Raj Suryanarayanan

University of Minnesota Duluth, Duluth, Minnesota, United States

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Publications (129)399.72 Total impact

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    ABSTRACT: Crystallization of trehalose dihydrate (C12H22O11·2H2O) was induced by storing tablets of amorphous anhydrous trehalose (C12H22O11) at 65% RH (RT). Our goal was to evaluate the advantages and limitations of two approaches of profiling spatial distribution of drug crystallization in tablets. The extent of crystallization, as a function of depth, was determined in tablets stored for different time-periods. The first approach was glancing angle X-ray diffractometry, where the penetration depth of X-rays was modulated by the incident angle. Based on the mass attenuation coefficient of the matrix, the depth of X-ray penetration was calculated as a function of incident angle which in turn enabled us to "calculate" the extent of crystallization to different depths. In the second approach, the tablets were split into halves and the split surfaces were analyzed directly. Starting from the tablet surface and moving toward the midplane, XRD patterns were collected in 36 "regions", in increments of 0.05 mm. The results obtained by the two approaches were, in general, in good agreement. Additionally, the results obtained were validated by determining the "average" crystallization in the entire tablet by using synchrotron radiation in the transmission mode. The glancing angle method could detect crystallization up to ~ 650 µm and had a "surface bias". Being a nondestructive technique, this method will permit repeated analyses of the same tablet at different time points, for example during a stability study. On the other hand, split tablet analyses, while a "destructive" technique, provided comprehensive and unbiased depth profiling information.
    Molecular Pharmaceutics 09/2015; DOI:10.1021/acs.molpharmaceut.5b00567 · 4.38 Impact Factor
  • Pinal Mistry · Sarat Mohapatra · Tata Gopinath · Frederick G Vogt · Raj Suryanarayanan ·
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    ABSTRACT: The effects of specific drug-polymer interactions (ionic or hydrogen-bonding) on the molecular mobility of model amorphous solid dispersions (ASDs) were investigated. ASDs of ketoconazole (KTZ), a weakly basic drug, with each of polyacrylic acid (PAA), poly(2-hydroxyethyl methacrylate) (PHEMA) and polyvinylpyrrolidone (PVP) were prepared. Drug-polymer interactions in the ASDs were evaluated by IR and solid-state NMR, the molecular mobility quantified by dielectric spectroscopy and crystallization onset monitored by differential scanning calorimetry (DSC) and variable temperature X-ray diffractometry (XRD). KTZ likely exhibited ionic interactions with PAA, hydrogen-bonding with PHEMA and weaker dipole-dipole interactions with PVP. Based on dielectric spectroscopy, the α-relaxation times of the ASDs followed the order: PAA > PHEMA > PVP. In addition, the presence of ionic interactions also translated to a dramatic and disproportionate decrease in mobility as a function of polymer concentration. Based on both DSC and variable temperature XRD, an increase in strength of interaction translated to higher crystallization onset temperature and a decrease in extent of crystallization. Stronger drug-polymer interactions, by reducing the molecular mobility, can potentially delay the crystallization onset temperature as well as crystallization extent.
    Molecular Pharmaceutics 06/2015; 12(9). DOI:10.1021/acs.molpharmaceut.5b00333 · 4.38 Impact Factor
  • Seema Thakral · Raj Suryanarayanan ·
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    ABSTRACT: (i) Prepare a freeze-dried injectable indomethacin (IMC) dosage form. (ii) Convert IMC to its tris salt during freeze-drying so as to facilitate rapid dissolution (reconstitution). (iii) Modulate salt crystallinity by annealing the frozen solution. Aqueous IMC solutions buffered with tris were freeze dried, with or without annealing the frozen solutions. The lyophiles were characterized by X-ray diffractometry, differential scanning calorimetry and infra-red spectroscopy and also subjected to water sorption and dissolution studies. Based on IR spectroscopy, the final lyophile was confirmed to contain the IMC tris salt. In the absence of annealing, the lyophile was X-ray amorphous with a glass transition temperature of 19°C. Annealing the frozen solutions caused a substantial increase in lyophile crystallinity. Interestingly, both the amorphous and partially crystalline lyophiles dissolved "instantaneously" and completely in the dissolution medium. In contrast, the crystalline IMC as well as its physical mixture with tris exhibited much slower dissolution with ~ 50% drug dissolved in 30 min. In situ IMC tris salt formation resulted in an elegant lyophile with a very short reconstitution time. Tris served two roles - as a buffer in the prelyophilization solution and as the counterion for the salt in the final lyophile. This approach for solubility enhancement could be extended to other acidic drugs wherein salt formation was observed during freeze-drying.
