Interaction of naproxen with noncrystalline acetyl β- and acetyl γ-cyclodextrins in the solid and liquid state

Abstract

Randomly acetylated, amorphous β-cyclodextrin (AcβCd) and γ-cyclodextrin (AcγCd), having an average substitution degree per anhydroglucose unit, respectively, of 1.1 and 0.95 (∼7.7 acetyl residues per macrocycle), were investigated for their interactions in the solid and liquid state with naproxen (NAP). Differential scanning calorimetry (DSC), supported by X-ray powder diffractometry (XRD), of NAP–AcβCd and NAP–AcγCd blends revealed an apparent decrease in drug crystallinity which was related to a heating-induced solid-state interaction between the drug and each carrier. A solubility of ∼0.40 NAP mass fraction in amorphous AcβCd and amorphous AcγCd at room temperature was determined. Phase-solubility analysis at 25, 37, and 45°C accounted for A L-type inclusion complexation of NAP with AcβCd ( K 1:1,25°C=4.5(4)×10 3 l mol −1) and AcγCd ( K 1:1,25°C=0.80(7)×10 3 l mol −1) and revealed a solubilizing efficiency of AcβCd toward NAP ∼4 times that of AcγCd. Equimolar drug–carrier combinations prepared from the respective blends by grinding, kneading, coevaporation and freeze-drying were characterized by DSC and XRD and tested for dissolution rate of NAP using the dispersed amount and continuous flow through methods. The best performance in terms of dissolution rate enhancement (∼23 times and ∼10 times the dissolution efficiency of pure drug in the dispersed amount and continuous flow through tests, respectively) was displayed by the NAP–AcβCd colyophilized product.