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Kakumanu, Vasu Kumar; Bansal, Arvind K.

doi:10.1023/a:1021453810624

Cited by 64 publications

(14 citation statements)

References 13 publications

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“…The amorphous state of HP and DHP could not be generated using either quench cooling, solvent evaporation or lyophilization, thus Tg for HP and DHP was calculated based on the empirical relationship Tg = 0.7 Tm K (Kelvin). The calculated Tg is an estimated rough value [5]. A single Tg was observed with all binary mixtures with PVPK30 at different percentage drug load (DL), suggesting drug polymer miscibility.…”

Section: Resultsmentioning

confidence: 99%

“…In solid dispersions, hydrophilic polymers have been utilized to stabilize the high energy amorphous form of drugs. These polymers offer a solubility advantage by improving wettability, and interfering with crystallization, thus maintaining the molecular dispersion of the drug in solution [5]. As a result, during the last decade, solid dispersions have drawn the attention of formulators as a new tool for improving the bioavailability of poorly-soluble drugs where solubility is limited by high crystallinity [6].…”

Section: Introductionmentioning

confidence: 99%

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Hydrogen Bonding: Between Strengthening the Crystal Packing and Improving Solubility of Three Haloperidol Derivatives

et al. 2016

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Abstract:The purpose of this study is to confirm the impact of polar functional groups on inter and intra-molecular hydrogen bonding in haloperidol (HP) and droperidol (DP) and, hence, their effects on dissolution using a new approach. To confirm our theory, a new molecule: deshydroxy-haloperidol (DHP) was designed and its synthesis was requested from a contract laboratory. The molecule was then studied and compared to DP and HP. Unlike DHP, both the HP and DP molecules have hydrogen donor groups, therefore, DHP was used to confirm the relative effects of the hydrogen donor group on solubility and crystal packing. The solid dispersions of the three structurally related molecules: HP, DP, and DHP were prepared using PVPK30, and characterized using XRPD and IR. A comparative dissolution study was carried out in aqueous medium. The absence of a hydrogen bonding donor group in DHP resulted in an unexpected increase in its aqueous solubility and dissolution rate from solid dispersion, which is attributed to weaker crystal pack. The increased dissolution rate of HP and DP from solid dispersions is attributed to drug-polymer hydrogen bonding that interferes with the drug-drug intermolecular hydrogen bonding and provides thermodynamic stability of the dispersed drug molecules. The drug-drug intermolecular hydrogen bond is the driving force for precipitation and crystal packing.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hydrogen Bonding: Between Strengthening the Crystal Packing and Improving Solubility of Three Haloperidol Derivatives

et al. 2016

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“…[4][5][6][7] The improved stability of these dispersions has been attributed to a number of factors including polymer glass transition temperature (T g ), dispersion T g , molecular mobility, and formation of drug-polymer specific interactions. [8][9][10][11][12] However, there is currently no clearly defined rationale for polymer choice in terms of achieving maximum stabilization of the dispersion. It is clear that in order to better understand the role of the polymers on the physical stability of the resulting solid dispersions, more fundamental studies on crystallization behavior from amorphous systems are required.…”

Section: Introductionmentioning

confidence: 99%

Influence of polymer chemistry on crystal growth inhibition of two chemically diverse organic molecules

2011

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The purpose of this study was to understand how different polymers affect the crystal growth rates of two chemically diverse organic drug molecules (bifonazole and nimesulide) from the undercooled melt regime close to the glass transition temperature. Bifonazole is an antifungal drug that contains no traditional hydrogen bond donors, only acceptors. In contrast, nimesulide contains both hydrogen bond donor and acceptor groups. Therefore, the potential hydrogen bonding interactions with polymers vary between the two compounds. For bifonazole, poly(vinylpyrrolidone) (PVP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), poly(vinylpyrrolidone-vinyl acetate) (PVP/VA) and poly(acrylic acid) (PAA) were investigated, while for nimesulide, PVP, PVP/VA and poly(vinyl acetate) (PVAc) were probed. Polymers were incorporated at a level of 5%w/w by cryomilling followed by melt quenching. Linear crystal growth rates in the presence and absence of polymers were measured as a function of temperature (18-100 C for bifonazole and 18-80 C for nimesulide) using optical microscopy. Differential scanning calorimetry (DSC) and infrared spectroscopy were performed for further characterization. All of the polymers decreased the growth rates of both drugs, however large differences could be observed between polymers in terms of the extent of crystal growth inhibition. For bifonazole, PAA was a notably better crystal growth inhibitor compared to the other polymers. This may be related to formation of specific interactions between the drug and the polymer. For nimesulide, the order of effectiveness was PVP$PVP/VA>PVAc and, compared to bifonazole, differences seen between polymers were more modest. Infrared (IR) spectroscopy and density functional calculations strongly suggested that amorphous nimesulide formed an intramolecular hydrogen bond. IR spectroscopy showed that drug-polymer intermolecular hydrogen bonding did occur, but was hampered by the partial loss of the hydrogen bond donor to the intramolecular hydrogen bond. Hence the effectiveness of a polymer appears to depend not only on the chemistry of the drug, but also on the availability of hydrogen bonding groups.

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“…slowed chemical reactions), as well as resistance towards crystallization [ 28 – 30 ]. Molecular mobility in the vitrified or supercooled state can be evaluated using multiple methods, including dielectric spectroscopy [ 31 , 32 ], isothermal microcalorimetry [ 33 ], nuclear magnetic resonance [ 34 ] and differential scanning calorimetry [ 35 – 37 ].…”

Section: Introductionmentioning

confidence: 99%

Storage stability of liposomes stored at elevated subzero temperatures in DMSO/sucrose mixtures

et al. 2018

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Cryopreservation of biological materials is predominantly done using liquid nitrogen, and its application involves high maintenance costs and the need for periodical refilling of liquid nitrogen. Stable storage in mechanical freezers at −80°C would eliminate these issues and allow for shipment of frozen specimens using dry ice. In this work, the possibility of increasing the storage temperature of cryopreserved samples to −80°C by using combinations of DMSO and sucrose has been studied. Preservation efficacy was studied by measuring stability of liposomes encapsulated with carboxyfluorescein during storage at −150, −80 and −25°C for up to three months. Thermal and molecular mobility properties of the different DMSO-sucrose formulations were measured using differential scanning calorimetry, whereas hydrogen bonding interactions of the formulations were probed by Fourier transform infrared spectroscopy. It was found that addition of sucrose to DMSO solutions increases the Tg, and decreases molecular mobility in the glassy state at a particular temperature. Although it was expected that storage above or close to Tg at −80°C would affect liposome stability, stability was found to be similar compared to that of samples stored at −150°C. Higher molecular mobility in the glassy state could not be associated with faster CF-leakage rates. Distinct differences in storage stability at −25°C, far above Tg, were found among the sucrose/DMSO formulations, which were explained by the differences in permeability of sucrose and DMSO resulting in different levels of osmotic stress in the formulations.

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Cited by 64 publications

References 13 publications

Hydrogen Bonding: Between Strengthening the Crystal Packing and Improving Solubility of Three Haloperidol Derivatives

Hydrogen Bonding: Between Strengthening the Crystal Packing and Improving Solubility of Three Haloperidol Derivatives

Influence of polymer chemistry on crystal growth inhibition of two chemically diverse organic molecules

Storage stability of liposomes stored at elevated subzero temperatures in DMSO/sucrose mixtures

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