Raj Suryanarayanan - Academia.edu (original) (raw)

Papers by Raj Suryanarayanan

Pharmaceutical Research, Feb 1, 2007

Pharmaceutical Development and Technology, 1999

The object of this investigation was to perform detailed solid-state characterization studies on ... more The object of this investigation was to perform detailed solid-state characterization studies on the different solid forms of AG337 and to determine the conditions of their interconversions. Solid-state characterization was done using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot stage microscopy, Karl Fischer titrimetry, ambient and variable temperature X-ray powder diffractometry (XRD) and TGA coupled with FTIR (TGA/FTIR). In addition to five polymorphic forms of the anhydrate (I alpha to I epsilon), a hemihydrate (C14H12N4OS.2HCl.0.5H2O, II), a monohydrate (C14H12N4OS.2HCl.H2O; III), as well as a dihydrate (C14H12N4OS.2HCl.2H2O; IV) were identified. The 'as is' anhydrate, I alpha, resisted water uptake until stored at 98% RH (room temperature), where it transformed directly to IV, II and III transformed to IV at RH values > or = 7.6 and 84% respectively. Heating II and III to 130 degrees C in the variable temperature XRD resulted in the formation of I beta and I gamma respectively. On the other hand, I delta and I epsilon were obtained when II and III were respectively stored at 60 degrees C under vacuum. Variable temperature XRD, by providing information about the solid-state as a function of temperature, assisted in the interpretation of the DSC and TGA results. TGA/FTIR provided direct evidence that the thermal events observed in the temperature ranges of 25-150 degrees C and 200-250 degrees C were due to loss of water and loss of hydrogen chloride respectively. In addition to the conventional analytical techniques such as XRD, DSC, TGA and KFT, two other techniques, (variable temperature XRD and TGA/FTIR), were very useful in these solid-state characterization studies.

Pharmaceutical Research, Sep 2, 2010

Molecular Pharmaceutics, 2016

We investigated the influence of sorbed water concentration on the molecular mobility and crystal... more We investigated the influence of sorbed water concentration on the molecular mobility and crystallization behavior in a model amorphous drug and a solid dispersion. The temperature scaling (Tg/T) allowed us to simultaneously evaluate the effects of water content and temperature on the relaxation time. In the supercooled dispersions, once scaled, the relaxation times of the systems with different water content overlapped. Thus, the observed increase in mobility could be explained by the "plasticization" effect of water. This effect also explained the decrease in crystallization onset temperature brought about by water. That is, plasticization is the underlying mechanism governing the observed increase in mobility and physical instability in the supercooled state. Similar results were observed in the glassy drug substance. A single linear relationship was observed between crystallization time (time for 0.5% crystallization) and Tg/T in both dry and water containing systems. Since fragility is unaffected by modest amounts of water, much like crystallization time, the mobility in the glass is expected to scale with Tg.

Pharmaceutical Research, 2004

Pharmaceutical Research, Oct 1, 2003

PURPOSE: To use an inverse gas chromatographic (IGC) method to determine the glass transition tem... more PURPOSE: To use an inverse gas chromatographic (IGC) method to determine the glass transition temperature (Tg) of some amorphous pharmaceuticals and to extend this technique for the in situ study of the plasticizing effect of water on these materials.METHODS: Amorphous sucrose and colyophilized sucrose-PVP mixtures were the model compounds. Both IGC and differential scanning calorimetry (DSC) were used to determine their Tg. By controlling the water vapor pressure in the IGC sample column, it was possible to determine the Tg of plasticized amorphous phases. Under identical temperatures and vapor pressures, the water uptake was independently quantified in an automated water sorption apparatus.RESULTS: The Tg of the dry phases, determined by IGC and by DSC, were in very good agreement. With an increase in the environmental relative humidity (RH), there was a progressive decrease in Tg as a result of the plasticizing effect of water. Because the water uptake was independently quantified, it was possible to use the Gordon-Taylor equation to predict the Tg values of the plasticized materials. The predicted values were in very good agreement with those determined experimentally using IGC. A unique advantage of this technique is that it provides complete control over the sample environment and is thus ideally suited for the characterization of highly reactive amorphous phases.CONCLUSIONS: An IGC method was used (a) to determine the glass transition temperature of amorphous pharmaceuticals and (b) to quantify the plasticizing effect of water on multicomponent systems.

