Studies on the dissolution behavior of doxorubicin hydrochloride freeze-dried product.

Hayakawa, Eiji; Furuya, Kunitoshi; Kuroda, Tokuyuki; Moriyama, Masuo; Kondô, Akira

doi:10.1248/cpb.38.3434

Cited by 10 publications

(4 citation statements)

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“…Theoretically, in comparison to the crystalline state, amorphous compounds would have higher solubility and dissolution because of their higher entropy, enthalpy, and surface free energy. However, much lower dissolution behaviors have been observed on several amorphous drugs than their crystalline counterparts, for example, cefpodoxime proxetil, carvedilol, simvastatin, capecitabine, ritonavir, doxorubicin hydrochloride, and so on. All the above abnormal dissolution behaviors were ascribed to the gelation of amorphous drugs during the dissolution process.…”

Section: Discussionmentioning

confidence: 99%

Incorporation of Complexation into a Coamorphous System Dramatically Enhances Dissolution and Eliminates Gelation of Amorphous Lurasidone Hydrochloride

Heng¹,

Su²,

Cheng³

et al. 2019

Mol. Pharmaceutics

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As a BCS II drug, the atypical antipsychotic agent lurasidone hydrochloride (LH) has low oral bioavailability mainly because of its poor aqueous solubility/dissolution. Unexpectedly, amorphous LH exhibited a much lower dissolution than that of its stable crystalline form arising from its gelation during the dissolution process. In the current study, a supramolecular coamorphous system of LH with l-cysteine hydrochloride (CYS) was prepared and characterized by powder X-ray diffraction and differential scanning calorimetry. Surprisingly, in comparison to crystalline and amorphous LH, such a coamorphous system dramatically enhanced solubility (at least ∼50-fold in the physiological pH range) and dissolution (∼1200-fold) of LH, and exhibited superior physical stability under long-term storage condition. More importantly, the coamorphous system was able to eliminate gelation of amorphous LH during dissolution. In order to further explore the mechanism of such improvement, the internal interactions of the coamorphous system in the solid state and in aqueous solution were investigated. Fourier transform infrared spectroscopy, Raman spectroscopy, and solid-state 13C NMR suggested that intermolecular hydrogen bonds formed between the nitrogen atom in the benzisothiazole ring of LH and the NH3 + group of CYS after coamorphization. A fluorescence quenching test with a Stern–Volmer plot and density functional theory modeling, phase-solubility study, and NMR test in D2O indicated that ground-state complexation occurred between LH and CYS in aqueous solution, which contributed to the solubility and dissolution enhancement of LH. The current study offers a promising strategy to overcome poor solubility/dissolution and be able to eliminate gelation of amorphous materials by coamorphization and complexation.

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Section: Discussionmentioning

confidence: 99%

Incorporation of Complexation into a Coamorphous System Dramatically Enhances Dissolution and Eliminates Gelation of Amorphous Lurasidone Hydrochloride

Heng¹,

Su²,

Cheng³

et al. 2019

Mol. Pharmaceutics

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show abstract

“…Despite its relatively low molar mass (580 g/mol), it exhibits features typical of high molecular weight species, such as the capability to act as a water gelator. This feature has been described in several papers back in the nineties [5][6] [7] [8] and has recently been the subject of a deep investigation that revealed the peculiar association of DX molecules into supramolecular aggregates made of hundreds of units (distorted dimers). [9] Interestingly, the closely related molecule epirubicin hydrochloride, that differs from DX only for the stereochemistry at the C4' carbon atom in the aminosugar moiety of the drug, does not form gels in the same conditions that induce DX gelling.…”

mentioning

confidence: 96%

The self-association equilibria of doxorubicin at high concentration and ionic strength characterized by fluorescence spectroscopy and molecular dynamics simulations

