane (TRIS) salt of a substituted 5,6,7,8-tetrahydro-1,8-naphthyri... more The Tris(hydroxymethyl)aminomethane (TRIS) salt of a substituted 5,6,7,8-tetrahydro-1,8-naphthyridine compound (I) in a mannitol-based formulation was stressed at various conditions. Liquid chromatography/mass spectrometry (LC/MS) and liquid chromatography/tandem mass spectrometry (LC/MS/MS) analyses of the stressed samples revealed that oxidation and dimerization were the primary degradation pathways for this compound. 1 Hand 13 C-nuclear magnetic resonance (NMR) spectroscopy were used to characterize the isolated dimers. The aromatized degradate, Noxide, amide, and three dimeric products were all confirmed by either LC/MS using authentic standards or NMR spectroscopy. In general, the aromatized product was always the primary degradate produced under all stress conditions. When stressed at 80 8C, the TRIS counterion also underwent thermal degradation to yield formaldehyde in situ which reacted with the parent compound to form a unique methylene-bridged dimeric product and an N-formyl degradate. A minor condensation product between the compound I and the TRIS counterion was also detected in the 80 8C stressed samples. Under 40 8C/75% RH stress conditions, TRIS derived degradates were insignificant, while dimers formed by compound I became predominant. In addition, two hydroxylated products (7-OH and 5-OH) were also detected. Mechanisms for the formation of the oxidative and dimeric degradates were proposed.
Metallurgical and Materials Transactions, Feb 1, 2000
Recently, we have shown that the ternary originally thought to be Ti 3 Al 2 N 2 was Ti 4 AlN 3. [... more Recently, we have shown that the ternary originally thought to be Ti 3 Al 2 N 2 was Ti 4 AlN 3. [1] In this work, polycrystalline, fully dense, predominantly single-phase bulk samples of Ti 4 AlN 3Ϫx were fabricated by reactive hot isostatic pressing ("hipping") of AlN, TiN, and Ti or TiH 2 powders at 1275 ЊC for 24 hours at 70 MPa. The pressed samples were further annealed under Ar for 168 hours at 1598 K, to obtain predominantly single-phase samples. The current Ti-Al-N isothermal (1598 K) phase diagram, based on Ti 3 Al 2 N 2 , has been revised to take into account the presence of Ti 4 AlN 3Ϫx instead and to reflect the fact that Ti 2 AlN is in equilibrium with all the binary and ternary phases in the Ti-Al-N system except AlN.
Metallurgical and Materials Transactions A-physical Metallurgy and Materials Science, Feb 1, 2000
Bulk samples of Ti{sub 4}AlN{sub 3} were fabricated by reactive hot isostatic pressing (hipping) ... more Bulk samples of Ti{sub 4}AlN{sub 3} were fabricated by reactive hot isostatic pressing (hipping) of TiH{sub 2}, AlN, and TiN powders at 1,275 C for 24 hours under 70 MPa. Further annealing at 1,325 C for 168 hours under Ar resulted in dense, predominantly single-phase samples, with <1 vol pct of TiN as a secondary phase. This ternary nitride, with a grain size of {approx}20 {micro}m on average, is relatively soft (Vickers hardness 2.5 GPa), lightweight (4.6 g/cm{sup 3}), and machinable. Its Young's and shear moduli are 310 and 127 GPa, respectively. The compressive and flexural strengths at room temperature are 475 and 350 MPa, respectively. At 1000 C, the deformation is plastic, with a maximum compressive stress of {approx}450 MPa. Ti{sub 4}AlN{sub 3} thermal shocks gradually, whereby the largest strength loss (50 pct) is seen at a {Delta}T of 1,000 C. Further increases in quench temperature, however, increase the retained strength before it ultimately decreases once again. This material is also damage tolerant; a 100 N-load diamond indentation, which produced an {approx}0.4 mm defect, reduces the flexural strength by only {approx}12 pct. The thermal-expansion coefficient in the 25 C to 1,100 C temperature range is 9.7 {+-} 0.2 xmore » 10{sup {minus}6} C{sup {minus}1}. The room-temperature electrical conductivity is 0.5 x 10{sup 6} ({Omega}{center{underscore}dot}m){sup {minus}1}. The resistivity increases linearly with increasing temperature. Ti{sub 4}AlN{sub 3} is stable up to 1,500 C in Ar, but decomposes in air to form TiN at {approx}1,400 C.« less
Molecular Pharmaceutics, Dec 21, 2018
Process induced phase transformations (PIPTs) of active pharmaceutical ingredients (APIs) can alt... more Process induced phase transformations (PIPTs) of active pharmaceutical ingredients (APIs) can alter APIs' physicochemical properties and impact performance of pharmaceutical drug products. In this study, we investigated compression induced amorphization of crystalline posaconazole (POSA), where the impact of mechanical stresses and excipients on amorphization were explored. 19 F solid-state NMR (ssNMR) was utilized to detect and quantify amorphous content in the compressed tablets, and finite element analysis (FEA) was conducted to understand stress distributions in the compression process. Both applied macroscopic axial stress and shear stress were found to be important to amorphization of crystalline POSA. Punch velocity, an important compression process parameter, had negligible effect on amorphization up to 100 mm/s. Two diluents, microcrystalline cellulose (MCC) and dibasic calcium phosphate anhydrous (DCPA), and one lubricant, magnesium stearate (MgSt), were evaluated for their impact on amorphization in this study. It was found that both MCC and DCPA significantly enhanced amorphization of POSA at a low drug loading (5% w/w). 1% (w/w) blended lubricant effectively reduced the amorphous content in MCC-POSA tablets, however, had minimal effect on either neat POSA or DCPA-POSA tablets. Drug loading, or excipient concentration, was demonstrated to have a significant impact on the extent of amorphization. These observed excipient effects support the important role of interparticulate stresses in amorphization of crystalline POSA.
