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

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.

Development of raft-forming liquid and chewable tablet formulations incorporating quercetin solid dispersions for treatment of gastric ulcers

“…The improvement in quercetin solubility when formulated as a solid dispersion is considered to result from the water solubility of PVP. When polymer chains with attached drug molecules were dissolved in the solution medium, PVP acted as the wetting agents facilitating solution medium to come in contact and penetrate into the pure drug resulting in increased the solubility of quercetin ( Chen et al, 2020 ). The solubility of quercetin solid dispersions was enhanced significantly by increasing the content the hydrophilic carrier (1:10 > 1:8 > 1:5 > 1:3), which may be explained by the high dispersion or dilution of the quercetin phase and improved wettability ( Lu et al, 2014 ).…”

Compatibility between Drugs and Polymer in Nanoparticles Produced by the Miniemulsion‐Solvent Evaporation Technique

“…A comparison of t can provide information on the miscibility and the intermolecular forces between the drug and the polymer in the blend. [44] The group contribution method of Van Krevelen, Hoftyzer, and Fedors was used to estimate the partial solubility parameters ( d , p , and h ) (Table S2, Supporting Information). [15,45] Generally, mixtures with |Δ t | < 7 MPa 1/2 are considered miscible whereas mixtures are immiscible for |Δ t | > 10 MPa 1/2 .…”

Recent and Relevant Methodology in the Advancement of Solid Dispersion

“…They concluded that, drug solubility improves by SE, but BM provides better results which clearly, indicates that intermolecular forces are more efficient than the solvent mediated. 23 Dingkun Zhang et al developed Andrographolide (ADG) solid dispersion using silica (SiO2) as a carrier by solvent evaporation method.SD formed a unique structure to disperse the drug and release drug rapidly to improve the dissolution of ADG. 24 Muhammad Tayyab Ansari et al developed solid dispersions (SDs) of artemether by solvent evaporation using artemether and polyethylene glycol 6000; self-emulsified solid dispersions (SESDs) containing artemether, polyethylene glycol 6000, cremophor-A-25, olive oil, hydroxypropylmethylcellulose and transcutol.…”