Formation of physically stable amorphous drugs by milling with Neusilin

Abstract

Each of four drugs (ketoprofen, indomethacin, naproxen, and progesterone) was milled with Neusilin (amorphous magnesium aluminosilicate) to effect conversion from crystalline to amorphous states, and the physical stability of the resultant drugs was investigated. Ball milling the drugs alone for 48 h resulted in no amorphization. X-ray powder diffractometry (XPD), birefringence, and differential scanning calorimetry (DSC) data indicated amorphization of all the four drugs on ball milling with Neusilin. Fourier transform infrared spectroscopy (FTIR) data showed a reduction in the absorbance of the free and the hydrogen-bonded acid carbonyl peaks accompanied by a corresponding increase in the absorbance of the carboxylate peak, indicating an acid-base reaction between the carboxylic acid-containing drugs and Neusilin on milling. On storage of milled powders (at 40 degrees C and 75% RH for 4 weeks), XPD, birefringence, and DSC data showed the absence of reversion to the crystalline state, and FTIR data revealed continued absence of the carbonyl peaks. Whereas the carboxylic acid-containing drugs convert from their crystalline acid form to amorphous salt form on milling with Neusilin, progesterone seems to interact with Neusilin via hydrogen bonding. The amorphous Neusilin-bound states of all four drugs were physically stable during storage. The water of adsorption seems to mediate the conversion of the crystalline state to an amorphous Neusilin-bound state.