Understanding Concomitant Physical and Chemical Transformations of Simvastatin During Dry Ball Milling

Dattatray Modhave, Isha Saraf, Anjali Karn, Amrit Paudel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


The present study investigates concomitant processes of solid-state disordering and oxidation of simvastatin during milling. The separate dry ball milling of crystalline and amorphous powders of simvastatin were conducted at ambient temperature for 10 and 60 min each. The relative crystallinity was determined using X-ray scattering and oxidative degradation was analyzed using liquid chromatography. The physical and chemical transformations in the milled powder were evaluated using modulated differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy. The disordering during milling of the crystalline powder was found to progressively decrease the crystallinity. For the amorphous starting material, milling for 10 min induced a large extent of recrystallization, while milling for 60 min largely re-amorphized the powder. This solid-state disordering and/or ordering were accompanied by progressive air oxidation during milling. The infrared spectroscopic analysis revealed the molecular manifestations associated with the physicochemical transformations in the disordered solid states. The melting point of simvastatin depressed systematically with the increase in the degree of disorder as well as the degradation. The in situ cooling in DSC of milled samples from their molten state led to the formation of the co-amorphous phase between the drug and degradation products, which showed a consistent increase in glass transition temperature with the increase in the content of degradation products. The study overall demonstrates the solid-state re-ordering and disordering of crystalline and amorphous simvastatin accompanied by chemical degradation as the consequence of the mechano-activation.

Original languageEnglish
Article number152
JournalAAPS PharmSciTech
Issue number5
Publication statusPublished - 1 Jul 2020


  • chemical degradation
  • crystallinity
  • milling
  • solid-state disorder

ASJC Scopus subject areas

  • Pharmaceutical Science

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