Interaction of naproxen with alpha-cyclodextrin and its noncyclic analog maltohexaose.
OBJECTIVE
To study the effect of mechanical grinding on crystallinity changes of naproxen (NAP) in mixtures with alpha-cyclodextrin (alphaCd), amorphous alphaCd, and maltohexaose (M6); and the possible formation of a pseudo-inclusion complex between NAP and M6 in aqueous solution.


METHODS
NAP-additive physical mixtures at 0.30, 0.18, and 0.10 mass fraction of drug were tested, after increasing grinding times, by differential scanning calorimetry (DSC) and X-ray powder diffractometry (XRD). Interaction in aqueous solution was examined by phase-solubility and fluorescence analyses supported by molecular modelling.


RESULTS
In the mixtures with each additive the fusion enthalpy per unit mass of NAP decreased and the half width at half maximum of selected X-ray diffraction peaks of NAP increased with the progress of grinding time following the loss of crystallinity of the samples. The mechanical treatment apparently did not affect the chemical integrity of the drug. Particularly active in the equimolar mixture was the best amorphizing agent, M6. Solution studies and molecular modelling confirmed M6 may have the feature of a supermolecule for NAP, which forms a 1:1 pseudo-inclusion complex that was as stable as the true inclusion complex with alphaCd.


CONCLUSIONS
The intrinsically amorphous linear analog of aCd might be a potential amorphism-inducing agent and solubilizer for scarcely water soluble drugs.
Bettinetti
G
G
Dipartimento di Chimica Farmaceutica, Università di Pavia, Italy. betti@chifar.unipv.it
Sorrenti
M
M
Negri
A
A
Setti
M
M
Mura
P
P
Melani
F
F
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D018360:Crystallography, X-Ray; D003505:Cyclodextrins / Q000737:chemistry*; D004347:Drug Interactions; D008958:Models, Molecular; D009288:Naproxen / Q000737:chemistry*; D009844:Oligosaccharides / Q000737:chemistry*; D012995:Solubility; D013696:Temperature; D013818:Thermogravimetry; D014867:Water / Q000737:chemistry; D047391:alpha-Cyclodextrins
D000894:Anti-Inflammatory Agents, Non-Steroidal; D003505:Cyclodextrins; D009844:Oligosaccharides; D047391:alpha-Cyclodextrins; D014867:Water; C016549:maltohexaose; D009288:Naproxen; C032613:alpha-cyclodextrin