38 research outputs found
A holistic multi evidence approach to study the fragmentation behaviour of crystalline mannitol
Mannitol is an essential excipient employed in orally disintegrating tablets due to its high palatability. However its fundamental disadvantage is its fragmentation during direct compression, producing mechanically weak tablets. The primary aim of this study was to assess the fracture behaviour of crystalline mannitol in relation to the energy input during direct compression, utilising ball milling as the method of energy input, whilst assessing tablet characteristics of post-milled powders. Results indicated that crystalline mannitol fractured at the hydrophilic (011) plane, as observed through SEM, alongside a reduction in dispersive surface energy. Disintegration times of post-milled tablets were reduced due to the exposure of the hydrophilic plane, whilst more robust tablets were produced. This was shown through higher tablet hardness and increased plastic deformation profiles of the post-milled powders, as observed with a lower yield pressure through an out-of-die Heckel analysis. Evaluation of crystal state using x-ray diffraction/differential scanning calorimetry showed that mannitol predominantly retained the β-polymorph; however x-ray diffraction provided a novel method to calculate energy input into the powders during ball milling. It can be concluded that particle size reduction is a pragmatic strategy to overcome the current limitation of mannitol fragmentation and provide improvements in tablet properties
Effect of Cryogrinding on Chemical Stability of the Sparingly Water-Soluble Drug Furosemide
Purpose To investigate the effect of cryogrinding on chemical
stability of the diuretic agent furosemide and its mixtures with
selected excipients.
Methods Furosemide was ground at liquid nitrogen temperature
for 30, 60, 120 and 180 min. Mixtures of furosemide-PVP
and furosemide-inulin (1:1) were milled under cryogenic conditions.
Materials were analyzed by XRD, UPLC, MS and NMR.
Results Upon increasing the milling time, a significant build-up
of an unidentified impurity 1, probably the main degradation
product, was noticed. Cogrinding of furosemide with PVP and
inulin worsened chemical stabilization of the pharmaceutical.
The main degradation product formed upon cryomilling was
subsequently identified as 4-chloro-5-sulfamoylanthranilic acid
(CSA). Based on some theoretical considerations involving
specific milling conditions, the milling intensity and an expected
specific milling dose have been calculated. Results indicate that
cryogenic grinding is capable to initiate mechanically induced
decomposition of furosemide.Conclusions Cryogenic grinding can activate and accelerate
not only structural changes (solid state amorphization) but also
chemical decomposition of pharmaceuticals. A cryogenic
milling device should be considered as a chemical reactor,
where under favourable conditions chemical reactions could be
mechanically initiated
Solid state amorphization of pharmaceuticals induced by mechanical milling
International audienc
Scaling laws and size effects for amorphous crystallization kinetics: Constraints imposed by nucleation and growth specificities
International audienceIn the present paper we review different aspects of the crystallization of amorphous compounds in relation to specificities of the nucleation and growth rates. Its main purpose is: i) to underline the interest of a scaling analysis of recrystallization kinetics to identify similarities or disparities of experimental kinetic regimes. ii) to highlight the intrinsic link between the nucleation rate and growth rate with a temperature dependent characteristic transformation time Ď„(T), and a characteristic size Îľ(T). The consequences on the influence of the sample size on kinetics of crystallization is considered. The significance of size effect and confinement for amorphous stabilization in the pharmaceutical sciences is discussed
Some facets of molecular disorder in crystalline and amorphous pharmaceutical
International audienc
The technological solutions to enhance the bioavailability of tadalafil
International audienc
Structure determination of phase II of the antifungal drug griseofulvin by powder X-ray diffraction
International audienceTwo new crystalline polymorphs of the widely used antiÂfungal drug griseofulvin (phases II and III), which originate from the crystallization of the melt, have been detected recently. The crystal structure of phase II of griseofulvin {systematic name: (2S,6′R)-7-chloro-2′,4,6-trimethÂoxy-6′-methyl-3H,4′H-spiroÂ[1-benzoÂfuran-2,1′-cycloÂhex-2-ene]-3,4′-dione}, C17H17ClO6, has been solved by powder X-ray diffraction (PXRD). The PXRD pattern of this new phase was recorded at room temperature using synchrotron radiation. The starting structural model was generated by a Monte Carlo simulated annealing method. The final structure was obtained through Rietveld refinement with soft restraints for interÂatomic bond lengths and angles, except for the aromatic ring, where a rigid-body constraint was applied. The symmetry is orthoÂrhomÂbic (space group P212121) and the asymmetric unit contains two molÂecules