A comparative assessment of solubility advantage from glassy and crystalline forms of a water-insoluble drug

Chawla, Garima; Bansal, Arvind K.

doi:10.1016/j.ejps.2007.05.111

Cited by 66 publications

(48 citation statements)

References 19 publications

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“…Even though there was a decrease in T g from 345 K to 321 K to 318 K in 0 to 2 to 6 h and √ t became 0.15 within 2 h at 75 % RH (as seen in the earlier section), crystallization was not seen in amorphous IBS in the presence of moisture. The results were concordant with the solubility studies reported earlier by the authors where complete devitrification occurred after 6 h of complete immersion of amorphous sample into the dissolution medium [11]. …”

Section: Physical Stability Studiessupporting

confidence: 82%

“…Amorphous IBS has pharmaceutical advantages which were highlighted in a previous study by the authors, where amorphous IBS showed a 2.5 folds increase in the solubility over the crystalline form [11]. Thus, amorphous IBS can be used to design a stable drug product exhibiting an enhanced solubility.…”

Section: δHmentioning

confidence: 83%

“…The sharp fusion endotherm at 456 K in DSC, the powder X-ray diffraction (PXRD) pattern and the Fourier transfer infrared (FTIR) spectra revealed that the sample of crystalline IBS to be the polymorphic form A (low melting, metastable form) without any contamination from other polymorphic forms [11]. DSC of the in situ quench-cooled IBS exhibited a sigmoid shape endotherm (glass transition) at 344.7 K ± 1.0 K (onset T g ), which is a reflection of the gradual softening of a glass to its ultraviscous equilibrium liquid state.…”

Section: Resultsmentioning

confidence: 99%

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Molecular Mobility and Physical Stability of Amorphous Irbesartan

Chawla

2009

Sci. Pharm.

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Amorphous systems have attracted considerable attention due to their favorable properties; however, their stability issues still pose a major challenge. The purpose of the present work was to investigate the role of molecular mobility and moisture in the physical stability of a selected pharmaceutical amorphous system. Irbesartan (IBS), a relatively stable glass, was chosen as the model drug, as it exhibits a good physical stability (resistance to crystallization) at temperatures below the glass transition (T g -50 K). The amorphous system was annealed at temperatures 298 K (25 °C) and 313 K (40 °C) at 0 and 75 % RH to study the effect of temperature and moisture on its relaxation behavior. Differential scanning calorimetry (DSC) was used to characterize both the crystalline and the freshly prepared glass, and to monitor the extent of relaxation at temperatures below glass transition (Tg) as well as heat capacity changes as a function of temperature. Molecular relaxation time constant (τ) decreased drastically from 302 years to 68 hours with the increase in annealing temperature as determined by Kohlrausch-William-Watts (KWW) equation. IBS was found to be 'relatively' stable in the amorphous state and presented a challenge for temporal measurements. Hence, at low annealing temperatures, (T g -50 K or below) initial relaxation time (τ 0 ) was estimated using the calorimetric based approach. Amorphous IBS was non-hygroscopic and retained its glassy nature under the accelerated stability conditions. The extent of relaxation in the amorphous drug in the presence of moisture was also estimated.

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Section: Physical Stability Studiessupporting

confidence: 82%

Section: δHmentioning

confidence: 83%

Section: Resultsmentioning

confidence: 99%

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Molecular Mobility and Physical Stability of Amorphous Irbesartan

Chawla

2009

Sci. Pharm.