Journal of Pharmaceutical Sciences, Sep 1, 2009

Molecular pharmaceutics, Jan 20, 2015

We investigated the influence of polymer concentration (2.5-20% w/w) on the molecular mobility an... more We investigated the influence of polymer concentration (2.5-20% w/w) on the molecular mobility and the physical stability in solid dispersions of nifedipine (NIF) with polyvinylpyrrolidone (PVP). With an increase in polymer concentration, the α-relaxation times measured by broadband dielectric spectroscopy were longer, which reflects a decrease in molecular mobility. In the supercooled state, at a given temperature (between 55 and 75 °C), the relaxation time increased linearly as a function of polymer concentration (2.5-20% w/w). The temperature dependence of the relaxation time indicated that the fragility of the dispersion, and by extension the mechanism by which the polymer influences the relaxation time, was independent of polymer concentration. The time for NIF crystallization also increased as a function of polymer concentration. Therefore, by using molecular mobility as a predictor, a model was built to predict NIF crystallization from the dispersions in the supercooled state...

Pharmaceutical research, 2002

To characterize the phase transitions in a multicomponent system during the various stages of the... more To characterize the phase transitions in a multicomponent system during the various stages of the freeze-drying process and to evaluate the crystallization behavior below Tg' (glass transition temperature of maximally freeze-concentrated amorphous phase) in frozen aqueous solutions and during freeze-drying. X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC) were used to study frozen aqueous solutions of mannitol with or without trehalose. By attaching a vacuum pump to the low-temperature stage of the diffractometer, it was possible to simulate the freeze-drying process in situ in the sample chamber of the XRD. This enabled real-time monitoring of the solid state of the solutes during the process. In rapidly cooled aqueous solutions containing only mannitol (10% w/w), the solute was retained amorphous. Annealing of frozen solutions or primary drying. both below Tg', resulted in crystallization of mannitol hydrate. Similar effects were observed in th...

Pharmaceutical research, 2001

The object of this study was to demonstrate the applicability of variable temperature X-ray powde... more The object of this study was to demonstrate the applicability of variable temperature X-ray powder diffractometry (XRD) to investigate solid-state reactions using aspartame as a model compound. Aspartame exists as a hemihydrate (ASH) under ambient conditions and converts to aspartame anhydrate (ASA) at approximately 130 degrees C. ASA on further heating to approximately 180 degrees C undergoes decomposition (intramolecular cyclization) to form a diketopiperazine derivative (DKP). The dehydration as well as the decomposition kinetics were studied isothermally at several temperatures. The unique feature of this technique is that it permits simultaneous quantification of the reactant as well as the product. While the dehydration of ASH appeared to follow first-order kinetics, the cyclization of ASA was a nucleation controlled process. The rate constants were obtained at various temperatures, which permitted the calculation of the activation energies of dehydration and cyclization from ...

Molecular Pharmaceutics, 2014

Journal of Pharmaceutical Sciences, 2014

Molecular Pharmaceutics, 2015

We investigated the influence of drug-polymer hydrogen bonding interactions on molecular mobility... more We investigated the influence of drug-polymer hydrogen bonding interactions on molecular mobility and the physical stability in solid dispersions of nifedipine with each of the polymers polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMCAS), and poly(acrylic acid) (PAA). The drug-polymer interactions were monitored by FT-IR spectroscopy, the molecular mobility was characterized using broadband dielectric spectroscopy, and the crystallization kinetics was evaluated by powder X-ray diffractometry. The strength of drug-polymer hydrogen bonding, the structural relaxation time, and the crystallization kinetics were rank ordered as PVP > HPMCAS > PAA. At a fixed polymer concentration, the fraction of the drug bonded to the polymer was the highest with PVP. Addition of 20% w/w polymer resulted in ∼65-fold increase in the relaxation time in the PVP dispersion and only ∼5-fold increase in HPMCAS dispersion. In the PAA dispersions, there was no evidence of drug-polymer interactions and the polymer addition did not influence the relaxation time. Thus, the strongest drug-polymer hydrogen bonding interactions in PVP solid dispersions translated to the longest structural relaxation times and the highest resistance to drug crystallization.

