Submerged Eutectic-Assisted, Solvent-Free Mechanochemical Formation of a Propranolol Salt and Its Other Multicomponent Solids.

Salt preparation via a solid-state reaction offers a solution to challenges posed by current pharmaceutical research, which include combining development of novel forms of active pharmaceutical ingredients with greener, sustainable synthesis. This work investigated in detail the mechanism of salt formation between propranolol (PRO) and capric acid (CAP) and explored the solid eutectic phases comprising this salt, propranolol caprate (PRC). The salt structure was solved by X-ray diffraction, and the properties in the crystalline and supercooled states were fully characterised using thermal analysis, nuclear magnetic resonance, Fourier-transform infrared spectroscopy and broadband dielectric spectroscopy (BDS). PRC forms via a submerged eutectic phase composed of PRO and CAP, below room temperature, by mechanochemistry without an extra input of energy. Two other solid eutectic phases are composed of PRC and either CAP or PRO, at 0.28 and 0.82 mol fraction of PRO, respectively. BDS indicated that the supercooled PRC has ionic character, whereas the supercooled PRC-PRO eutectic had predominantly non-ionic properties despite comprising the salt. In conclusion, knowledge of the mechanism of formation of multicomponent systems can help in designing more sustainable pharmaceutical processes.

Characterisation and fundamental insight into the formation of new solid state, multicomponent systems of propranolol.

The physiochemical properties of acidic or basic active pharmaceutical ingredients (APIs) can be optimised by forming salts with different counterions. The aim of this work was to synthesise a novel salt of propranolol (PRO) using sebacic acid (SEBA) as the counterion and to gain mechanistic understanding of not only the salt formation, but also its eutectic phase formation with SEBA. Thermal analysis showed a solid-state reaction occurring between PRO and SEBA leading to the formation of dipropranolol sebacate (DPS) melting at app. 170 °C and the eutectic composed of DPS and SEBA melting at app. 103 °C, comprising 0.33 mol fraction of PRO as determined by the Tammann plot. X-ray diffraction and Fourier-transform infrared spectroscopy (FTIR) confirmed the identity of the new multicomponent phases of PRO. DPS can be conveniently obtained by heat-induced crystallisation, grinding and conventional solvent crystallisation. Detailed analysis by FTIR revealed H-bond interactions between DPS and SEBA at the inter-phase in the eutectic. Bravais, Friedel, Donnay and Harker crystal morphology coupled with full interaction maps analysis allowed to understand further the nature of interactions which led to formation of the eutectic phase. This work contributes to furthering research on multicomponent pharmaceutical systems to harness their full potential.

Enhancement of the Physical Stability of Amorphous Sildenafil in a Binary Mixture, with either a Plasticizing or Antiplasticizing Compound.

The main purpose of this paper was to evaluate the impact of both high- and low-Tg polymer additives on the physical stability of an amorphous drug, sildenafil (SIL). The molecular mobility of neat amorphous SIL was strongly affected by the polymeric excipients used (Kollidon VA64 (KVA) and poly(vinylacetate) (PVAc)). The addition of KVA slowed down the molecular dynamics of amorphous SIL (antiplasticizing effect), however, the addition of PVAc accelerated the molecular motions of the neat drug (plasticizing effect). Therefore, in order to properly assess the effect of the polymer on the physical stability of SIL, the amorphous samples at both: isothermal (at constant temperature-353 K) and isochronal (at constant relaxation time-τα = 1.5 ms) conditions were compared. Our studies showed that KVA suppressed the recrystallization of amorphous SIL more efficiently than PVAc. KVA improved the physical stability of the amorphous drug, regardless of the chosen concentration. On the other hand, in the case of PVAc, a low polymer content (i.e., 25 wt.%) destabilized amorphous SIL, when stored at 353 K. Nevertheless, at high concentrations of this excipient (i.e., 75 wt.%), its effect on the amorphous pharmaceutical seemed to be the opposite. Therefore, above a certain concentration, the PVAc presence no longer accelerates the SIL recrystallization process, but inhibits it.

Anticrystal Engineering of Ketoprofen and Ester Local Anesthetics: Ionic Liquids or Deep Eutectic Mixtures?

Ionic liquids (ILs) and deep eutectic mixtures (DEMs) are potential solutions to the problems of low solubility, polymorphism, and low bioavailability of drugs. The aim of this work was to develop and investigate ketoprofen (KET)-based ILs/DEMs containing an ester local anesthetic (LA): benzocaine (BEN), procaine (PRO) and tetracaine (TET) as the second component. ILs/DEMs were prepared via a mechanosynthetic process that involved the mixing of KET with an LA in a range of molar ratios and applying a thermal treatment. After heating above the melting point and quench cooling, the formation of supercooled liquids with Tgs that were dependent on the composition was observed for all KET-LA mixtures with exception of that containing 95 mol% of BEN. The KET-LA mixtures containing either ≥ 60 mol% BEN or 95 mol% of TET showed crystallization to BEN and TET, respectively, during either cooling or second heating. KET decreased the crystallization tendency of BEN and TET and increased their glass-forming ability. The KET-PRO systems showed good glass-forming ability and did not crystallize either during the cooling or during the second heating cycle irrespective of the composition. Infrared spectroscopy and molecular modeling indicated that KET and LAs formed DEMs, but in the KET-PRO systems small quantities of carboxylate anions were present.

Mechanochemical activation with cyclodextrins followed by compaction as an effective approach to improving dissolution of rutin.

Rutin is one of the most important flavonoids with poor bioavailability. This work aimed at addressing the issue of poor biopharmaceutical performance of rutin by applying a combination of complexation with secondary processing into tablets. Mechanical activation was the most suitable method of rutin complex formation with (2-hydroxypropyl)-ß-cyclodextrin (HP-ß-CD), while the ß-cyclodextrin (ß-CD) complex successfully formed by kneading with an ethanol/water mixture. Complexation was confirmed by thermal analysis, powder X-ray diffraction and vibrational spectroscopy. Dynamic vapour sorption showed that stability of powders at high humidity conditions was satisfactory, however, the ß-CD complex retained around 8% of moisture. The complexes were compacted with or without tricalcium phosphate (TRI-CAFOS) filler at a range of compression pressures (19-113 MPa). The best tabletability was determined for rutin/HP-ß-CD, compressibility for the TRI-CAFOS blends with complexes and compactibility for the rutin/HP-ß-CD + TRI-CAFOS mix. Dissolution studies showed quicker and more complete dissolution (pH 1.2) of rutin/HP-ß-CD tablets, however the compacts comprising the filler were superior than pure complexes. The tablets manufactured in this study appear to be promising delivery systems of rutin and it is recommended to combine rutin/HP-ß-CD with TRI-CAFOS and compact at 38-76 MPa.