    Pharmaceutical Research 06/2015; 32(11). DOI:10.1007/s11095-015-1732-0 · 3.42 Impact Factor
  • Khushboo Kothari · Vishard Ragoonanan · Raj Suryanarayanan ·
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    ABSTRACT: 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. The predicted crystallization times were in excellent agreement with the experimental data.
    Molecular Pharmaceutics 04/2015; 12(5). DOI:10.1021/mp500800c · 4.38 Impact Factor
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    Kapildev K. Arora · Sunny P. Bhardwaj · Pinal Mistry · Raj Suryanarayanan ·
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    ABSTRACT: The physical form of anhydrous adefovir dipivoxil (AD), obtained following the dehydration of AD dihydrate, was governed by the kinetics of water removal. The rate and extent of water removal following the dehydration of AD dihydrate was manipulated by altering the sample size, pan configuration, and heating rate in a differential scanning calorimeter. Interestingly, when there was moderate resistance to water removal, a new anhydrous polymorph (melting point 80°C) was obtained. High resistance to water removal resulted in amorphous AD. Variable temperature XRD of AD provided direct and unambiguous evidence of this new polymorph. We have prepared and characterized this new anhydrous polymorph as well as amorphous AD. Based on HPLC, AD dihydrate heated under different conditions in the DSC was observed to be chemically stable. When exposed to water vapor (RH ≥ 80%; 25°C), the new polymorph had a stronger propensity to convert to AD dihydrate than the amorphous anhydrate or AD form I. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci
    Journal of Pharmaceutical Sciences 12/2014; 104(3). DOI:10.1002/jps.24296 · 2.59 Impact Factor
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    Naveen K Thakral · Sarat Mohapatra · Gregory A Stephenson · Raj Suryanarayanan ·
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    ABSTRACT: Tablets of amorphous indomethacin were compressed at 10, 25, 50 or 100 MPa using either an unlubricated or lubricated die and stored individually at 35 °C in sealed Mylar® pouches. At selected time points, tablets were analyzed by two dimensional X-ray diffractometry (2D-XRD), which enabled us to profile the extent of drug crystallization in tablets, both in the radial and axial directions. To evaluate the role of lubricant, magnesium stearate was used as "internal" and/or "external" lubricant. Indomethacin crystallization propensity increased as a function of compression pressure, with 100 MPa pressure causing crystallization immediately after compression (detected using synchrotron radiation). However, the drug crystallization was not uniform throughout the tablets. In unlubricated systems, pronounced crystallization in the radial surface could be attributed to die wall friction. The tablet core remained substantially amorphous, irrespective of the compression pressure. Lubrication of the die wall with magnesium stearate, as external lubricant, dramatically decreased drug crystallization in the radial surface. The spatial heterogeneity in drug crystallization, as a function of formulation composition and compression pressure, was systematically investigated. When formulating amorphous systems as tablets, the potential for compression induced crystallization warrants careful consideration. Very low levels of crystallization on the tablet surface, while profoundly affecting product performance (decrease in dissolution rate), may not be readily detected by conventional analytical techniques. Early detection of crystallization could be pivotal in the successful design of a dosage form where, in order to obtain the desired bioavailability, the drug may be in a high energy state. Specialized X-ray diffractometric techniques (2D; use of high intensity synchrotron radiation) enabled detection of very low levels of drug crystallization and revealed the heterogeneity in crystallization within the tablet.