Journal of Pharmaceutical Sciences, 2014

In dielectric spectroscopy, a technique traditionally used to characterize molecular mobility in ... more In dielectric spectroscopy, a technique traditionally used to characterize molecular mobility in polymers, the sample is usually analyzed as a thin film. In recent years, the technique has been extended to characterize both drug substances and drug products and has revealed a correlation between molecular mobility and stability. However, for pharmaceutical systems, analysis of powders is strongly preferred over films. Therefore, the dielectric behavior of several compounds of pharmaceutical interest-nifedipine, indomethacin, itraconazole, and griseofulvin-obtained using powder and film samples were compared. The magnitudes of the intrinsic dielectric properties were affected by the sample configuration with the powder samples consistently yielding lower values. The use of effective medium theories enabled us to account for the effect of air in the powder samples. The relaxation time, a property of immense importance to the pharmaceutical community, was not influenced by the sample configuration.

Molecular Pharmaceutics, 2014

We investigated the correlation between molecular mobility and physical stability in three model ... more We investigated the correlation between molecular mobility and physical stability in three model systems, including griseofulvin, nifedipine, and nifedipine-polyvinylpyrrolidone dispersion, and identified the specific mobility mode responsible for instability. The molecular mobility in the glassy as well as the supercooled liquid states of the model systems were comprehensively characterized using dynamic dielectric spectroscopy. Crystallization kinetics was monitored by powder X-ray diffractometry using either a laboratory (in the supercooled state) or a synchrotron (glassy) X-ray source. Structural (α-) relaxation appeared to be the mobility responsible for the observed physical instability at temperatures above Tg. Although the direct measurement of the structural relaxation time below Tg was not experimentally feasible, dielectric measurements in the supercooled state were used to provide an estimate of the α-relaxation times as a function of temperature in glassy pharmaceuticals. Again, there was a strong correlation between the α-relaxation and physical instability (crystallization) in the glassy state but not with any secondary relaxations. These results suggest that structural relaxation is a major contributor to physical instability both above and below Tg in these model systems.

Pharmaceutical Research, Feb 1, 2007

Pharmaceutical Development and Technology, 1999

The object of this investigation was to perform detailed solid-state characterization studies on ... more The object of this investigation was to perform detailed solid-state characterization studies on the different solid forms of AG337 and to determine the conditions of their interconversions. Solid-state characterization was done using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot stage microscopy, Karl Fischer titrimetry, ambient and variable temperature X-ray powder diffractometry (XRD) and TGA coupled with FTIR (TGA/FTIR). In addition to five polymorphic forms of the anhydrate (I alpha to I epsilon), a hemihydrate (C14H12N4OS.2HCl.0.5H2O, II), a monohydrate (C14H12N4OS.2HCl.H2O; III), as well as a dihydrate (C14H12N4OS.2HCl.2H2O; IV) were identified. The 'as is' anhydrate, I alpha, resisted water uptake until stored at 98% RH (room temperature), where it transformed directly to IV, II and III transformed to IV at RH values > or = 7.6 and 84% respectively. Heating II and III to 130 degrees C in the variable temperature XRD resulted in the formation of I beta and I gamma respectively. On the other hand, I delta and I epsilon were obtained when II and III were respectively stored at 60 degrees C under vacuum. Variable temperature XRD, by providing information about the solid-state as a function of temperature, assisted in the interpretation of the DSC and TGA results. TGA/FTIR provided direct evidence that the thermal events observed in the temperature ranges of 25-150 degrees C and 200-250 degrees C were due to loss of water and loss of hydrogen chloride respectively. In addition to the conventional analytical techniques such as XRD, DSC, TGA and KFT, two other techniques, (variable temperature XRD and TGA/FTIR), were very useful in these solid-state characterization studies.