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“…However, the actual solubility enhancement is limited owing to a devitrification process that takes place upon exposure to an aqueous environment. This effect is believed to be overcome by preparing solid dispersions using polymers with a high glass transition temperature (T g ) [10]. Despite their sometimes poor physical stability, solid dispersions have been shown to slow down devitrification, enhance wettability and effectively disperse drugs in polymer matrices [5,11].…”

Section: Introductionmentioning

confidence: 99%

Release profile and characteristics of electrosprayed particles for oral delivery of a practically insoluble drug

Bohr

Kristensen²,

Dyas³

et al. 2012

J. R. Soc. Interface.

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acid) (PLGA) microspheres containing celecoxib were prepared via electrospraying, and the influence of three processing parameters namely flow rate, solute concentration and drug loading, on the physico-chemical properties of the particles and the drug-release profile was studied. Microspheres with diameters between 2 and 8 mm were produced and a near-monodisperse size distribution was achieved ( polydispersivity indices of 6-12%). Further, the inner structure of the particles showed that the internal porosity of the particles increased with increasing solvent concentration. X-ray powder diffraction (XRPD) analysis indicated that the drug was amorphous and remained stable after eight months of storage. Drug release was studied in USP 2 (United States Pharmacopeia Dissolution Apparatus 2) dissolution chambers, and differences in release profiles were observed depending on the parametric values. Changes in release rate were found to be directly related to the influence of the studied parameters on particle size and porosity. The results indicate that electrospraying is an attractive technique for producing drug-loaded microspheres that can be tailored towards an intended drug-delivery application. Compared with the more conventional spray-drying process, it provides better control of particle characteristics and less aggregation during particle formation. In particular, this study demonstrated its suitability for preparing capsules in which the drug is molecularly dispersed and released in a sustained manner to facilitate improved bioavailability.

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“…IBS, 2-butyl-3-[[29-(1H-tetrazol-5-yl) [1,19-biphenyl]-4-yl] methyl]1,3-diazaspiro [4,4] non-1-en-4-one ( Fig. 1), is a potent long acting non-peptide AII receptor antagonist used in the treatment of hypertension (6). IBS was chosen as a model candidate because of its low dissolution rate and solubility-limited bioavailability (7).…”

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confidence: 99%

Improved dissolution of a poorly water soluble drug in solid dispersions with polymeric and non-polymeric hydrophilic additives

Chawla¹,

Bansal²

2008

Acta Pharmaceutica

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Aqueous solubility of a drug can be a critical limitation to its oral absorption. Lipophilic molecules, especially those belonging to the biopharmaceutics classification system (BCS) class II and IV, dissolve slowly, poorly and irregularly, and hence pose serious delivery challenges, like incomplete release from the dosage form, poor bioavailability, increased food effect, and high inter-patient variability (1). Many solubilization techniques have been described that either change the nature of the solvent environment (co- Irbesartan (IBS) is a hydrophobic drug with poor aqueous solubility and dissolution rate. Solid dispersions (SDs) of IBS were prepared with both small molecules (tartaric acid and mannitol) and polymeric additives (polyvinylpyrrolidone, PVP, and hydroxypropyl methylcellulose, HPMC). A 9.5 and 7 folds enhancement in solubility over the crystalline form (14.6 mg mL -1 ) was observed for tartaric acid (138 mg mL -1 ) and PVP (103 mg mL -1 ), respectively. Powder X-ray diffraction confirmed that IBS existed in the glassy state in all cases, even with excipients having low glass transition temperature. Thermal methods (differential scanning calorimetry and hot stage microscopy) were used to evaluate the miscibility of the drug and additives. These techniques suggested that tartaric acid led to generation of »amorphous solutions« in contrast to »amorphous suspensions« in other three cases.The in vitro dissolution of IBS depended on the additive load and increased with increasing concentration in the case of tartaric acid, an acidifying excipient. The results indicate the suitability of even small molecules for providing solubility benefits, which can be attributed to the good glass forming ability and reasonable ability of IBS to remain in the glassy state.

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A comparative assessment of solubility advantage from glassy and crystalline forms of a water-insoluble drug

Cited by 66 publications

References 19 publications

Molecular Mobility and Physical Stability of Amorphous Irbesartan

Molecular Mobility and Physical Stability of Amorphous Irbesartan

Release profile and characteristics of electrosprayed particles for oral delivery of a practically insoluble drug

Improved dissolution of a poorly water soluble drug in solid dispersions with polymeric and non-polymeric hydrophilic additives

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