Prediction of Onset of Crystallization from Experimental Relaxation Times. II. Comparison between Predicted and Experimental Onset Times

Bhugra, Chandan; Shmeis, Rama; Krill, Steven L.; Pikal, Michael J.

doi:10.1002/jps.21162

Cited by 73 publications

(89 citation statements)

References 25 publications

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“…Most of these studies have been performed on single component systems. [126][127][128] In one particular publication, however, they included solid dispersions of phenobarbital with 8% w/w of PVP or l-proline. [129] The crystallization rates were followed using microscopy at different temperatures above Tg, and one point below Tg, after crystallization was first induced above Tg.…”

Section: The Role Of Hydrogen Bondsmentioning

confidence: 99%

Review: physical chemistry of solid dispersions

2009

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Objectives With poorly soluble drug candidates emerging in the drug discovery pipeline, the importance of the solid dispersion formulation approach is increasing. This strategy includes complete removal of drug crystallinity, and molecular dispersion of the poorly soluble compound in a hydrophilic polymeric carrier. The potential of this technique to increase oral absorption and hence bioavailability is enormous. Nevertheless, some issues have to be considered regarding thermodynamic instability, as well in supersaturated solutions that are formed upon dissolution as in the solid state. Key findings After a brief discussion on the historical background of solid dispersions and their current role in formulation, an overview will be given on the physical chemistry and stability of glass solutions as they form supersaturated solutions, and during their shelf life. Conclusions Thorough understanding of these aspects will elicit conscious evaluation of carrier properties and eventually facilitate rational excipient selection. Thus, full exploitation of the solid dispersion strategy may provide an appropriate answer to drug attrition due to low aqueous solubility in later stages of development.

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Section: The Role Of Hydrogen Bondsmentioning

confidence: 99%

Review: physical chemistry of solid dispersions

2009

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“…As pointed out earlier, while nifedipine and felodipine have nearly identical T g values ($428C), felodipine is much more resistant to crystallization than nifedipine. 11,15 Bhugra et al 11 found a significant curvature in a log-log plot of correlation between crystallization onset times and dielectric relaxation times in amorphous nifedipine near T g . The curvature reflects much lower crystallization onset times than expected.…”

Section: Implications Of B-relaxations On the Physical Stability Of Smentioning

confidence: 99%

“…Crystallization (or at least evidence of nucleation) in amorphous pharmaceuticals has been reported upon storage at temperatures much below the T g for times much less than the typical pharmaceutical shelf-life of 2 years. 7,[10][11][12] It is clear that if the local motions are directly involved in causing crystallization, then storage even below (T g À 50) could result in crystallization over the shelf-life. Thus the long held belief of ''negligible'' contribution of mobility towards instability at temperatures at or below (T g À 50) 13,14 may be considered to be invalid.…”

Section: Introductionmentioning

confidence: 99%

Local Mobility in Amorphous Pharmaceuticals—Characterization and Implications on Stability

Bhattacharya

Suryanarayanan

2009

Journal of Pharmaceutical Sciences

206

166

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“…It was reported that the crystallization onset times measured above the T g were both well correlated and well coupled with the measured molecular mobility. 12) On the other hand, detailed understanding of the relationship between the mobility and stability of amorphous materials is still forthcoming, especially below T g . 14) There- fore, it was considered suitable to compare the physical stability at a temperature above T g of amorphous troglitazones.…”

Section: Resultsmentioning

confidence: 99%

“…11) Bhugra et al reported that crystallization onset times measured above the glass transition temperature (T g ) were well correlated with the relaxation time. 12) On the other hand, it was reported that predictions of stability can not be made based on mobility alone, although relaxation time is one of the most important factors involved in the recrystallization process. 7,13) When the molecular mobility was focused on, the molecular weight showed the inverse relationship with mobility.…”

mentioning

confidence: 99%

Do Amorphous Troglitazones Prepared from Two Diastereomer-Pairs Have the Same Molecular Mobility and Crystallization Rate at the Surface?

Furuyama

Hasegawa

Yada

et al. 2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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Amorphization of poorly water soluble drugs is useful in terms of the improvement of dissolution rate and bioavailability because amorphous compounds possess higher energy than their crystalline forms. 1,2) On the other hand, amorphous compounds are thermodynamically unstable and may crystallize during storage. [3][4][5] Owing to the physical instability of amorphous compounds, product development and regulatory approval may become difficult unless it can be demonstrated that conversion to the crystalline state during handling and storage periods will not occur. 6) Although the storage experiments are conducted to predict the stability of amorphous compounds, this is a time-and material-consuming method. 7)Therefore, it is preferable to be able to evaluate the physical stability of amorphous compounds more easily.Amorphous compounds change their physical and thermodynamic characteristics until they reach a metastable state. 8)As freshly prepared amorphous compounds move toward a more equilibrium state, energy decreases, free volume decreases, and structural order increases.9,10) This process is known as structural relaxation. Many studies used structural relaxation time as an indicator of molecular mobility. 11)Bhugra et al. reported that crystallization onset times measured above the glass transition temperature (T g ) were well correlated with the relaxation time.12) On the other hand, it was reported that predictions of stability can not be made based on mobility alone, although relaxation time is one of the most important factors involved in the recrystallization process.7,13) When the molecular mobility was focused on, the molecular weight showed the inverse relationship with mobility.14)The molecule at the surface of amorphous compounds has enhanced molecular mobility. [15][16][17] In addition, the surface of amorphous compounds is thought to be easily affected by the external environment such as humidity and temperature. It was reported that crystallization at the amorphous surface was faster than that of the bulk. 18,19) The surface affects crystal nucleation and the rate of crystal growth. 19) This implied that an amorphous surface and the bulk may show different properties. It is important to evaluate properties at the surface in terms of physical stability of amorphous compounds. 20)Inverse gas chromatography (iGC) is becoming popular in the pharmaceutical sector.21) Many studies using iGC have been reported. [22][23][24] Planinšek et al. reported that the surface amorphization rate of indomethacin during milling evaluated by surface energy using iGC, was higher than that of bulk evaluated by crystallization enthalpy and temperature using differential scanning calorimetry (DSC). 25) This means that iGC seems suitable for the characterization of surface properties.Troglitazone, used as the model drug in this study, has two asymmetric carbons and the drug substance is produced as a mixture of equal amounts of four isomers. These isomers are composed of two diastereomer-pairs, RR/SS and RS/SR, which have...

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Prediction of Onset of Crystallization from Experimental Relaxation Times. II. Comparison between Predicted and Experimental Onset Times

Cited by 73 publications

References 25 publications

Review: physical chemistry of solid dispersions

Review: physical chemistry of solid dispersions

Local Mobility in Amorphous Pharmaceuticals—Characterization and Implications on Stability

Do Amorphous Troglitazones Prepared from Two Diastereomer-Pairs Have the Same Molecular Mobility and Crystallization Rate at the Surface?

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