Effect of the pH grade of silicates on chemical stability of coground amorphous quinapril hydrochloride and its stabilization using pH-modifiers.

The effect of pH grade of silicates on chemical stability of amorphous drugs coground with silicates (Neusilin and Aerosil) was investigated using quinapril HCl (QHCl) as a model drug. The ability of pH-modifiers (ascorbic acid and MgO) to improve chemical stability was explored. PXRD and polarized light microscopy indicated complete amorphization of all samples by cryo-grinding. All samples remained amorphous during stability study at 40 degrees C and 48% RH. In general, drug degradation was greater in the QHCl/silicate (1:3) coground amorphous samples than the neat amorphous QHCl. The rate of diketopiperazine formation by cyclization of QHCl was higher in the presence of lower pH grades than higher pH grades of silicates. However, the pH-stability profile of coground amorphous systems prepared with different pH grades of silicates was not consistent with the pH-stability profile of the drug in solution. A basic pH-modifier (MgO) in a lower pH grade silicate (Neusilin US2) stabilized coground amorphous QHCl. Also, an acidic pH-modifier (ascorbic acid) in a higher pH grade silicate (Neusilin FL2) suppressed QHCl hydrolysis. The pH grade of silicates is a major factor affecting the chemical stability of a coground amorphous drug and pH-modifiers are useful for chemical stabilization without compromising physical stability.