Pharmaceutical Research, Sep 2, 2010

Molecular Pharmaceutics, 2016

We investigated the influence of sorbed water concentration on the molecular mobility and crystal... more We investigated the influence of sorbed water concentration on the molecular mobility and crystallization behavior in a model amorphous drug and a solid dispersion. The temperature scaling (Tg/T) allowed us to simultaneously evaluate the effects of water content and temperature on the relaxation time. In the supercooled dispersions, once scaled, the relaxation times of the systems with different water content overlapped. Thus, the observed increase in mobility could be explained by the "plasticization" effect of water. This effect also explained the decrease in crystallization onset temperature brought about by water. That is, plasticization is the underlying mechanism governing the observed increase in mobility and physical instability in the supercooled state. Similar results were observed in the glassy drug substance. A single linear relationship was observed between crystallization time (time for 0.5% crystallization) and Tg/T in both dry and water containing systems. Since fragility is unaffected by modest amounts of water, much like crystallization time, the mobility in the glass is expected to scale with Tg.

Pharmaceutical Research, 2004

Pharmaceutical Research, Oct 1, 2003

PURPOSE: To use an inverse gas chromatographic (IGC) method to determine the glass transition tem... more PURPOSE: To use an inverse gas chromatographic (IGC) method to determine the glass transition temperature (Tg) of some amorphous pharmaceuticals and to extend this technique for the in situ study of the plasticizing effect of water on these materials.METHODS: Amorphous sucrose and colyophilized sucrose-PVP mixtures were the model compounds. Both IGC and differential scanning calorimetry (DSC) were used to determine their Tg. By controlling the water vapor pressure in the IGC sample column, it was possible to determine the Tg of plasticized amorphous phases. Under identical temperatures and vapor pressures, the water uptake was independently quantified in an automated water sorption apparatus.RESULTS: The Tg of the dry phases, determined by IGC and by DSC, were in very good agreement. With an increase in the environmental relative humidity (RH), there was a progressive decrease in Tg as a result of the plasticizing effect of water. Because the water uptake was independently quantified, it was possible to use the Gordon-Taylor equation to predict the Tg values of the plasticized materials. The predicted values were in very good agreement with those determined experimentally using IGC. A unique advantage of this technique is that it provides complete control over the sample environment and is thus ideally suited for the characterization of highly reactive amorphous phases.CONCLUSIONS: An IGC method was used (a) to determine the glass transition temperature of amorphous pharmaceuticals and (b) to quantify the plasticizing effect of water on multicomponent systems.

Journal of Pharmaceutical Sciences, Sep 1, 2009

Molecular pharmaceutics, Jan 20, 2015

We investigated the influence of polymer concentration (2.5-20% w/w) on the molecular mobility an... more We investigated the influence of polymer concentration (2.5-20% w/w) on the molecular mobility and the physical stability in solid dispersions of nifedipine (NIF) with polyvinylpyrrolidone (PVP). With an increase in polymer concentration, the α-relaxation times measured by broadband dielectric spectroscopy were longer, which reflects a decrease in molecular mobility. In the supercooled state, at a given temperature (between 55 and 75 °C), the relaxation time increased linearly as a function of polymer concentration (2.5-20% w/w). The temperature dependence of the relaxation time indicated that the fragility of the dispersion, and by extension the mechanism by which the polymer influences the relaxation time, was independent of polymer concentration. The time for NIF crystallization also increased as a function of polymer concentration. Therefore, by using molecular mobility as a predictor, a model was built to predict NIF crystallization from the dispersions in the supercooled state...

Pharmaceutical research, 2002

To characterize the phase transitions in a multicomponent system during the various stages of the... more To characterize the phase transitions in a multicomponent system during the various stages of the freeze-drying process and to evaluate the crystallization behavior below Tg' (glass transition temperature of maximally freeze-concentrated amorphous phase) in frozen aqueous solutions and during freeze-drying. X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC) were used to study frozen aqueous solutions of mannitol with or without trehalose. By attaching a vacuum pump to the low-temperature stage of the diffractometer, it was possible to simulate the freeze-drying process in situ in the sample chamber of the XRD. This enabled real-time monitoring of the solid state of the solutes during the process. In rapidly cooled aqueous solutions containing only mannitol (10% w/w), the solute was retained amorphous. Annealing of frozen solutions or primary drying. both below Tg', resulted in crystallization of mannitol hydrate. Similar effects were observed in th...