Tasca

Alba

Galantini

et al. 2019

Colloids and Surfaces A: Physicochemical and Engineering Aspect

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Graphical abstract ABSTRACTThe self-association equilibria of doxorubicin hydrochloride (DX), at high drug and NaCl concentrations, are studied by temperature scan fluorescence spectroscopy, with the support of molecular dynamics (MD) calculations. Even though all anthracyclines show dimerization equilibria, DX only can further associate into long polymeric chains according to DXmon ⇄ DXdim ⇄ DXpol. This is reflected not only in the mechanical properties of DXpol solutions (behaving as thixotropic gels) but also in their spectroscopic behaviour. Fluorescence, in particular, is the technique of election to study this complex set of equilibria. Upon increasing the temperature, DXpol melts into DXdim, which in turn is in equilibrium with DXmon. Since DXdim is non fluorescent, with a fluorescence temperature scan experiment the DXpol⇄ DXmon equilibrium is probed. However, also information on the DX dimerization equilibrium can be derived together with the relevant thermodynamic parameters ruling the dimerization process (ΔH dim°= −56 kJ mol −1 ; ΔS dim°= −97 J mol −1 K −1 ). The residence time of DX molecules in the dimer (74.7 μs), as well as the monomers mutual orientation in the dimer, are characterized by means of theoretical and computational modelling.

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“…However, permeation measurements indicate that, although DX dimers are mainly present at low drug concentration, larger aggregates composed of about 40 molecules are present at DX concentrations above 0.5 mg mL −1 . Furthermore, it is known that aqueous solutions of DX, at concentrations above a threshold value, form self‐standing gels in the presence of simple inorganic salts . This behaviour is incompatible with mere dimerisation because the mechanism of jellification by low‐molecular‐weight gelators unavoidably requires the self‐assembly of small molecules into long, anisotropic structures (usually fibres) .…”

Section: Introductionmentioning

confidence: 99%

“…[18] Furthermore, it is known that aqueous solutions of DX, at concentrations above at hreshold value, form self-standing gels in the presence of simple inorganic salts. [19,20] This behaviour is incompatible with mere dimerisation because the mechanismo fj ellification by low-molecular-weight gelators unavoidably requires the self-assembly of small molecules into long, anisotropic structures (usually fibres). [21,22] Molecular gels are indeed composed of zero-dimensional units that interact non-covalently to give rise to 1D polymerico bjects.…”

Section: Introductionmentioning

confidence: 99%

A Stereochemically Driven Supramolecular Polymerisation

Tasca

D’Abramo

Galantini

et al. 2018

Chemistry A European J

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Anthracyclines self-assemble in water into dimers. In the presence of sufficiently high salt (NaCl) concentrations, solutions of the antibiotic doxorubicin, but not those of the closely related molecules daunomycin and epirubicin, turn into gels barely compatible with the presence of small oligomers. The use of spectroscopic, scattering, imaging and computational techniques, allowed light to be shed on the self-assembly process that triggered doxorubicin gelification. A complex picture emerged, with doxorubicin molecules assembled into long, highly chiral, supramolecular aggregates made of hundreds of units, showing redshifted fluorescence spectra, very short fluorescence lifetimes and small-angle X-ray scattering profiles compatible with long cylinders. The involvement of specific chemical groups and the need for a specific stereochemistry of the monomers in the formation of a hydrogen-bond network to stabilise the supramolecular aggregates was supported by molecular dynamics calculations. A salt-induced, temperature-dependent, cooperative nucleation-elongation supramolecular polymerisation of the doxorubicin molecules is deduced.

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Studies on the dissolution behavior of doxorubicin hydrochloride freeze-dried product.

Cited by 10 publications

References 0 publications

Incorporation of Complexation into a Coamorphous System Dramatically Enhances Dissolution and Eliminates Gelation of Amorphous Lurasidone Hydrochloride

Incorporation of Complexation into a Coamorphous System Dramatically Enhances Dissolution and Eliminates Gelation of Amorphous Lurasidone Hydrochloride

The self-association equilibria of doxorubicin at high concentration and ionic strength characterized by fluorescence spectroscopy and molecular dynamics simulations

A Stereochemically Driven Supramolecular Polymerisation

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