Periodic Reporting for period 1 - OMECRY (Organic Mesocrystals: Formation and controlling of oriented nanoparticles of molecular solids for drug development)
Periodo di rendicontazione: 2019-10-01 al 2021-09-30
Low aqueous solubility restricts the oral use of almost 90 % of new drug substances and even 40 % of drugs with market approval show poor solubility. A new approach to disintegrate the drug particles rapidly in an aqueous solution is highly requisite. Mesocrystals are self-assembled and crystallographically oriented attachments of nanoparticles formed via non-classical crystallization (NCC). The mesocrystals internal and external features such as voids, nanoparticles building units, crystallographic orientation, micron-size particles, and reactive surfaces will enable this drug for high dissolution. Therefore, the overall objective of this project has been to prepare low aqueous soluble drug in the form of mesocrystals and test their dissolution rate. Since the mesocrystals word was coined less than two decades ago, this formation process needs still better understanding to unveil the nucleation and growth of crystals. Investigating the formation of nucleus and growth shed light on to further understand the mechanism of NCC. Therefore, the in-situ characterizations of their different crystallization pathways in NCC were also included in this objective.
The ibuprofen was chosen as model compound since this solubility is low as about 21 mg/L at 25 °C. Based on experimental methods and in situ studies, this action concludes that the high supersaturation with dispersed particles at the initial stage of crystallization and suitable additives are required to form ibuprofen mesocrystals. The experimental observation of liquid-liquid phase separation was apparent in pharmaceutical solids with low melting point and in situ studies confirmed that the dense liquid phase is not amorphous, and their molecular interactions are different than dimer of ibuprofen due to closely packed molecular environment. The dissolution of ibuprofen mesocrystals has enhanced compared with their classical grown single crystals.
The ibuprofen was chosen as model compound since this solubility is low as about 21 mg/L at 25 °C. Based on experimental methods and in situ studies, this action concludes that the high supersaturation with dispersed particles at the initial stage of crystallization and suitable additives are required to form ibuprofen mesocrystals. The experimental observation of liquid-liquid phase separation was apparent in pharmaceutical solids with low melting point and in situ studies confirmed that the dense liquid phase is not amorphous, and their molecular interactions are different than dimer of ibuprofen due to closely packed molecular environment. The dissolution of ibuprofen mesocrystals has enhanced compared with their classical grown single crystals.
Biomimetic and slow solvent evaporation crystal growth methods were used to produce ibuprofen mesocrystals. Water and 2-propanol as well as water and ethanol were used as binary solvents, with the former yielding mesocrystals, but the single crystals were obtained with the latter solvents. The biomimetic method produced precipitates of ibuprofen whereas mother liquid left at different solvent ratios was used for slow solvent evaporation to produce mesocrystals. The single crystals results were used to compare the mesocrystals characterized by Raman, PXRD, SEM, TG/DSC, SAXS and in vitro drug dissolution studies (WP1). Different additives such as Hydroxypropyl methylcellulose (HPMC), Pluronic-F127, Polyvinylpyrrolidone (PVP), Polyvinyl alcohol (PVA), and Polyacrylic acid (PAA) and their amounts were varied to control the mesocrystallization. The carboxylic acid groups in both PAA and ibuprofen may initially form dimer which was controlled to stabilize the basic nanoparticle building unit to form mesocrystals. The other additives produced only aggregates of ibuprofen (WP2). The in vitro drug dissolution test was performed in phosphate buffer during the secondment period for the mesocrystals, precipitate and single crystals. The dissolution rate has enhanced for the mesocrystals compared with the single crystals. It was challenging to control the transformation of mesocrystals to single crystal thus the presence of undesired single crystals in mesocrystals may affect the dissolution rate. However, the enhanced dissolution rate due to this new mesocrystals strategy can retain the crystallographic features and properties as single crystals at the same time enhance the drug dissolution (WP3).The OMECRY project results were disseminated through different scientific conferences and invited talks (WP4), book chapter, news, research articles. The review work on organic mesocrystals will also be published.
Though mesocrystals have been studied for an inorganic system, they are less known in organic system and their use in drug design is very limited. The systematic investigation to explore the prenucleation cluster formation before nucleation in NCC is necessary for pharmaceutical small molecules to enhance the drug properties. This action has made significant progress to produce ibuprofen mesocrystals right from observation of prenucleation cluster to mesocrystals confirmation through in situ studies such as Raman and SAXS and focused ion beam SEM. There is a deceptive understanding about mesocrystals, and classical grown crystals observed via Ostwald ripening which has been avoided clearly as this study probed the prenucleation cluster during crystallization and confirmed the nanoparticle attachments in mesocrystals. This ibuprofen can be taken as a model compound and this method can be extended to mesocrystallization of other pharmaceutical solids including non-zwitterions. Since solubility is a long-standing issue, drugs with enhanced solubility definitely will have an impact on sustainable development in pharmaceutical industry in terms of developing the drug dissolution and reducing the cost of processability.