![Research paper thumbnail of Oxidation of Ti[sub n+1]AlX[sub n] (n=1-3 and X=C, N): II. Experimental Results](https://attachments.academia-assets.com/107811626/thumbnails/1.jpg)
](Journal of The Electrochemical Society, 2001
In this, Part II of a two-part study, the oxidation kinetics in air of the ternary compounds Ti 2... more In this, Part II of a two-part study, the oxidation kinetics in air of the ternary compounds Ti 2 AlC, Ti 2 AlC 0.5 N 0.5 , Ti 4 AlN 2.9, and Ti 3 AlC 2 are reported. For the first two compounds, in the 1000-1100°C temperature range and for short times ͑Ϸ20 h͒ the oxidation kinetics are parabolic. The parabolic rate constants are k x (m 2 /s) ϭ 2.68 ϫ 10 5 exp Ϫ 491.5 (kJ/mol)/RT for Ti 2 AlC, and 2.55 ϫ 10 5 exp Ϫ 458.7 (kJ/mol)/RT for Ti 2 AlC 0.5 N 0.5. At 900°C, the kinetics are quasi-linear, and up to 100 h the outermost layers that form are almost pure rutile, dense, and protective. For the second pair, at short times ͑Ͻ10 h͒ the oxidation kinetics are parabolic at all temperatures examined ͑800-1100°C͒, but become linear at longer times. The k x values are 3.2 ϫ 10 5 exp Ϫ 429 ͑kJ/mol͒/RT, for Ti 4 AlN 2.9 and 1.15 ϫ 10 5 exp Ϫ 443 ͑kJ/mol͒/RT for Ti 3 AlC 2. In all cases, the scales that form are comprised mainly of a rutile-based solid solution, (Ti 1Ϫy Al y ͒O 2Ϫy/2 where y Ͻ 0.05, and some Al 2 O 3. The oxidation occurs by the inward diffusion of oxygen and the outward diffusion of Al and Ti. The C and N atoms are presumed to also diffuse outward through the oxide layer. At the low oxygen partial pressure side, the Al 3ϩ ions dissolve in and diffuse through the (Ti 1Ϫy Al y ͒O 2Ϫy/2 layer and react with oxygen to form Al 2 O 3 at the high oxygen pressure side. This demixing results in the formation of pores that concentrate along planes, especially at longer times and higher temperatures. These layers of porosity impede the diffusion of Al, but not those of Ti and oxygen, which results in the formation of highly striated scales where three layers, an Al 2 O 3-rich, a TiO 2-rich, and a porous layer repeat multiple ͑Ͼ10͒ times. The presence of oxygen also reduces the decomposition ͑into TiX x and Al͒ temperatures of Ti 4 AlN 2.9 and Ti 3 AlC 2 from a T Ͼ 1400°C, to one less than 1100°C.
Metallurgical and Materials Transactions, Feb 1, 2000
Bulk samples of Ti 4 AIN 3 were fabricated by reactive hot isostatic pressing (hipping) of TiH 2 ... more Bulk samples of Ti 4 AIN 3 were fabricated by reactive hot isostatic pressing (hipping) of TiH 2 , AlN, and TiN powders at 1275 ЊC for 24 hours under 70 MPa. Further annealing at 1325 ЊC for 168 hours under Ar resulted in dense, predominantly single-phase samples, with Ͻ1 vol pct of TiN as a secondary phase. This ternary nitride, with a grain size of Ϸ20 m on average, is relatively soft (Vickers hardness 2.5 GPa), lightweight (4.6 g/cm 3), and machinable. Its Young's and shear moduli are 310 and 127 GPa, respectively. The compressive and flexural strengths at room temperature are 475 and 350 MPa, respectively. At 1000 ЊC, the deformation is plastic, with a maximum compressive stress of Ϸ450 MPa. Ti 4 AlN 3 thermal shocks gradually, whereby the largest strength loss (50 pct) is seen at a ⌬T of 1000 ЊC. Further increases in quench temperature, however, increase the retained strength before it ultimately decreases once again. This material is also damage tolerant; a 100 N-load diamond indentation, which produced an Ϸ0.4 mm defect, reduces the flexural strength by only Ϸ12 pct. The thermal-expansion coefficient in the 25 ЊC to 1100 ЊC temperature range is 9.7Ϯ0.2 ϫ 10 Ϫ6 ЊC Ϫ1. The room-temperature electrical conductivity is 0.5 ϫ 10 6 (⍀ и m) Ϫ1. The resistivity increases linearly with increasing temperature. Ti 4 AlN 3 is stable up to 1500 ЊC in Ar, but decomposes in air to form TiN at Ϸ1400 ЊC.
