Kenneth Harris opened a general discussion of the paper by Herma Cuppen: It is well established f... more Kenneth Harris opened a general discussion of the paper by Herma Cuppen: It is well established from solid-state NMR and other techniques that the NH3+ group in crystalline amino acids undergoes rapid rotation about the C–NH3+ bond. Is the phase transition between the β and α phases of DL-norleucine associated with any significant discontinuity in the rate of this motion, and/or the temperature dependence of the rate of this motion? Furthermore, is there any evidence for disorder (dynamic or static) of the alkyl chain of the norleucine molecules in the α and β phases, and if so, does the nature of this disorder change significantly at the phase transition? Herma Cuppen answered: Rotation barriers about the C–NH3+ bond depend on the motive of the hydrogen bonding network in the crystalline phases. For DL-norleucine this motive stays intact during the transition, and I therefore do not expect a large difference for the two phases. The changes occur where the aliphatic chains interact. In a previous study,1 we determined the rotation barrier of the methyl group by means of molecular dynamics simulations for both phases. We found them to be identical, and to be in agreement with experimental values for DL-norvaline2 and DL-norleucine.3 We did not find any correlation between internal movement of the molecules and the onset of the transition.
International journal of pharmaceutics, Jan 20, 2018
Due to the complex nature of the pharmaceutical supply chain, the industry faces several major ch... more Due to the complex nature of the pharmaceutical supply chain, the industry faces several major challenges when it comes to ensuring an adequate supply of quality drug products. These challenges are not only the causes of supply chain disruptions and financial loss, but can also prevent underserved and remote areas from receiving life-saving drugs. As a preliminary demonstration to mitigate all these challenges, at MIT we have developed active pharmaceutical ingredients manufacturing in a miniature platform. However, manufacturing of final oral solid dosage as tablets from drug substances had not been demonstrated. In this study, a compact, portable, re-configurable, and automated tablet manufacturing system, roughly the size of a North American household oven, [72.4 cm (length) ×53.3 cm (width) ×134.6 cm (height)] was designed, built and demonstrated. This miniature system is able to manufacture on-demand tablets from drug crystals on a scale of hundreds to thousands per day. Ibupro...
International journal of pharmaceutics, Jan 4, 2017
We demonstrate the coating of tablets using an injection molding (IM) process that has advantage ... more We demonstrate the coating of tablets using an injection molding (IM) process that has advantage of being solvent free and can provide precision coat features. The selected core tablets comprising 10% w/w griseofulvin were prepared by an integrated hot melt extrusion-injection molding (HME-IM) process. Coating trials were conducted on a vertical injection mold machine. Polyethylene glycol and polyethylene oxide based hot melt extruded coat compositions were used. Tablet coating process feasibility was successfully demonstrated using different coating mold designs (with both overlapping and non-overlapping coatings at the weld) and coat thicknesses of 150 and 300 μm. The resultant coated tablets had acceptable appearance, seal at the weld, and immediate drug release profile (with an acceptable lag time). Since IM is a continuous process, this study opens opportunities to develop HME-IM continuous processes for transforming powder to coated tablets.
While porous silica supports have been previously studied as carriers for nanocrystalline forms o... more While porous silica supports have been previously studied as carriers for nanocrystalline forms of poorly water-soluble active pharmaceutical ingredients (APIs), increasing the loading of API in these matrices is of great importance if these carriers are to be used in drug formulations. A dual-stage mixed-suspension, mixed-product removal (MSMPR) crystallizer was designed in which the poorly soluble API fenofibrate was loaded into the porous matrices of pore sizes 35 nm-300 nm in the first stage, and then fed to a second stage in which the crystals were further grown in the pores. This resulted in high loadings of over 50 wt % while still producing nanocrystals confined to the pores without the formation of bulk-sized crystals on the surface of the porous silica. The principle was extended to another highly insoluble API, griseofulvin, to improve its loading in porous silica in a benchtop procedure. This work demonstrates a multi-step crystallization principle API in porous silica matrices with loadings high enough to produce final dosage forms of these poorly water-soluble APIs.
