The Influence of Thermal and Mechanical Preparative Techniques on the Amorphous State of Four Poorly Soluble Compounds

Patterson, James E.; James, Michael B.; Forster, Angus; Lancaster, Robert W.; Butler, James; Rades, Thomas

doi:10.1002/jps.20424

Cited by 127 publications

(88 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…T 1 H is sensitive to motional processes of the order of the 1 H NMR frequency, 25 here 300 MHz, and is typically sensitive to high-frequency local motions. The Wideline measurements of T 1 H provide an overview of high-frequency local motions which can be refined by measurements of 13 C T 1 relaxation times (at the expense of greatly increased experimental time), since these provide information on site-specific dynamics. The detailed values are given in Table SI of the Supporting Information and the results for characteristic carbons are shown in Figure 7.…”

Section: Molecular Mobility From Nmr Relaxation Timesmentioning

confidence: 99%

“…These differences are much smaller than those typically observed between amorphous and truly crystalline materials. 24 Experiments to measure site-specific 1 H T 1ρ values by transferring the partially relaxed 1 H magnetisation to 13 C via cross-polarisation prior to measurement were relatively uninformative, showing uniform behaviour across sites, cf. Figure S9 and Table SII of Supporting Information, although again a more step-like character to the temperature dependence was observed for the AR material.…”

Section: Molecular Mobility From Nmr Relaxation Timesmentioning

confidence: 99%

“…Supporting Information mentioned in the main text: X-ray diffractograms of AR and AM forms of valsartan; plots of 13 …”

Section: Supporting Informationmentioning

confidence: 99%

See 2 more Smart Citations

Characterization of Two Distinct Amorphous Forms of Valsartan by Solid-State NMR

et al. 2015

View full text Add to dashboard Cite

Valsartan (VAL) is an antihypertensive drug marketed in an amorphous form. Amorphous materials can have different physicochemical properties depending on preparation method, thermal history, etc., but the nature of such materials is difficult to study by diffraction techniques. This study characterizes two different amorphous forms of valsartan (AR and AM) using solid-state NMR (SSNMR) as a primary investigation tool, supported by solution-state NMR, FT-IR, TMDSC, and dissolution tests. The two forms are found to be clearly distinct, with a significantly higher level of structural arrangement in the AR form, as observed in 13C, 15N, and 1H SSNMR. 13C and 15N NMR indicates that the fully amorphous material (AM) contains an approximately equal ratio of cis–trans conformers about the amide bond, whereas the AR form exists mainly as one conformer, with minor conformational “defects”. 1H ultrafast MAS NMR shows significant differences in the hydrogen bonding involving the tetrazole and acid hydrogens between the two materials, while 15N NMR shows that both forms exist as a 1,2,3,4-tetrazole tautomer. NMR relaxation times show subtle differences in local and bulk molecular mobility, which can be connected with the glass transition, the stability of the glassy material, and its response to aging. Counterintuitively the fully amorphous material is found to have a significantly lower dissolution rate than the apparently more ordered AR material.

show abstract

Section: Molecular Mobility From Nmr Relaxation Timesmentioning

confidence: 99%

Section: Molecular Mobility From Nmr Relaxation Timesmentioning

confidence: 99%

See 1 more Smart Citation

Characterization of Two Distinct Amorphous Forms of Valsartan by Solid-State NMR

et al. 2015

View full text Add to dashboard Cite

show abstract

“…The amorphous glass state has however the disadvantage of being thermodynamically unstable against the nucleation of crystalline phases (Bhardwaj et al, 2013;Zhou et al, 2002). The microscopic mechanisms governing the kinetic stability of amorphous API remains unclear, and the crystallization kinetics appears to be determined by a large number of factors such as preparation method, thermal and mechanical treatments employed during formulation (Patterson et al, 2005), storage temperature, application of pressure or exposure to humidity (Yu, 2001). It is generally found that storage well below the glass transition temperature T g (e.g., at T g -50 K) prevents crystallization of the amorphous state and thus ensures a physically stable drug during its shelf-life (Capen et al, 2012;Pogna et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Collective relaxation dynamics and crystallization kinetics of the amorphous Biclotymol antiseptic

Tripathi

Romanini

Tamarit

et al. 2015

International Journal of Pharmaceutics

View full text Add to dashboard Cite

We employ dielectric spectroscopy to monitor the relaxation dynamics and crystallization kinetics of the Biclotymol antiseptic in its amorphous phase. The glass transition temperature of the material as determined by dielectric spectroscopy is T g = 290±1 K. The primary (α) relaxation dynamics is observed to follow a Vogel-Fulcher-Tammann temperature dependence, with a kinetic fragility index m = 86±13, which classifies Biclotymol as a relatively fragile glass former. A secondary relaxation is also observed, corresponding to an intramolecular dynamic process of the non-rigid Biclotymol molecule. The crystallization kinetics, measured at four different temperatures above the glass transition temperature, follows an Avrami behavior with exponent virtually equal to n = 2, indicating one-dimensional crystallization into needle-like crystallites, as experimentally observed, with a time-constant nucleation rate. The activation barrier for crystallization is found to be E a = 115±22 kJ mol -1 .

show abstract

“…The drug is dispersed in a polymer on a molecular level and a single homogeneous amorphous solid is formed, in many cases aided by drug-polymer intermolecular interactions (e.g. the formation of hydrogen bonds between the drug and polymer) (Patterson et al, 2005;Vasconcelos et al, 2007). The capability of the polymer to inhibit crystallisation of the amorphous form has been reported to be possible also at low polymer concentrations (Van den Mooter et al, 2001), and nucleation and crystal growth of the amorphous drug is inhibited by the intermolecular interactions.…”

Section: Introductionmentioning

confidence: 99%

Stabilisation of amorphous furosemide increases the oral drug bioavailability in rats

Nielsen

Rades

2015

International Journal of Pharmaceutics

Self Cite

View full text Add to dashboard Cite

A glass solution of the amorphous sodium salt of furosemide (ASSF) and polyvinylpyrrolidone (PVP) (80:20 w/w%) was prepared by spray drying. It was investigated if PVP was able to stabilise ASSF during storage and dissolution and whether this influenced the in vivo performance of the glass solution after oral dosing to rats. The glass solution had a glass transition temperature of 121.3±0.5°C, which was significantly higher than that of the pure drug (101.2°C). ASSF in the glass solution was stable for at least 168 days when stored at 20°C and 0% relative humidity. The glass solution exhibited fast dissolution in simulated intestinal medium, pH 6.5; the intrinsic dissolution rate was found to be 10.1±0.6 mg/cm 2 /min, which was significantly faster than the pure ASSF. When investigating the stability during dissolution in stimulated intestinal medium at pH 6.5, the ASSF in the glass solution showed signs of crystallinity after 1 min of dissolution, but crystallised to a lesser extent than pure ASSF. The stabilising effect of PVP on ASSF, led to improved relative oral bioavailability in rats of 263%, when compared to the pure ASSF.

show abstract

The Influence of Thermal and Mechanical Preparative Techniques on the Amorphous State of Four Poorly Soluble Compounds

Cited by 127 publications

References 15 publications

Characterization of Two Distinct Amorphous Forms of Valsartan by Solid-State NMR

Characterization of Two Distinct Amorphous Forms of Valsartan by Solid-State NMR

Collective relaxation dynamics and crystallization kinetics of the amorphous Biclotymol antiseptic

Stabilisation of amorphous furosemide increases the oral drug bioavailability in rats

Contact Info

Product

Resources

About