International Journal of Pharmaceutics, 2018
Drug development is a long process which requires careful evaluation of the drug substance (activ... more Drug development is a long process which requires careful evaluation of the drug substance (active pharmaceutical ingredient, API), drug product (tablet, capsule etc.) and the bioperformance (both preclinical and clinical) before testing the efficacy of the final dosage form. The earliest assessment of a new drug substance requires an understanding of the safety and clinical performance (Phase 1) wherein faster processes (like on-site formulation strategy) have been set in place for quick clinical read-outs. One key gap that exists in this early assessment is the ability to evaluate modified release drug products. Here, an additive manufacturing approach is used to prepare polyvinyl alcohol (PVA) capsule shells using 3D printing (3DP), where the shells can be filled with either a solid or a liquid vehicle containing the API. In this work we demonstrate how we can delay the release of the API from the printed capsules allowing us to evaluate regional absorption in pre-clinical studies. By using 3DP, a new method to provide a series of release profiles is demonstrated, where the induction time of a delayed burst release is controlled by the wall thicknesses of printed capsules. New hanging baskets were also designed and 3D printed for the dissolution tests to better understand the rupturing of these capsules in an USP 2 dissolution apparatus. By controlling the wall thickness of the capsule, the induction time of drug release can be controlled from 12 to 198 minutes. This wide range of induction times demonstrated with this 3DP strategy is not currently available in a commercially available oral drug product form. Varying the induction times to the drug release to interrogate different regions of the GI tract is exhibited in vivo (beagle dogs) and initial analysis suggested a good in vitro/in vivo relationship (IVIVR).
Advanced Science, 2020
The past decade has seen the materialization of immune checkpoint blockade as an emerging approac... more The past decade has seen the materialization of immune checkpoint blockade as an emerging approach to cancer treatment. However, the overall response and patient survival are still modest. Various efforts to study the “cancer immunogram” have highlighted complex biology that necessitates a multipronged approach. This includes increasing the antigenicity of the tumor, strengthening the immune infiltration in the tumor microenvironment, removing the immunosuppressive mechanisms, and reducing immune cell exhaustion. The coordination of these approaches, as well as the ability to enhance them through delivery, is evaluated. Due to their success in multiple preclinical models, external‐stimuli‐responsive nanoparticles have received tremendous attention. Several studies report success in distantly located tumor regression, metastases, and reoccurrence in preclinical mouse models. However, clinical translation in this space remains low. Herein, the recent advancement in external‐stimuli‐re...
Biomaterials Science
To examine the impact of ultrasound transduction on endothelial barrier function, a 3D printable ... more To examine the impact of ultrasound transduction on endothelial barrier function, a 3D printable perfused hydrogel vascular model was developed to assess endothelial permeability and enable live imaging of cell–cell junctions.
ABSTRACT Includes abstract and vita. Thesis (Ph.D.)--Drexel University, 2006. Includes bibliograp... more ABSTRACT Includes abstract and vita. Thesis (Ph.D.)--Drexel University, 2006. Includes bibliographical references.
Journal of Pharmaceutical Innovation, 2020
Flexible manufacturing systems are needed in the pharmaceutical industry due to the future challe... more Flexible manufacturing systems are needed in the pharmaceutical industry due to the future challenges of volatility, uncertainty, complexity, and ambiguity [ 1 ]. Compared to traditional manufacturing systems that dominate the pharmaceutical industry today, processes that are better able to react to changes in the types of products being sold, the volume of sales, and the facilities needed for production will be an asset to an organization. Many emerging technologies are inherently adaptable, though the types of flexibility exhibited vary widely. The nature of these emerging technologies is examined here, and the case is made that flexibility should be valued as much as cost and time when selecting technologies, even though flexible manufacturing systems require extra time and money initially. An outlook on this type of manufacturing is shared with the assertion that flexible development and manufacturing would help reduce overall cost and better serve patient needs following the initial investment period. In the next decade, concentrated effort is needed from industry, academia, suppliers, and regulators to enable more agile and nimble pharmaceutical development and manufacturing.
