Raloxifene HCl – quercetin co-amorphous system: preparation, characterization, and investigation of its behavior in phosphate buffer

Abstract

Purpose

Raloxifene HCl (RLX), a practically insoluble drug used in the treatment of osteoporosis in post-menopausal women; was modified at its molecular level to enhance its solubility using co-amorphous technology.

Methods

In this study, RLX was co-amorphized with Quercetin (QCT; a nutraceutical flavonoid) using solvent evaporation (SE), quench cooling (QC), and ball milling (BM) techniques. The prepared co-amorphous systems (CAMs) were characterized using XRD, DSC, and FT-IR. For the simultaneous analysis of RLX and QCT, an RP-HPLC method was developed to quantify the drugs in the prepared systems. Behavior in aqueous media was investigated by studying amorphous and equilibrium solubility, and drug release of RLX using USP phosphate buffer pH 6.8.

Results

Solvent evaporation (RQ(SE)) was able to produce a homogeneous system, where quench cooling showed thermal degradation of the drug, and ball milling was not able to amorphize the blend. From the DSC results, it was found that RQ(SE) was able to increase the glass transition temperature by 40 °C. It was observed that the solubility of RLX reduced, as RLX formed phosphate aggregates in the buffer media which further formed complexes with QCT; this was determined by investigating the residual particles from solubility studies. Though the solubility was reduced, drug release of RQ(SE) exhibited improvement in concentration by 2.3 times.

Conclusions

RQ(SE) formed a stable CAM; though the solubility of RLX in presence of QCT reduced, from the drug release study, it was apparent that the co-amorphous technique improved the concentration of RLX.

Graphical Abstract

Keywords:

• Raloxifene HCl
• Quercetin
• co-amorphous systems
• phosphate aggregates
• weekly basic drugs
• amorphous solid dispersions
• weekly acidic ionizable drugs

Acknowledgments

The authors extend their gratitude toward – 1) Apotex Research Pvt. Ltd., for their timely help in providing Raloxifene HCl for research work. 2) Dr. Lynne S Taylor, Department of Industrial and Physical Pharmacy, Purdue University for providing the resources and infrastructure to perform DSC, XRD, and FT-IR. 3) Department of Science and Technology, Govt. of India for providing Navya Sree K S with Science and Engineering Research Board- Purdue University Overseas Visiting Doctoral Fellowship.

Author contributions

Navya Sree K S – investigation, data curation, conceptualization, and writing of original draft; Swapnil J Dengale – conceptualization, editing, and reviewing; Srinivas Mutalik – draft editing and reviewing; Krishnamurthy Bhat – conceptualization and supervision.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.