Pharmaceutical research, 2001

The object of this study was to demonstrate the applicability of variable temperature X-ray powde... more The object of this study was to demonstrate the applicability of variable temperature X-ray powder diffractometry (XRD) to investigate solid-state reactions using aspartame as a model compound. Aspartame exists as a hemihydrate (ASH) under ambient conditions and converts to aspartame anhydrate (ASA) at approximately 130 degrees C. ASA on further heating to approximately 180 degrees C undergoes decomposition (intramolecular cyclization) to form a diketopiperazine derivative (DKP). The dehydration as well as the decomposition kinetics were studied isothermally at several temperatures. The unique feature of this technique is that it permits simultaneous quantification of the reactant as well as the product. While the dehydration of ASH appeared to follow first-order kinetics, the cyclization of ASA was a nucleation controlled process. The rate constants were obtained at various temperatures, which permitted the calculation of the activation energies of dehydration and cyclization from ...

Molecular Pharmaceutics, 2014

Journal of Pharmaceutical Sciences, 2014

Molecular Pharmaceutics, 2015

We investigated the influence of drug-polymer hydrogen bonding interactions on molecular mobility... more We investigated the influence of drug-polymer hydrogen bonding interactions on molecular mobility and the physical stability in solid dispersions of nifedipine with each of the polymers polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMCAS), and poly(acrylic acid) (PAA). The drug-polymer interactions were monitored by FT-IR spectroscopy, the molecular mobility was characterized using broadband dielectric spectroscopy, and the crystallization kinetics was evaluated by powder X-ray diffractometry. The strength of drug-polymer hydrogen bonding, the structural relaxation time, and the crystallization kinetics were rank ordered as PVP > HPMCAS > PAA. At a fixed polymer concentration, the fraction of the drug bonded to the polymer was the highest with PVP. Addition of 20% w/w polymer resulted in ∼65-fold increase in the relaxation time in the PVP dispersion and only ∼5-fold increase in HPMCAS dispersion. In the PAA dispersions, there was no evidence of drug-polymer interactions and the polymer addition did not influence the relaxation time. Thus, the strongest drug-polymer hydrogen bonding interactions in PVP solid dispersions translated to the longest structural relaxation times and the highest resistance to drug crystallization.

Journal of Pharmaceutical Sciences, 2014

In dielectric spectroscopy, a technique traditionally used to characterize molecular mobility in ... more In dielectric spectroscopy, a technique traditionally used to characterize molecular mobility in polymers, the sample is usually analyzed as a thin film. In recent years, the technique has been extended to characterize both drug substances and drug products and has revealed a correlation between molecular mobility and stability. However, for pharmaceutical systems, analysis of powders is strongly preferred over films. Therefore, the dielectric behavior of several compounds of pharmaceutical interest-nifedipine, indomethacin, itraconazole, and griseofulvin-obtained using powder and film samples were compared. The magnitudes of the intrinsic dielectric properties were affected by the sample configuration with the powder samples consistently yielding lower values. The use of effective medium theories enabled us to account for the effect of air in the powder samples. The relaxation time, a property of immense importance to the pharmaceutical community, was not influenced by the sample configuration.

Molecular Pharmaceutics, 2014

We investigated the correlation between molecular mobility and physical stability in three model ... more We investigated the correlation between molecular mobility and physical stability in three model systems, including griseofulvin, nifedipine, and nifedipine-polyvinylpyrrolidone dispersion, and identified the specific mobility mode responsible for instability. The molecular mobility in the glassy as well as the supercooled liquid states of the model systems were comprehensively characterized using dynamic dielectric spectroscopy. Crystallization kinetics was monitored by powder X-ray diffractometry using either a laboratory (in the supercooled state) or a synchrotron (glassy) X-ray source. Structural (α-) relaxation appeared to be the mobility responsible for the observed physical instability at temperatures above Tg. Although the direct measurement of the structural relaxation time below Tg was not experimentally feasible, dielectric measurements in the supercooled state were used to provide an estimate of the α-relaxation times as a function of temperature in glassy pharmaceuticals. Again, there was a strong correlation between the α-relaxation and physical instability (crystallization) in the glassy state but not with any secondary relaxations. These results suggest that structural relaxation is a major contributor to physical instability both above and below Tg in these model systems.