3D Printing in Medicine, 2019
Purpose: Microneedle patches are arrays of tiny needles that painlessly pierce the skin to delive... more Purpose: Microneedle patches are arrays of tiny needles that painlessly pierce the skin to deliver medication into the body. Biocompatible microneedles are usually fabricated via molding of a master structure. Microfabrication techniques used for fabricating these master structures are costly, time intensive, and require extensive expertise to control the structure's geometry of the structure, despite evidence that microneedle geometry is a key design parameter. Here, a commercially available 3D printer is utilized, for the first time, to quickly and easily manufacture microneedle masters. Design/methodology/approach: Because commercially available 3D printers are not typically used for micron-scale fabrication, the influence of three different sources of error-stair-stepping, aliasing, and light abberations-on the resulting structure is investigated. A custom Matlab code is written to control the light intensity projected off of each individual micromirror (through grayscale) at a given time. The effect of the layer height, the number of layers, and grayscale on the sharpness, surface texture, and dimensional fidelity of the final structure is described. Findings: The Autodesk Ember is successfully utilized to fabricate sharp microneedles with a tip radius of approximately 15 μm in less than 30 min per patch (as compared to weeks to months for existing approaches). Utilization of grayscale improves surface texture and sharpness, and dimensional fidelity within ±5% of desired dimensions is achieved. Originality/value: The described 3D printing technique enables investigators to accurately fabricate microneedles within minutes at low cost. Rapid, iterative optimization of microneedle geometry through 3D printing will accelerate microneedle research through improved understanding of the relationship between microneedle structure and function.
International Journal of Pharmaceutics, 2018
Graphical abstract Figure. No Caption available. Abstract Fused deposition modeling (FDM) 3D prin... more Graphical abstract Figure. No Caption available. Abstract Fused deposition modeling (FDM) 3D printing (3DP) has a potential to change how we envision manufacturing in the pharmaceutical industry. A more common utilization for FDM 3DP is to build upon existing hot melt extrusion (HME) technology where the drug is dispersed in the polymer matrix. However, reliable manufacturing of drug‐containing filaments remains a challenge along with the limitation of active ingredients which can sustain the processing risks involved in the HME process. To circumvent this obstacle, a single step FDM 3DP process was developed to manufacture thin‐walled drug‐free capsules which can be filled with dry or liquid drug product formulations. Drug release from these systems is governed by the combined dissolution of the FDM capsule ‘shell’ and the dosage form encapsulated in these shells. To prepare the shells, the 3D printer files (extension ‘.gcode’) were modified by creating discrete zones, so‐called ‘zoning process’, with individual print parameters. Capsules printed without the zoning process resulted in macroscopic print defects and holes. X‐ray computed tomography, finite element analysis and mechanical testing were used to guide the zoning process and printing parameters in order to manufacture consistent and robust capsule shell geometries. Additionally, dose consistencies of drug containing liquid formulations were investigated in this work.
Metallurgical and Materials Transactions A-physical Metallurgy and Materials Science, Feb 1, 2000
Recently, the authors have shown that the ternary originally thought to be Ti{sub 3}Al{sub 2}N{su... more Recently, the authors have shown that the ternary originally thought to be Ti{sub 3}Al{sub 2}N{sub 2} was Ti{sub 4}AlN{sub 3}. In this work, polycrystalline, fully dense, predominantly single-phase bulk samples of Ti{sub 4}AlN{sub 3{minus}x} were fabricated by reactive hot isostatic pressing (hipping) of AlN, TiN, and Ti or TiH{sub 2} powders at 1,275 C for 24 hours at 70 MPa. The pressed samples were further annealed under Ar for 168 hours at 1,598 K, to obtain predominantly single-phase samples. The current Ti-Al-N isothermal (1,598 K) phase diagram, based on Ti{sub 3}Al{sub 2}N{sub 2}, has been revised to take into account the presence of Ti{sub 4}AlN{sub 3{minus}x} instead and to reflect the fact that Ti{sub 2}AlN is in equilibrium with all the binary and ternary phases in the Ti-Al-N system except AlN.
ABSTRACT Includes abstract and vita. Thesis (Ph.D.)--Drexel University, 2006. Includes bibliograp... more ABSTRACT Includes abstract and vita. Thesis (Ph.D.)--Drexel University, 2006. Includes bibliographical references.