The combination of hot-melt extrusion and injection molding (HME-IM) is a promising process techn... more The combination of hot-melt extrusion and injection molding (HME-IM) is a promising process technology for continuous manufacturing of tablets. However, there has been limited research on its application to formulate crystalline drug-containing immediate-release tablets. Furthermore, studies that have applied the HME-IM process to molded tablets have used a noncontinuous 2-step approach. The present study develops maltodextrin (MDX)-based extrusion-molded immediate-release tablets for a crystalline drug (griseofulvin) using an integrated twin-screw HME-IM continuous process. At 10% w/w drug loading, MDX was selected as the tablet matrix former based on a preliminary screen. Furthermore, liquid and solid polyols were evaluated for melt processing of MDX and for impact on tablet performance. Smooth-surfaced tablets, comprising crystalline griseofulvin solid suspension in the amorphous MDX-xylitol matrix, were produced by a continuous process on a twin-screw extruder coupled to a horizontally opening IM machine. Real-time HME process profiles were used to develop automated HME-IM cycles. Formulation adjustments overcame process challenges and improved tablet strength. The developed MDX tablets exhibited adequate strength and a fast-dissolving matrix (85% drug release in 20Â min), and maintained performance on accelerated stability conditions.
Double Salt Ionic Liquids (DSILs) were prepared by mixing 1ethyl-3-methylimidazolium bis(trifluor... more Double Salt Ionic Liquids (DSILs) were prepared by mixing 1ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([C 2 mim][NTf 2 ]) and trihexyl(tetradecyl)phosphonium bis(trifluoromethylsulfonyl)imide ([P 66614 ][NTf 2 ]) in their miscible range: [C 2 mim] x [P 66614 ] (1-x) [NTf 2 ] (0 ≤ x ≤ 0.29). 1 H NMR, 19 F NMR, and FT-IR spectroscopic studies indicated that the [NTf 2 ]anions preferentially interact with the [C 2 mim] + cations. Solubility studies showed that solutes with long alkyl chains (e.g., heptane, methyl palmitate), which have good solubility in [P 66614 ][NTf 2 ] but are not totally miscible, have tunable solubility in the DSILs and the presence of even minor amounts of [C 2 mim] + significantly decreases their solubility. However, the solubilities of benzene, toluene, 1-octanol, and poly(ethylene glycol) (PEG-300) in [C 2 mim] x [P 66614 ] (1-x) [NTf 2 ] were controlled by their miscibility with [P 66614 ][NTf 2 ], and can't be tuned by changing the ion concentrations within the miscibility range.
This study provides a framework for robust tablet development using an integrated hot-melt extrus... more This study provides a framework for robust tablet development using an integrated hot-melt extrusion-injection molding (IM) continuous manufacturing platform. Griseofulvin, maltodextrin, xylitol and lactose were employed as drug, carrier, plasticizer and reinforcing agent respectively. A pre-blended drug-excipient mixture was fed from a loss-in-weight feeder to a twin-screw extruder. The extrudate was subsequently injected directly into the integrated IM unit and molded into tablets. Tablets were stored in different storage conditions up to 20 weeks to monitor physical stability and were evaluated by polarized light microscopy, DSC, SEM, XRD and dissolution analysis. Optimized injection pressure provided robust tablet formulations. Tablets manufactured at low and high injection pressures exhibited the flaws of sink marks and flashing respectively. Higher solidification temperature during IM process reduced the thermal induced residual stress and prevented chipping and cracking issues. Polarized light microscopy revealed a homogeneous dispersion of crystalline griseofulvin in an amorphous matrix. DSC underpinned the effect of high tablet residual moisture on maltodextrin-xylitol phase separation that resulted in dimensional instability. Tablets with low residual moisture demonstrated long term dimensional stability. This study serves as a model for IM tablet formulations for mechanistic understanding of critical process parameters and formulation attributes required for optimal product performance.