    Molecular Pharmaceutics 12/2014; 12(1). DOI:10.1021/mp5005788 · 4.38 Impact Factor
  • Khushboo Kothari · Vishard Ragoonanan · Raj Suryanarayanan ·
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    ABSTRACT: 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.
    Molecular Pharmaceutics 11/2014; 12(1). DOI:10.1021/mp5005146 · 4.38 Impact Factor
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    ABSTRACT: Physical instability of amorphous solid dispersions can be a major impediment to their widespread use. We characterized the molecular mobility in amorphous solid dispersions of itraconazole (ITZ) with each polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose acetate succinate (HPMCAS) with the goal of investigating the correlation between molecular mobility and physical stability. Dielectric spectra showed two mobility modes: α-relaxation at temperatures above the glass transition temperature (Tg) and β-relaxation in the sub-Tg range. HPMCAS substantially increased the α-relaxation time, with an attendant increase in crystallization onset time and a decrease in crystallization rate constant, demonstrating the correlation between α-relaxation and stability. The inhibitory effect on α-relaxation as well as stability was temperature dependent and diminished as the temperature was increased above Tg. PVP, on the other hand, affected neither the α-relaxation time nor the crystallization onset time, further establishing the link between α-relaxation and crystallization onset in solid dispersions. However, it inhibited the crystallization rate, an effect attributed to factors other than mobility. Interestingly, both of the polymers acted as plasticizers of β-relaxation, ruling out the latter's involvement in physical stability.
    Molecular Pharmaceutics 10/2014; 11(11). DOI:10.1021/mp5004515 · 4.38 Impact Factor
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    ABSTRACT: The objectives of this study were to measure the apparent surface acidity of common excipients and to correlate the acidity with the chemical stability of an acid-sensitive active pharmaceutical ingredient (API) in binary API-excipient powder mixtures. The acidity of 26 solid excipients was determined by two methods, (i) by measuring the pH of their suspensions or solutions and (ii) the pH equivalent (pHeq) measured via ionization of probe molecules deposited on the surface of the excipients. The chemical stability of an API, atorvastatin calcium (AC), in mixtures with the excipients was evaluated by monitoring the appearance of an acid-induced degradant, atorvastatin lactone, under accelerated storage conditions. The extent of lactone formation in AC-excipient mixtures was presented as a function of either solution/suspension pH or pHeq. No lactone formation was observed in mixtures with excipients having pHeq > 6, while the lactone levels were pronounced (> 0.6% after 6 weeks at 50°C/20% RH) with excipients exhibiting pHeq < 3. The three pHeq regions (> 6, 3-6, and < 3) were consistent with the reported solution pH-stability profile of AC. In contrast to the pHeq scale, lactone formation did not show any clear trend when plotted as a function of the suspension/solution pH. Two mechanisms to explain the discrepancy between the suspension/solution pH and the chemical stability data were discussed. Acidic excipients, which are expected to be incompatible with an acid-sensitive API, were identified based on pHeq measurements. The incompatibility prediction was confirmed in the chemical stability tests using AC as an example of an acid-sensitive API.
    AAPS PharmSciTech 10/2014; 16(2). DOI:10.1208/s12249-014-0231-7 · 1.64 Impact Factor
  • Prakash Sundaramurthi · Raj Suryanarayanan ·
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    ABSTRACT: According to label claims, in commercial solid dosage forms, azithromycin (AZI) exists either as a monohydrate (MH) or as a dihydrate (DH). Although these two forms are known to be relatively stable in the solid state, AZI sesquihydrate (SH) was observed in a drug product. This was believed to be a consequence of a processing-induced phase transformation. Our goal was to prepare and characterize AZI SH and map its solid-state transition pathways with other AZI phases. When dehydrated at temperatures <80°C, DH yielded an isomorphic dehydrate, whereas dehydration at ≥80°C yielded SH. Heating SH to 100°C or holding at 0% RH at room temperature, yielded an amorphous product through an intermediate isomorphic dehydrate, isostructural to SH. On the other hand, dehydration of MH (at ≥60°C) resulted in amorphization with no intermediate crystalline anhydrate. Diagnostic XRD peaks of AH, MH, SH, and DH enabled their unambiguous identification. However, the presence of crystalline excipients hindered active pharmaceutical ingredient characterization in drug product. Pattern subtraction method was used to selectively remove the contribution of the crystalline excipients to the overall diffraction pattern, thereby facilitating the physical characterization of AZI in the drug product. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci
    Journal of Pharmaceutical Sciences 10/2014; 103(10). DOI:10.1002/jps.24084 · 2.59 Impact Factor
  • Khushboo Kothari · Vishard Ragoonanan · Raj Suryanarayanan ·
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    ABSTRACT: 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. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci
    Journal of Pharmaceutical Sciences 10/2014; 103(10). DOI:10.1002/jps.24110 · 2.59 Impact Factor
  • Khushboo Kothari · Vishard Ragoonanan · Raj Suryanarayanan ·
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    ABSTRACT: 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.