Chemical Engineering Science, Mar 1, 2018
Here we present the microfluidic approach to engineer polymeric Janus particles using solvent dis... more Here we present the microfluidic approach to engineer polymeric Janus particles using solvent dissolution for potential drug delivery applications. Unlike the polymerization based particle generation techniques, this method does not suffer from potential toxicity concerns for drug delivery. This technique is based on dissolving away the solvent in the solution droplets containing designed concentration distribution of drug and polymer while preserving the concentration distribution during the transition of the droplet into a particle. We investigated the kinetics of solidification and concentration evolution in the droplets under different operational conditions. Our investigation demonstrated that the designed biphasic concentration of a drug surrogate introduced into two hemispheres of the droplets can be preserved in solidified particles. We conclude with practical guidelines for generating polymeric Janus particles using the dissolution technique. Highlights Monodisperse droplet generation regime for partially miscible liquids containing surfactants was experimentally evaluated. Experimental master curve for dissolution rate of solvent from a solidifying droplet in a rectangular channel was obtained. Micro Janus particle generation was achieved using microfluidic dissolution technique. The method is suitable for targeted drug delivery since it overcomes the liability of polymerization based techniquesnamely potential toxicity of residual monomers and degradation of the active drug
3D printing in medicine, Feb 4, 2019
Purpose: Microneedle patches are arrays of tiny needles that painlessly pierce the skin to delive... more Purpose: Microneedle patches are arrays of tiny needles that painlessly pierce the skin to deliver medication into the body. Biocompatible microneedles are usually fabricated via molding of a master structure. Microfabrication techniques used for fabricating these master structures are costly, time intensive, and require extensive expertise to control the structure's geometry of the structure, despite evidence that microneedle geometry is a key design parameter. Here, a commercially available 3D printer is utilized, for the first time, to quickly and easily manufacture microneedle masters. Design/methodology/approach: Because commercially available 3D printers are not typically used for micron-scale fabrication, the influence of three different sources of error-stair-stepping, aliasing, and light abberations-on the resulting structure is investigated. A custom Matlab code is written to control the light intensity projected off of each individual micromirror (through grayscale) at a given time. The effect of the layer height, the number of layers, and grayscale on the sharpness, surface texture, and dimensional fidelity of the final structure is described. Findings: The Autodesk Ember is successfully utilized to fabricate sharp microneedles with a tip radius of approximately 15 μm in less than 30 min per patch (as compared to weeks to months for existing approaches). Utilization of grayscale improves surface texture and sharpness, and dimensional fidelity within ±5% of desired dimensions is achieved. Originality/value: The described 3D printing technique enables investigators to accurately fabricate microneedles within minutes at low cost. Rapid, iterative optimization of microneedle geometry through 3D printing will accelerate microneedle research through improved understanding of the relationship between microneedle structure and function.
Abstract This section covers the source material properties general founded in polymers to 3D pri... more Abstract This section covers the source material properties general founded in polymers to 3D printing technologies and applications to drug delivery. Several published examples are used to highlight the advantages of certain technologies along with the disadvantages of others. In addition, because of the novelty of this technology, a brief discussion on the regulatory impact and implementation of 3D printing in a clinical and commercial setting is also included.
International Journal of Pharmaceutics, Sep 1, 2016
Journal of Pharmaceutical and Biomedical Analysis, Dec 1, 2003
The Tris(hydroxymethyl)aminomethane (TRIS) salt of a substituted 5,6,7,8-tetrahydro-1,8-naphthyri... more The Tris(hydroxymethyl)aminomethane (TRIS) salt of a substituted 5,6,7,8-tetrahydro-1,8-naphthyridine compound (I) in a mannitol-based formulation was stressed at various conditions. Liquid chromatography/mass spectrometry (LC/MS) and liquid chromatography/tandem mass spectrometry (LC/MS/MS) analyses of the stressed samples revealed that oxidation and dimerization were the primary degradation pathways for this compound. 1 Hand 13 C-nuclear magnetic resonance (NMR) spectroscopy were used to characterize the isolated dimers. The aromatized degradate, Noxide, amide, and three dimeric products were all confirmed by either LC/MS using authentic standards or NMR spectroscopy. In general, the aromatized product was always the primary degradate produced under all stress conditions. When stressed at 80 8C, the TRIS counterion also underwent thermal degradation to yield formaldehyde in situ which reacted with the parent compound to form a unique methylene-bridged dimeric product and an N-formyl degradate. A minor condensation product between the compound I and the TRIS counterion was also detected in the 80 8C stressed samples. Under 40 8C/75% RH stress conditions, TRIS derived degradates were insignificant, while dimers formed by compound I became predominant. In addition, two hydroxylated products (7-OH and 5-OH) were also detected. Mechanisms for the formation of the oxidative and dimeric degradates were proposed.
Metallurgical and Materials Transactions, Feb 1, 2000
Recently, we have shown that the ternary originally thought to be Ti 3 Al 2 N 2 was Ti 4 AlN 3. [... more Recently, we have shown that the ternary originally thought to be Ti 3 Al 2 N 2 was Ti 4 AlN 3. [1] In this work, polycrystalline, fully dense, predominantly single-phase bulk samples of Ti 4 AlN 3Ϫx were fabricated by reactive hot isostatic pressing ("hipping") of AlN, TiN, and Ti or TiH 2 powders at 1275 ЊC for 24 hours at 70 MPa. The pressed samples were further annealed under Ar for 168 hours at 1598 K, to obtain predominantly single-phase samples. The current Ti-Al-N isothermal (1598 K) phase diagram, based on Ti 3 Al 2 N 2 , has been revised to take into account the presence of Ti 4 AlN 3Ϫx instead and to reflect the fact that Ti 2 AlN is in equilibrium with all the binary and ternary phases in the Ti-Al-N system except AlN.
