Influence of Preparation Methods on Physicochemical and Pharmacokinetic Properties of Co-amorphous Formulations: The Case of Co-amorphous Atorvastatin: Naringin

  • Athira Nair
  • Raghava Varma
  • Karthik Gourishetti
  • Krishnamurthy Bhat
  • Swapnil DengaleEmail author
Original Article



The goal of the study was to investigate the influence of processing methods on the physicochemical and pharmacokinetic properties of co-amorphous materials.


Co-amorphous formulations of atorvastatin (ATV) and naringin (NRG) in the molar ratio 1:1 were prepared by quench cooling (ANQC), solvent evaporation (ANSE), and ball milling (ANBM) and characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (XRPD), and Fourier transform infrared spectroscopy (FTIR). Further, the performance of prepared co-amorphous formulations was evaluated in vitro and in vivo.


All processing methods yielded homogeneous co-amorphous formulation, which was confirmed by single glass transition (Tg) event and diffuse halo in DSC and XRPD, respectively. Irrespective of processing method employed, all co-amorphous formulations were found stable at 30 °C for 90 days in dry conditions (under vacuum). Significant improvement in the solubility of ATV was observed in ANQC and ANSE co-amorphous formulations, highest being 56-fold for the later. ATV from ANSE formulation showed highest drug release (97%), while surprisingly ANQC showed significantly lower ATV release as compared to the physical mixture. Amongst three preparation methods, solubility advantage of ANSE could translate into efficacious pharmacokinetic parameters, where the improvement in ATV exposure (AUC 0-t) and plasma concentration (Cmax) were found 4.5-fold and 7-fold, respectively, as compared to the physical mixture.


It was concluded that the preparation methods of co-amorphous formulations have a profound effect on physical properties like stability, physicochemical properties like solubility, dissolution rate, and pharmacokinetic properties like AUC and Cmax.


Co-amorphous Atorvastatin Naringin Ball milling Solvent evaporation Quench cooling 



The authors would want to acknowledge the kind help of Ms. Zenab A. (Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences) and Mr. Ashutosh (Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences) regarding the operation of the ball mill and rotary evaporator, respectively.

Compliance with Ethical Standards

Studies were conducted in accordance with CPSEA guidelines and were approved by Institutional Animal Ethics Committee (IAEC/KMC/101/2015), Manipal University (MU).

Conflict of Interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Supplementary material

12247_2019_9381_MOESM1_ESM.docx (313 kb)
ESM 1 (DOCX 312 kb)


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmaceutical Quality Assurance, Manipal College of Pharmaceutical SciencesManipal Academy of Higher EducationManipalIndia
  2. 2.Department of Pharmacology, Manipal College of Pharmaceutical SciencesManipal Academy of Higher EducationManipalIndia

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