    Molecular Pharmaceutics 08/2014; 11(9). DOI:10.1021/mp500229d · 4.38 Impact Factor
  • Sisir Bhattacharya · Sunny P Bhardwaj · Raj Suryanarayanan ·
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    ABSTRACT: To determine the effect of annealing on the two secondary relaxations in amorphous sucrose and in sucrose solid dispersions. Sucrose was co-lyophilized with either PVP or sorbitol, annealed for different time periods and analyzed by dielectric spectroscopy. In an earlier investigation, we had documented the effect of PVP and sorbitol on the primary and the two secondary relaxations in amorphous sucrose solid dispersions (1). Here we investigated the effect of annealing on local motions, both in amorphous sucrose and in the dispersions. The average relaxation time of the local motion (irrespective of origin) in sucrose, decreased upon annealing. However, the heterogeneity in relaxation time distribution as well as the dielectric strength decreased only for β1- (the slower relaxation) but not for β2-relaxations. The effect of annealing on β2-relaxation times was neutralized by sorbitol while PVP negated the effect of annealing on both β1- and β2-relaxations. An increase in local mobility of sucrose brought about by annealing could be negated with an additive.
    Pharmaceutical Research 05/2014; 31(10). DOI:10.1007/s11095-014-1379-2 · 3.42 Impact Factor
  • Vishard Ragoonanan · Raj Suryanarayanan ·
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    ABSTRACT: We hypothesize that ultrasonication can accelerate solute crystallization in freeze-concentrates. Our objective is to demonstrate ultrasonication as a potential predictive tool for evaluating physical stability of excipients in frozen solutions. The crystallization tendencies of lyoprotectants (trehalose, sucrose), carboxylic acid buffers (citric, tartaric, malic, and acetic) and an amino acid buffer (histidine HCl) were studied. Aqueous solutions of buffers, lyoprotectants and mixtures of the two were cooled from room temperature to -20°C and sonicated to induce solute crystallization. The crystallized phases were identified by X-ray diffractometry (laboratory or synchrotron source). Sonication accelerated crystallization of trehalose dihydrate in frozen trehalose solutions. Sonication also enhanced solute crystallization in tartaric (200 mM; pH 5), citric (200 mM pH 4) and malic (200 mM; pH 4) acid buffers. At lower buffer concentrations, longer annealing times following sonication were required to facilitate solute crystallization. The time for crystallization of histidine HCl progressively increased as a function of sucrose concentration. The insonation period required to effect crystallization also increased with sucrose concentration. Sonication can substantially accelerate solute crystallization in the freeze-concentrate. Ultrasonication may be useful in assessing the crystallization tendency of formulation constituents used in long term frozen storage and freeze-drying.