Metallurgical and Materials Transactions A-physical Metallurgy and Materials Science, Feb 1, 2000
Bulk samples of Ti{sub 4}AlN{sub 3} were fabricated by reactive hot isostatic pressing (hipping) ... more Bulk samples of Ti{sub 4}AlN{sub 3} were fabricated by reactive hot isostatic pressing (hipping) of TiH{sub 2}, AlN, and TiN powders at 1,275 C for 24 hours under 70 MPa. Further annealing at 1,325 C for 168 hours under Ar resulted in dense, predominantly single-phase samples, with <1 vol pct of TiN as a secondary phase. This ternary nitride, with a grain size of {approx}20 {micro}m on average, is relatively soft (Vickers hardness 2.5 GPa), lightweight (4.6 g/cm{sup 3}), and machinable. Its Young's and shear moduli are 310 and 127 GPa, respectively. The compressive and flexural strengths at room temperature are 475 and 350 MPa, respectively. At 1000 C, the deformation is plastic, with a maximum compressive stress of {approx}450 MPa. Ti{sub 4}AlN{sub 3} thermal shocks gradually, whereby the largest strength loss (50 pct) is seen at a {Delta}T of 1,000 C. Further increases in quench temperature, however, increase the retained strength before it ultimately decreases once again. This material is also damage tolerant; a 100 N-load diamond indentation, which produced an {approx}0.4 mm defect, reduces the flexural strength by only {approx}12 pct. The thermal-expansion coefficient in the 25 C to 1,100 C temperature range is 9.7 {+-} 0.2 xmore » 10{sup {minus}6} C{sup {minus}1}. The room-temperature electrical conductivity is 0.5 x 10{sup 6} ({Omega}{center{underscore}dot}m){sup {minus}1}. The resistivity increases linearly with increasing temperature. Ti{sub 4}AlN{sub 3} is stable up to 1,500 C in Ar, but decomposes in air to form TiN at {approx}1,400 C.« less
Molecular Pharmaceutics, Dec 21, 2018
Process induced phase transformations (PIPTs) of active pharmaceutical ingredients (APIs) can alt... more Process induced phase transformations (PIPTs) of active pharmaceutical ingredients (APIs) can alter APIs' physicochemical properties and impact performance of pharmaceutical drug products. In this study, we investigated compression induced amorphization of crystalline posaconazole (POSA), where the impact of mechanical stresses and excipients on amorphization were explored. 19 F solid-state NMR (ssNMR) was utilized to detect and quantify amorphous content in the compressed tablets, and finite element analysis (FEA) was conducted to understand stress distributions in the compression process. Both applied macroscopic axial stress and shear stress were found to be important to amorphization of crystalline POSA. Punch velocity, an important compression process parameter, had negligible effect on amorphization up to 100 mm/s. Two diluents, microcrystalline cellulose (MCC) and dibasic calcium phosphate anhydrous (DCPA), and one lubricant, magnesium stearate (MgSt), were evaluated for their impact on amorphization in this study. It was found that both MCC and DCPA significantly enhanced amorphization of POSA at a low drug loading (5% w/w). 1% (w/w) blended lubricant effectively reduced the amorphous content in MCC-POSA tablets, however, had minimal effect on either neat POSA or DCPA-POSA tablets. Drug loading, or excipient concentration, was demonstrated to have a significant impact on the extent of amorphization. These observed excipient effects support the important role of interparticulate stresses in amorphization of crystalline POSA.
Journal of The Electrochemical Society, 2001
In this, Part II of a two-part study, the oxidation kinetics in air of the ternary compounds Ti 2... more In this, Part II of a two-part study, the oxidation kinetics in air of the ternary compounds Ti 2 AlC, Ti 2 AlC 0.5 N 0.5 , Ti 4 AlN 2.9, and Ti 3 AlC 2 are reported. For the first two compounds, in the 1000-1100°C temperature range and for short times ͑Ϸ20 h͒ the oxidation kinetics are parabolic. The parabolic rate constants are k x (m 2 /s) ϭ 2.68 ϫ 10 5 exp Ϫ 491.5 (kJ/mol)/RT for Ti 2 AlC, and 2.55 ϫ 10 5 exp Ϫ 458.7 (kJ/mol)/RT for Ti 2 AlC 0.5 N 0.5. At 900°C, the kinetics are quasi-linear, and up to 100 h the outermost layers that form are almost pure rutile, dense, and protective. For the second pair, at short times ͑Ͻ10 h͒ the oxidation kinetics are parabolic at all temperatures examined ͑800-1100°C͒, but become linear at longer times. The k x values are 3.2 ϫ 10 5 exp Ϫ 429 ͑kJ/mol͒/RT, for Ti 4 AlN 2.9 and 1.15 ϫ 10 5 exp Ϫ 443 ͑kJ/mol͒/RT for Ti 3 AlC 2. In all cases, the scales that form are comprised mainly of a rutile-based solid solution, (Ti 1Ϫy Al y ͒O 2Ϫy/2 where y Ͻ 0.05, and some Al 2 O 3. The oxidation occurs by the inward diffusion of oxygen and the outward diffusion of Al and Ti. The C and N atoms are presumed to also diffuse outward through the oxide layer. At the low oxygen partial pressure side, the Al 3ϩ ions dissolve in and diffuse through the (Ti 1Ϫy Al y ͒O 2Ϫy/2 layer and react with oxygen to form Al 2 O 3 at the high oxygen pressure side. This demixing results in the formation of pores that concentrate along planes, especially at longer times and higher temperatures. These layers of porosity impede the diffusion of Al, but not those of Ti and oxygen, which results in the formation of highly striated scales where three layers, an Al 2 O 3-rich, a TiO 2-rich, and a porous layer repeat multiple ͑Ͼ10͒ times. The presence of oxygen also reduces the decomposition ͑into TiX x and Al͒ temperatures of Ti 4 AlN 2.9 and Ti 3 AlC 2 from a T Ͼ 1400°C, to one less than 1100°C.