ï‚· Users may download and print one copy of any publication from the public portal for the purpose... more ï‚· Users may download and print one copy of any publication from the public portal for the purpose of private study or research. ï‚· You may not further distribute the material or use it for any profit-making activity or commercial gain ï‚· You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Industrial Engineering Chemistry Process Design and Development, 1986
... Chem. Process Des. Dev. 1984, Shih, S. S.; Katzer, J. R.; Kwart, H.; Stiles, A. B. Presented ... more ... Chem. Process Des. Dev. 1984, Shih, S. S.; Katzer, J. R.; Kwart, H.; Stiles, A. B. Presented before the Dlvl-slon of Petroleum Chemlstry at the 173rd National Meetlng of the Ameri-can Chemical Soclety, Chlcago, 1977, ORQN 1. 23, 20. 20, 62. Yang, S. H.; Satterfield, C. N. Ind. ...
Di!usion coe$cients of supersaturated aqueous solutions of ammonium sulfate have been measured at... more Di!usion coe$cients of supersaturated aqueous solutions of ammonium sulfate have been measured at 2983C using Gouy interferometry and were observed to rapidly decrease with increasing concentration in the supersaturated region. Water activities in the supersaturated region were measured by electrodynamic levitation of single solution droplets. The number average cluster size, critical cluster size, degree of association and spinodal concentration were calculated employing these data. These results show that the true metastable zone width is much wider than previously thought with a calculated valve of the spinodal concentration at 69.63 molal.
Concentration gradients have been observed in a number of supersaturated binary solutions by seve... more Concentration gradients have been observed in a number of supersaturated binary solutions by several investigators. It is postulated that these gradients are due to the presence of solute clusters. The average size of these clusters have been determined by reanalyzing the data using the concept of number and weight average molecular weights. For all experimental observations to date, the calculations yielded a value of the number average cluster size ranging from 2 to 100 molecules. The number average cluster size is a strong function of the degree of association in the solution. The degree of association is a function of the solution temperature, time, the degree of supersaturation and possibly the thermal history of the solution. The calculated cluster sizes compare favorably to those determined independently from diffusivity observations.
Kenneth Harris opened a general discussion of the paper by Herma Cuppen: It is well established f... more Kenneth Harris opened a general discussion of the paper by Herma Cuppen: It is well established from solid-state NMR and other techniques that the NH3+ group in crystalline amino acids undergoes rapid rotation about the C–NH3+ bond. Is the phase transition between the β and α phases of DL-norleucine associated with any significant discontinuity in the rate of this motion, and/or the temperature dependence of the rate of this motion? Furthermore, is there any evidence for disorder (dynamic or static) of the alkyl chain of the norleucine molecules in the α and β phases, and if so, does the nature of this disorder change significantly at the phase transition? Herma Cuppen answered: Rotation barriers about the C–NH3+ bond depend on the motive of the hydrogen bonding network in the crystalline phases. For DL-norleucine this motive stays intact during the transition, and I therefore do not expect a large difference for the two phases. The changes occur where the aliphatic chains interact. In a previous study,1 we determined the rotation barrier of the methyl group by means of molecular dynamics simulations for both phases. We found them to be identical, and to be in agreement with experimental values for DL-norvaline2 and DL-norleucine.3 We did not find any correlation between internal movement of the molecules and the onset of the transition.
International journal of pharmaceutics, Jan 20, 2018
Due to the complex nature of the pharmaceutical supply chain, the industry faces several major ch... more Due to the complex nature of the pharmaceutical supply chain, the industry faces several major challenges when it comes to ensuring an adequate supply of quality drug products. These challenges are not only the causes of supply chain disruptions and financial loss, but can also prevent underserved and remote areas from receiving life-saving drugs. As a preliminary demonstration to mitigate all these challenges, at MIT we have developed active pharmaceutical ingredients manufacturing in a miniature platform. However, manufacturing of final oral solid dosage as tablets from drug substances had not been demonstrated. In this study, a compact, portable, re-configurable, and automated tablet manufacturing system, roughly the size of a North American household oven, [72.4 cm (length) ×53.3 cm (width) ×134.6 cm (height)] was designed, built and demonstrated. This miniature system is able to manufacture on-demand tablets from drug crystals on a scale of hundreds to thousands per day. Ibupro...
