Cryosynthesis of Co-Crystals of Poorly Water-Soluble Pharmaceutical Compounds and Their Solid Dispersions with Polymers. The “Meloxicam–Succinic Acid” System as a Case Study

Abstract

Co-crystals of pharmaceutical compounds are widely used to improve the properties of drug formulations, such as dissolution behavior, bioavailability, or tabletability. The main methods of their synthesis include co-crystallization from solution, melt, or cogrinding. Only a few examples have been documented when co-crystals have been obtained by freeze-drying, namely, in systems where the components of a target co-crystal had similar aqueous solubilities. This work illustrates the potential of freeze-drying for obtaining pharmaceutical cocrystals when the solubilities of individual components differ drastically. Co-crystals of a model system meloxicam and succinic acidcould be obtained both as a pure crystalline phase and forming a solid dispersion with a polymeric carrier. We show that even for pharmaceutical compounds with very low aqueous solubility, co-crystals with wellsoluble coformers can be successfully produced under well-optimized conditions of cooling and subsequent freeze-drying. The rate of release of meloxicam from the fine solid dispersion of its cocrystal with succinic acid in polyethylenglycol obtained by freeze-drying was significantly higher than dissolution rates of (a) pure meloxicam cocrystals with succinic acid obtained by different variants of freeze-drying (thin film freezing, TFF, and spray freeze-drying, SFD), (b) the powder of meloxicam cocrystal with succinic acid obtained by liquid-assisted cogrinding. The possibility to obtain co-crystals of components with very different aqueous solubilities not only by TFF or SFD techniques but also by freezing solutions in vials at temperatures significantly higher than that of liquid nitrogen is shown.

Glycine: The Gift that Keeps on Giving

“…Apart of being active as a pharmaceutical compound itself, glycine is widely used as an excipient in various pharmaceutical applications ranging from pulmonary delivery [196,309,318] to the solubilization of drugs, [195,319] the targeted delivery of drugs in cancer therapy [197,320,321] and intranasal delivery of drugs to brain. [322] Interestingly, in various solid formulations used in large porous particles prepared by freeze-drying, b-glycine is present as a component of the composites with drug molecules.…”

Tribochemistry, Mechanical Alloying, Mechanochemistry: What is in a Name?

“…Moreover, the scale of mechanochemical reactions has ranged from the mechanical manipulation of single atoms and molecules (predominantly, synthetic and natural polymers) using atomic force microscopy ( Kaupp, 2009 ; Ribas-Arino and Marx, 2012 ; Makarov, 2016 ; Li et al, 2017 ) to the induction of reactions in multi-component inorganic and organic powder mixtures in ball milling reactors or extruders ( Iwasaki et al, 2010 ; Am Ende et al, 2014 ; Oliveira et al, 2017 ; Andersen and Mack, 2018b ; Egleston et al, 2020 ). Alongside synthetic covalent chemical reactions, a wide range of supramolecular assemblies have been also prepared by mechanical treatment, including cocrystals and salts ( Myz et al, 2009 ; Weyna et al, 2009 ; Friščić, 2012 ; Myz et al, 2012 ; Braga et al, 2013 ; Hasa et al, 2015 ), as well as non-covalently bound mechano-composites such as drug delivery devices comprising active pharmaceutical ingredients with excipients ( Shakhtshneider et al, 2007 ; Shakhtshneider et al, 2014a ; Shakhtshneider et al, 2014b ; Lomovsky et al, 2017 ; Ogienko et al, 2018 ; Bychkov et al, 2019 ; Adekenov et al, 2020 ; Skripkina et al, 2020 ). Moreover, many organic mechanochemical syntheses have been successfully scaled-up ( Iwasaki et al, 2010 ; Am Ende et al, 2014 ; Crawford et al, 2017 ; Trofimova et al, 2018 ; Stolar et al, 2019 ; Baláž et al, 2020 ; Crawford et al, 2020 ; He et al, 2020 ; Titi et al, 2020 ; Stolar et al, 2021 ), offering a direct route to translate mechanochemical synthesis toward industrial scale applications.…”

Pulmonary Drug Delivery of Antimicrobials and Anticancer Drugs Using Solid Dispersions

“…Cocrystallisation is currently attracting considerable interest, due to the improved physicochemical properties that can be introduced to the API [ 169 , 170 ]. For example, cocrystals of meloxicam–succinic acid were combined with PEG 4000 to enhance aqueous solubility [ 171 ]. Cocrystals have largely been studied with a focus on improving oral drug delivery, and it is only recently that studies have begun to explore how cocrystals can be used for other administration routes, including pulmonary drug delivery.…”