Metallurgical and Materials Transactions, Feb 1, 2000
Bulk samples of Ti 4 AIN 3 were fabricated by reactive hot isostatic pressing (hipping) of TiH 2 ... more Bulk samples of Ti 4 AIN 3 were fabricated by reactive hot isostatic pressing (hipping) of TiH 2 , AlN, and TiN powders at 1275 ЊC for 24 hours under 70 MPa. Further annealing at 1325 ЊC for 168 hours under Ar resulted in dense, predominantly single-phase samples, with Ͻ1 vol pct of TiN as a secondary phase. This ternary nitride, with a grain size of Ϸ20 m on average, is relatively soft (Vickers hardness 2.5 GPa), lightweight (4.6 g/cm 3), and machinable. Its Young's and shear moduli are 310 and 127 GPa, respectively. The compressive and flexural strengths at room temperature are 475 and 350 MPa, respectively. At 1000 ЊC, the deformation is plastic, with a maximum compressive stress of Ϸ450 MPa. Ti 4 AlN 3 thermal shocks gradually, whereby the largest strength loss (50 pct) is seen at a ⌬T of 1000 ЊC. Further increases in quench temperature, however, increase the retained strength before it ultimately decreases once again. This material is also damage tolerant; a 100 N-load diamond indentation, which produced an Ϸ0.4 mm defect, reduces the flexural strength by only Ϸ12 pct. The thermal-expansion coefficient in the 25 ЊC to 1100 ЊC temperature range is 9.7Ϯ0.2 ϫ 10 Ϫ6 ЊC Ϫ1. The room-temperature electrical conductivity is 0.5 ϫ 10 6 (⍀ и m) Ϫ1. The resistivity increases linearly with increasing temperature. Ti 4 AlN 3 is stable up to 1500 ЊC in Ar, but decomposes in air to form TiN at Ϸ1400 ЊC.
International Journal of Pharmaceutics, 2018
Drug development is a long process which requires careful evaluation of the drug substance (activ... more Drug development is a long process which requires careful evaluation of the drug substance (active pharmaceutical ingredient, API), drug product (tablet, capsule etc.) and the bioperformance (both preclinical and clinical) before testing the efficacy of the final dosage form. The earliest assessment of a new drug substance requires an understanding of the safety and clinical performance (Phase 1) wherein faster processes (like on-site formulation strategy) have been set in place for quick clinical read-outs. One key gap that exists in this early assessment is the ability to evaluate modified release drug products. Here, an additive manufacturing approach is used to prepare polyvinyl alcohol (PVA) capsule shells using 3D printing (3DP), where the shells can be filled with either a solid or a liquid vehicle containing the API. In this work we demonstrate how we can delay the release of the API from the printed capsules allowing us to evaluate regional absorption in pre-clinical studies. By using 3DP, a new method to provide a series of release profiles is demonstrated, where the induction time of a delayed burst release is controlled by the wall thicknesses of printed capsules. New hanging baskets were also designed and 3D printed for the dissolution tests to better understand the rupturing of these capsules in an USP 2 dissolution apparatus. By controlling the wall thickness of the capsule, the induction time of drug release can be controlled from 12 to 198 minutes. This wide range of induction times demonstrated with this 3DP strategy is not currently available in a commercially available oral drug product form. Varying the induction times to the drug release to interrogate different regions of the GI tract is exhibited in vivo (beagle dogs) and initial analysis suggested a good in vitro/in vivo relationship (IVIVR).
