Solubility Improvement of Progesterone from Solid Dispersions Prepared by Solvent Evaporation and Co-milling.

Xing Chen,Ioannis Nikolakakis,Hisham Al-Obaidi,Ioannis Partheniadis

doi:10.3390/polym12040854

Abstract

The aim of this contribution was to evaluate the impact of processing methods and polymeric carriers on the physicochemical properties of solid dispersions of the poorly soluble drug progesterone (PG). Five polymers: hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP) and silica (SiO2), and two processing methods: solvent evaporation (SE) and mechano-chemical activation by co-milling (BM) were applied. H-bonding was demonstrated by FTIR spectra as clear shifting of drug peaks at 1707 cm−1 (C20 carbonyl) and 1668 cm−1 (C3 carbonyl). Additionally, spectroscopic and thermal analysis revealed the presence of unstable PG II polymorphic form and a second heating DSC cycle, the presence of another polymorph possibly assigned to form III, but their influence on drug solubility was not apparent. Except for PG–MCC, solid dispersions improved drug solubility compared to physical mixtures. For SE dispersions, an inverse relationship was found between drug water solubility and drug–polymer Hansen solubility parameter difference (Δδt), whereas for BM dispersions, the solubility was influenced by both the intermolecular interactions and the polymer Tg. Solubility improvement with SE was demonstrated for all except PG–MCC dispersions, whereas improvement with BM was demonstrated by the PG–HPMC, PG–PVP and PG–HPMCAS dispersions, the last showing impressive increase from 34.21 to 82.13 μg/mL. The extensive H-bonding between PG and HPMCAS was proved by FTIR analysis of the dispersion in the liquid state. In conclusion, although SE improved drug solubility, BM gave more than twice greater improvement. This indicates that directly operating intermolecular forces are more efficient than the solvent mediated.

Highlights

Poor aqueous solubility has always been a challenge in the development of hydrophobic drugs for oral delivery [1,2]
The vast number of publications on solid dispersions signifies the unambiguous importance of this promising strategy for improvement of drug solubility
It is interesting that the results of the present work proved hydroxypropyl methylcellulose acetate succinate (HPMCAS) as the best candidate among other polymers, and co-milling as the better method for the preparation of solid dispersion of PG with highest solubility

Summary

Introduction

Poor aqueous solubility has always been a challenge in the development of hydrophobic drugs for oral delivery [1,2]. One potential solution has been the use of solid dispersions in which the hydrophobic drug is mixed at molecular level with a hydrophilic carrier. Molecular interactions such as hydrogen bonding can be optimized by careful choice of the preparation conditions [3]. Mechano-chemical activation is often applied by dry or wet milling and is used to enhance the solubility and dissolution rate of poorly soluble drugs [3,6]. This is usually applied by co-milling drug with excipients and is commonly used for particle size reduction. It has the advantage of avoiding solvent use, simplifying the process compared with solvent-based methods such as spray drying or freeze-drying [4]

Methods

Results

Conclusion