    Pharmaceutical Research 01/2014; 31(6). DOI:10.1007/s11095-013-1257-3 · 3.42 Impact Factor
  • Naveen K Thakral · Vishard Ragoonanan · Raj Suryanarayanan ·
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    ABSTRACT: Model tablet formulations containing thiamine hydrochloride [as a nonstoichiometric hydrate (NSH)] and dicalcium phosphate dihydrate (DCPD) were prepared. In intact tablets, the water released by dehydration of DCPD mediated the transition of NSH to thiamine hydrochloride hemihydrate (HH). The use of an X-ray microdiffractometer with an area detector enabled us to rapidly and simultaneously monitor both the phase transformations. The spatial information, gained by monitoring the tablet from the surface to the core (depth profiling), revealed that both DCPD dehydration and HH formation progressed from the surface to the tablet core as a function of storage time. Film coating of the tablets with ethyl cellulose caused a decrease in both the reaction rates. There was a pronounced lag time, but once initiated, the transformations occurred simultaneously throughout the tablet. Thus the difference in the phase transformation behavior between the uncoated and the coated tablets could not have been discerned without the depth profiling. Incorporation of hydrophilic colloidal silica as a formulation component further slowed down the transformations. By acting as a water scavenger it maintained a very "dry" environment in the tablet matrix. Finally, by coating the NSH particles with hydrophobic colloidal silica, the formation of HH was further substantially decelerated. The microdiffractometric technique not only enabled direct analyses of tablets but also provided the critical spatial information. This helped in the selection of excipients with appropriate functionality to prevent the in situ phase transformations.
    Molecular Pharmaceutics 07/2013; 10(8). DOI:10.1021/mp400180n · 4.38 Impact Factor
  • A Saxena · Y C Jean · R Suryanarayanan ·
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    ABSTRACT: Our objective is to compare the physical properties of materials obtained from two different methods of annealing reversal, that is, water sorption-desorption (WSD) and heating above glass transition temperature (HAT). Trehalose was annealed by storing at 100 °C for 120 h. The annealing effect was reversed either by WSD or HAT, and the resulting materials were characterized by differential scanning calorimetry (DSC), water sorption studies, and positron annihilation spectroscopy (PAS). While the products obtained by the two methods of annealing reversal appeared to be identical by conventional characterization methods, they exhibited pronounced differences in their water sorption behavior. Positron annihilation spectroscopy (PAS), by measuring the fractional free volume changes in the processed samples, provided a mechanistic explanation for the differences in the observed behavior.
    Molecular Pharmaceutics 07/2013; 10(8). DOI:10.1021/mp400099r · 4.38 Impact Factor
  • Mehak Mehta · Sunny P Bhardwaj · Raj Suryanarayanan ·
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    ABSTRACT: A potential drawback with the use of mannitol as a bulking agent is its existence as mannitol hemihydrate (MHH; C6H14O6(.)0.5H2O) in the lyophile. Once formed during freeze-drying, MHH dehydration may require secondary drying under aggressive conditions which can be detrimental to the stability of thermolabile components. If MHH is retained in the lyophile, the water released by MHH dehydration during storage has the potential to cause product instability. We systematically identified the conditions under which anhydrous mannitol and MHH crystallized in frozen systems with the goal of preventing MHH formation during freeze-drying. When mannitol solutions were cooled, the temperature of solute crystallization was the determinant of the physical form of mannitol. Based on low temperature X-ray diffractometry (using both laboratory and synchrotron sources), MHH formation was observed when solute crystallization occurred at temperatures ⩽ -20 °C while anhydrous mannitol crystallized at temperatures ⩾ -10 °C. The transition temperature (anhydrate - MHH) appears to be ∼ -15 °C. The use of a freeze-dryer with controlled ice nucleation technology enabled anhydrous mannitol crystallization at ∼ -5 °C. Thus, ice crystallization followed by annealing at temperatures ⩾ -10 °C can be an effective strategy to prevent MHH formation.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 04/2013; 85(2). DOI:10.1016/j.ejpb.2013.04.010 · 3.38 Impact Factor
  • Kapildev K Arora · Seema Thakral · Raj Suryanarayanan ·
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    ABSTRACT: Purpose: To demonstrate two sequential solid-state reactions in intact tablets: dehydration of active pharmaceutical ingredient (API), and cocrystal formation between the anhydrous API and a second formulation component mediated by the released water. To evaluate the implication of this in situ phase transformation on the tablet dissolution behavior. Methods: Tablets containing theophylline monohydrate (TPM) and anhydrous citric acid (CA) were stored at 40°C in sealed polyester pouches and the relative humidity in the headspace above the tablet was continuously measured. Dehydration to anhydrous theophylline (TPA) and the product appearance (TPA-CA cocrystal) were simultaneously monitored by powder X-ray diffractometry. Carbamazepine dihydrate and nicotinamide formed the second model system. Results: The water of crystallization released by TPM dehydration was followed first by deliquescence of citric acid, evident from the headspace relative humidity (~ 68%; 40°C), and then the formation of TPA-CA cocrystal in intact tablets. The noncovalent synthesis resulted in a pronounced decrease in the dissolution rate of theophylline from the tablets. Similarly, the water released by dehydration of carbamazepine dihydrate caused the cocrystallization reaction between anhydrous carbamazepine and nicotinamide. Conclusions: The water released by API dehydration mediated cocrystal formation in intact tablets and affected dissolution behavior.