International journal of pharmaceutics, Jan 4, 2017
We demonstrate the coating of tablets using an injection molding (IM) process that has advantage ... more We demonstrate the coating of tablets using an injection molding (IM) process that has advantage of being solvent free and can provide precision coat features. The selected core tablets comprising 10% w/w griseofulvin were prepared by an integrated hot melt extrusion-injection molding (HME-IM) process. Coating trials were conducted on a vertical injection mold machine. Polyethylene glycol and polyethylene oxide based hot melt extruded coat compositions were used. Tablet coating process feasibility was successfully demonstrated using different coating mold designs (with both overlapping and non-overlapping coatings at the weld) and coat thicknesses of 150 and 300 μm. The resultant coated tablets had acceptable appearance, seal at the weld, and immediate drug release profile (with an acceptable lag time). Since IM is a continuous process, this study opens opportunities to develop HME-IM continuous processes for transforming powder to coated tablets.
While porous silica supports have been previously studied as carriers for nanocrystalline forms o... more While porous silica supports have been previously studied as carriers for nanocrystalline forms of poorly water-soluble active pharmaceutical ingredients (APIs), increasing the loading of API in these matrices is of great importance if these carriers are to be used in drug formulations. A dual-stage mixed-suspension, mixed-product removal (MSMPR) crystallizer was designed in which the poorly soluble API fenofibrate was loaded into the porous matrices of pore sizes 35 nm-300 nm in the first stage, and then fed to a second stage in which the crystals were further grown in the pores. This resulted in high loadings of over 50 wt % while still producing nanocrystals confined to the pores without the formation of bulk-sized crystals on the surface of the porous silica. The principle was extended to another highly insoluble API, griseofulvin, to improve its loading in porous silica in a benchtop procedure. This work demonstrates a multi-step crystallization principle API in porous silica matrices with loadings high enough to produce final dosage forms of these poorly water-soluble APIs.
The combination of hot-melt extrusion and injection molding (HME-IM) is a promising process techn... more The combination of hot-melt extrusion and injection molding (HME-IM) is a promising process technology for continuous manufacturing of tablets. However, there has been limited research on its application to formulate crystalline drug-containing immediate-release tablets. Furthermore, studies that have applied the HME-IM process to molded tablets have used a noncontinuous 2-step approach. The present study develops maltodextrin (MDX)-based extrusion-molded immediate-release tablets for a crystalline drug (griseofulvin) using an integrated twin-screw HME-IM continuous process. At 10% w/w drug loading, MDX was selected as the tablet matrix former based on a preliminary screen. Furthermore, liquid and solid polyols were evaluated for melt processing of MDX and for impact on tablet performance. Smooth-surfaced tablets, comprising crystalline griseofulvin solid suspension in the amorphous MDX-xylitol matrix, were produced by a continuous process on a twin-screw extruder coupled to a horizontally opening IM machine. Real-time HME process profiles were used to develop automated HME-IM cycles. Formulation adjustments overcame process challenges and improved tablet strength. The developed MDX tablets exhibited adequate strength and a fast-dissolving matrix (85% drug release in 20Â min), and maintained performance on accelerated stability conditions.
Double Salt Ionic Liquids (DSILs) were prepared by mixing 1ethyl-3-methylimidazolium bis(trifluor... more Double Salt Ionic Liquids (DSILs) were prepared by mixing 1ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([C 2 mim][NTf 2 ]) and trihexyl(tetradecyl)phosphonium bis(trifluoromethylsulfonyl)imide ([P 66614 ][NTf 2 ]) in their miscible range: [C 2 mim] x [P 66614 ] (1-x) [NTf 2 ] (0 ≤ x ≤ 0.29). 1 H NMR, 19 F NMR, and FT-IR spectroscopic studies indicated that the [NTf 2 ]anions preferentially interact with the [C 2 mim] + cations. Solubility studies showed that solutes with long alkyl chains (e.g., heptane, methyl palmitate), which have good solubility in [P 66614 ][NTf 2 ] but are not totally miscible, have tunable solubility in the DSILs and the presence of even minor amounts of [C 2 mim] + significantly decreases their solubility. However, the solubilities of benzene, toluene, 1-octanol, and poly(ethylene glycol) (PEG-300) in [C 2 mim] x [P 66614 ] (1-x) [NTf 2 ] were controlled by their miscibility with [P 66614 ][NTf 2 ], and can't be tuned by changing the ion concentrations within the miscibility range.