Advanced Science, 2020
The past decade has seen the materialization of immune checkpoint blockade as an emerging approac... more The past decade has seen the materialization of immune checkpoint blockade as an emerging approach to cancer treatment. However, the overall response and patient survival are still modest. Various efforts to study the “cancer immunogram” have highlighted complex biology that necessitates a multipronged approach. This includes increasing the antigenicity of the tumor, strengthening the immune infiltration in the tumor microenvironment, removing the immunosuppressive mechanisms, and reducing immune cell exhaustion. The coordination of these approaches, as well as the ability to enhance them through delivery, is evaluated. Due to their success in multiple preclinical models, external‐stimuli‐responsive nanoparticles have received tremendous attention. Several studies report success in distantly located tumor regression, metastases, and reoccurrence in preclinical mouse models. However, clinical translation in this space remains low. Herein, the recent advancement in external‐stimuli‐re...
Biomaterials Science
To examine the impact of ultrasound transduction on endothelial barrier function, a 3D printable ... more To examine the impact of ultrasound transduction on endothelial barrier function, a 3D printable perfused hydrogel vascular model was developed to assess endothelial permeability and enable live imaging of cell–cell junctions.
ABSTRACT Includes abstract and vita. Thesis (Ph.D.)--Drexel University, 2006. Includes bibliograp... more ABSTRACT Includes abstract and vita. Thesis (Ph.D.)--Drexel University, 2006. Includes bibliographical references.
Journal of Pharmaceutical Innovation, 2020
Flexible manufacturing systems are needed in the pharmaceutical industry due to the future challe... more Flexible manufacturing systems are needed in the pharmaceutical industry due to the future challenges of volatility, uncertainty, complexity, and ambiguity [ 1 ]. Compared to traditional manufacturing systems that dominate the pharmaceutical industry today, processes that are better able to react to changes in the types of products being sold, the volume of sales, and the facilities needed for production will be an asset to an organization. Many emerging technologies are inherently adaptable, though the types of flexibility exhibited vary widely. The nature of these emerging technologies is examined here, and the case is made that flexibility should be valued as much as cost and time when selecting technologies, even though flexible manufacturing systems require extra time and money initially. An outlook on this type of manufacturing is shared with the assertion that flexible development and manufacturing would help reduce overall cost and better serve patient needs following the initial investment period. In the next decade, concentrated effort is needed from industry, academia, suppliers, and regulators to enable more agile and nimble pharmaceutical development and manufacturing.
3D Printing in Medicine, 2019
Purpose: Microneedle patches are arrays of tiny needles that painlessly pierce the skin to delive... more Purpose: Microneedle patches are arrays of tiny needles that painlessly pierce the skin to deliver medication into the body. Biocompatible microneedles are usually fabricated via molding of a master structure. Microfabrication techniques used for fabricating these master structures are costly, time intensive, and require extensive expertise to control the structure's geometry of the structure, despite evidence that microneedle geometry is a key design parameter. Here, a commercially available 3D printer is utilized, for the first time, to quickly and easily manufacture microneedle masters. Design/methodology/approach: Because commercially available 3D printers are not typically used for micron-scale fabrication, the influence of three different sources of error-stair-stepping, aliasing, and light abberations-on the resulting structure is investigated. A custom Matlab code is written to control the light intensity projected off of each individual micromirror (through grayscale) at a given time. The effect of the layer height, the number of layers, and grayscale on the sharpness, surface texture, and dimensional fidelity of the final structure is described. Findings: The Autodesk Ember is successfully utilized to fabricate sharp microneedles with a tip radius of approximately 15 μm in less than 30 min per patch (as compared to weeks to months for existing approaches). Utilization of grayscale improves surface texture and sharpness, and dimensional fidelity within ±5% of desired dimensions is achieved. Originality/value: The described 3D printing technique enables investigators to accurately fabricate microneedles within minutes at low cost. Rapid, iterative optimization of microneedle geometry through 3D printing will accelerate microneedle research through improved understanding of the relationship between microneedle structure and function.
International Journal of Pharmaceutics, 2018
Graphical abstract Figure. No Caption available. Abstract Fused deposition modeling (FDM) 3D prin... more Graphical abstract Figure. No Caption available. Abstract Fused deposition modeling (FDM) 3D printing (3DP) has a potential to change how we envision manufacturing in the pharmaceutical industry. A more common utilization for FDM 3DP is to build upon existing hot melt extrusion (HME) technology where the drug is dispersed in the polymer matrix. However, reliable manufacturing of drug‐containing filaments remains a challenge along with the limitation of active ingredients which can sustain the processing risks involved in the HME process. To circumvent this obstacle, a single step FDM 3DP process was developed to manufacture thin‐walled drug‐free capsules which can be filled with dry or liquid drug product formulations. Drug release from these systems is governed by the combined dissolution of the FDM capsule ‘shell’ and the dosage form encapsulated in these shells. To prepare the shells, the 3D printer files (extension ‘.gcode’) were modified by creating discrete zones, so‐called ‘zoning process’, with individual print parameters. Capsules printed without the zoning process resulted in macroscopic print defects and holes. X‐ray computed tomography, finite element analysis and mechanical testing were used to guide the zoning process and printing parameters in order to manufacture consistent and robust capsule shell geometries. Additionally, dose consistencies of drug containing liquid formulations were investigated in this work.