    Pharmaceutical Research 04/2013; 30(7). DOI:10.1007/s11095-013-1022-7 · 3.42 Impact Factor
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    ABSTRACT: The goal was to investigate the correlation between molecular mobility and physical stability and identify the specific mobility mode responsible for instability. The molecular mobility of amorphous itraconazole, in the glassy as well as the supercooled liquid state, was comprehensively characterized using dynamic dielectric spectroscopy. Isothermal frequency sweeps in the 5 - 40 °C temperature range revealed a β-relaxation which exhibited Arrhenius temperature dependence. As the temperature approached Tg, β-relaxation became progressively less resolved due to interference from the high frequency tail of the alpha-relaxation and then transformed into an excess wing. Above Tg, non-linear temperature dependence of the alpha-relaxation was described by the Vogel-Tammann-Fulcher (VTF) model. Itraconazole was found to be a fragile glass former with a VTF strength parameter of ~ 4. Isothermal crystallization kinetics, at several temperatures over the range of 75 to 95 °C, was best described by the 3-dimensional nucleation and growth model. Primary relaxation appeared to be the mobility responsible for the observed physical instability at temperatures above Tg as indicated by the linear correlation of alpha-relaxation with both crystallization onset and kinetics (represented by the inverse of the crystallization rate constant). A strong coupling between global mobility and crystallization onset was evident. However, for growth kinetics, the coupling was less pronounced, indicating the involvement of factors other than global mobility.
    Molecular Pharmaceutics 12/2012; 10(2). DOI:10.1021/mp300487u · 4.38 Impact Factor
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    ABSTRACT: Solid-state NMR spectroscopy (SSNMR), coupled with powder X-ray diffraction (PXRD), was used to identify the physical forms of gabapentin in samples prepared by recrystallization, spray drying, dehydration, and milling. Four different crystalline forms of gabapentin were observed: form I, a monohydrate, form II, the most stable at ambient conditions, form III, produced by either recrystallization or milling, and an isomorphous desolvate produced from desolvating the monohydrate. As-received gabapentin (form II) was ball-milled for 45 min in both the presence and absence of hydroxypropylcellulose (HPC). The samples were then stored for 2 days at 50°C under 0% relative humidity and analyzed by (13)C SSNMR and PXRD. High-performance liquid chromatography was run on the samples to determine the amount of degradation product formed before and after storage. The (1)H T (1) values measured for the sample varied from 130 s for the as-received unstressed material without HPC to 11 s for the material that had been ball-milled in the presence of HPC. Samples with longer (1)H T (1) values were substantially more stable than samples that had shorter T (1) values. Samples milled with HPC had detectable form III crystals as well. These results suggest that SSNMR can be used to predict gabapentin stability in formulated products.
    AAPS PharmSciTech 11/2012; 14(1). DOI:10.1208/s12249-012-9879-z · 1.64 Impact Factor

Publication Stats

2k Citations
399.72 Total Impact Points


  • 1990-2015
    • University of Minnesota Duluth
      • • College of Pharmacy
      • • Department of Chemistry and Biochemistry
      Duluth, Minnesota, United States
  • 2002
    • Creighton University
      • Department of Pharmacy Sciences
      Omaha, Nebraska, United States