Effect of milling conditions on the solid-state conversion of ranitidine hydrochloride form 1

Powder samples of ranitidine hydrochloride forms 1 and 2 were milled using a vibrational ball mill (Retsch MM301) for periods up to 240min at 4, 12 and 35 degrees C. X-ray powder diffraction (XRPD), diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), solid-state nuclear magnetic resonance (NMR) and differential scanning calorimetry (DSC) were used to monitor solid-state properties of the milled samples. Milling of form 1 at 4 degrees C led to a powder temperature of 36 degrees C in the milling chamber and produced only amorphous drug; at 12 degrees C (powder temperature 45 degrees C) and at 35 degrees C (powder temperature 62 degrees C) progressive transformation of form 1 via amorphous drug to form 2 occurred. DSC of the milled samples showed a glass transition at 13-30 degrees C and a crystallization exotherm (T(c)) between 30 and 65 degrees C if the sample contained amorphous drug. The behaviour of the solid was speculated to be influenced by the relationship between powder temperature and T(c); at powder temperatures below T(c), amorphous drug is formed but no crystallization of form 2 occurs; at temperatures close to T(c), amorphous content initially increases with transformation to form 2 on continued milling. At temperatures much higher than T(c), at intermediate stages, less amorphous drug but both form 1 and form 2 are recovered, but continued milling gives only form 2. Form 2 did not transform to form 1 under any conditions used in this study.