This study provides a framework for robust tablet development using an integrated hot-melt extrus... more This study provides a framework for robust tablet development using an integrated hot-melt extrusion-injection molding (IM) continuous manufacturing platform. Griseofulvin, maltodextrin, xylitol and lactose were employed as drug, carrier, plasticizer and reinforcing agent respectively. A pre-blended drug-excipient mixture was fed from a loss-in-weight feeder to a twin-screw extruder. The extrudate was subsequently injected directly into the integrated IM unit and molded into tablets. Tablets were stored in different storage conditions up to 20 weeks to monitor physical stability and were evaluated by polarized light microscopy, DSC, SEM, XRD and dissolution analysis. Optimized injection pressure provided robust tablet formulations. Tablets manufactured at low and high injection pressures exhibited the flaws of sink marks and flashing respectively. Higher solidification temperature during IM process reduced the thermal induced residual stress and prevented chipping and cracking issues. Polarized light microscopy revealed a homogeneous dispersion of crystalline griseofulvin in an amorphous matrix. DSC underpinned the effect of high tablet residual moisture on maltodextrin-xylitol phase separation that resulted in dimensional instability. Tablets with low residual moisture demonstrated long term dimensional stability. This study serves as a model for IM tablet formulations for mechanistic understanding of critical process parameters and formulation attributes required for optimal product performance.
ï‚· Users may download and print one copy of any publication from the public portal for the purpose... more ï‚· Users may download and print one copy of any publication from the public portal for the purpose of private study or research. ï‚· You may not further distribute the material or use it for any profit-making activity or commercial gain ï‚· You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Industrial Engineering Chemistry Process Design and Development, 1986
... Chem. Process Des. Dev. 1984, Shih, S. S.; Katzer, J. R.; Kwart, H.; Stiles, A. B. Presented ... more ... Chem. Process Des. Dev. 1984, Shih, S. S.; Katzer, J. R.; Kwart, H.; Stiles, A. B. Presented before the Dlvl-slon of Petroleum Chemlstry at the 173rd National Meetlng of the Ameri-can Chemical Soclety, Chlcago, 1977, ORQN 1. 23, 20. 20, 62. Yang, S. H.; Satterfield, C. N. Ind. ...
Di!usion coe$cients of supersaturated aqueous solutions of ammonium sulfate have been measured at... more Di!usion coe$cients of supersaturated aqueous solutions of ammonium sulfate have been measured at 2983C using Gouy interferometry and were observed to rapidly decrease with increasing concentration in the supersaturated region. Water activities in the supersaturated region were measured by electrodynamic levitation of single solution droplets. The number average cluster size, critical cluster size, degree of association and spinodal concentration were calculated employing these data. These results show that the true metastable zone width is much wider than previously thought with a calculated valve of the spinodal concentration at 69.63 molal.
Concentration gradients have been observed in a number of supersaturated binary solutions by seve... more Concentration gradients have been observed in a number of supersaturated binary solutions by several investigators. It is postulated that these gradients are due to the presence of solute clusters. The average size of these clusters have been determined by reanalyzing the data using the concept of number and weight average molecular weights. For all experimental observations to date, the calculations yielded a value of the number average cluster size ranging from 2 to 100 molecules. The number average cluster size is a strong function of the degree of association in the solution. The degree of association is a function of the solution temperature, time, the degree of supersaturation and possibly the thermal history of the solution. The calculated cluster sizes compare favorably to those determined independently from diffusivity observations.
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