Molecular reactivity of busulfan through its experimental electrostatic properties in the solid state.
OBJECTIVE
In the route of developing novel liquid phase formulations based on the encapsulation of busulfan into liposomes in nontoxic solvents, drug crystallization inevitably occurs. In order to better understand the reactivity of busulfan, the characterization of its molecular properties was therefore considered as a key point. Also, preliminary attempts to prevent crystallization using cyclodextrins were explored.


METHODS
An accurate single-crystal high-resolution X-ray diffraction experiment at 100 K has been carried out. The experimental electron density of busulfan was refined using a multipole model. Busulfan/beta-cyclodextrin coprecipitates were analyzed by powder X-ray diffraction and 1H-NMR spectroscopy.


RESULTS
The electrostatic properties of busulfan and the methylsulfonate fragment dipole moment (3.2 D) were determined. The polar moieties play a key role in the crystallization of busulfan, which presents a nucleophilic region surrounding the sulfonate part, whereas the carbon chain displays an electrophilic character. This highlights the subtle busulfan/beta-cyclodextrin association.


CONCLUSIONS
Busulfan electrostatic properties were used to quantify its chemical reactivity. This explains the difficulty to formulate busulfan into liposomes due to a strong polar character of the methylsulfonate terminal groups. The complexation with cyclodextrins deserves to be further investigated to allow the formulation of busulfan in nontoxic solvents.
Ghermani
Nour Eddine
NE
Laboratoire Physico-Chimie, Pharmacotechnie, Biopharmacie (PPB) UMR CNRS 8612, Faculté de Pharmacie, Université Paris XI, 92296 Châtenay-Malabry Cedex, France. noureddine.ghermani@cep.u-psud.fr
Spasojević-de Biré
Anne
A
Bouhmaida
Nouzha
N
Ouharzoune
Souad
S
Bouligand
Jérôme
J
Layre
Anne
A
Gref
Ruxandra
R
Couvreur
Patrick
P
D002066:Busulfan / Q000737:chemistry*; D003460:Crystallization; D008968:Molecular Conformation; D055672:Static Electricity
D002066:Busulfan