Co-Amorphous Screening for the Solubility Enhancement of Poorly Water-Soluble Mirabegron and Investigation of Their Intermolecular Interactions and Dissolution Behaviors

Abstract

In the present study, the screening of Mirabegron (MBR) co-amorphous was performed to produce water-soluble and thermodynamically stable MBR co-amorphous with the purpose of overcoming the water solubility problem of MBR. MBR is Biopharmaceutics Classification System (BCS) class II drug used for the treatment of an overreactive bladder. The co-amorphous screening was carried out by means of the vacuum evaporation crystallization technique in methanol solvent using three water-soluble carboxylic acids, characterized by a pKa difference greater than 3 with MBR such as fumaric acid (FA), l-pyroglutamic acid (PG), and citric acid (CA). Powder X-ray diffraction (PXRD) results suggested that all solid materials produced at MBR-FA (1 equivalent (eq.)/1 equivalent (eq.)), MBR-PG (1 eq./1 eq.), and MBR-CA (1 eq./1 eq.) conditions were amorphous state solid materials. Furthermore, by means of solution-state nuclear magnetic resonance (NMR) (1H, 13C, and 2D) and attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy, we could assess that MBR and carboxylic acid molecules were linked via ionic interactions to produce MBR co-amorphous. Besides, solid-state cross polarization (CP)/magic angle spinning (MAS) 13C-NMR analysis was conducted for additional assessment of MBR co-amorphous. Afterwards, dissolution tests of MBR co-amorphouses, MBR crystalline solid, and MBR amorphous were carried out for 12 h to evaluate and to compare their solubilities, dissolution rates, and phase transformation phenomenon. Here, the results suggested that MBR co-amorphouses displayed more than 57-fold higher aqueous solubility compared to MBR crystalline solid, and PXRD monitoring result suggested that MBR co-amorphouses were able to maintain their amorphous state for more than 12 h. The same results revealed that MBR amorphous exhibited increased solubility of approximatively 6.7-fold higher compared to MBR crystalline solid. However, the PXRD monitoring result suggested that MBR amorphous undergo rapid phase transformation to crystalline form in just 35 min and that within an hour all MBR amorphous are completely converted to crystalline solid. Accordingly, the increase in MBR co-amorphous’ solubility was attributed to the presence of ionic interactions in MBR co-amorphous molecules. Moreover, from the differential scanning calorimetry (DSC) monitoring results, we predicted that the high glass transition temperature (Tg) of MBR co-amorphous compared to MBR amorphous was the main factor influencing the phase stability of MBR co-amorphous.

BX795-Organic Acid Coevaporates: Evaluation of Solid-State Characteristics, In Vitro Cytocompatibility and In Vitro Activity against HSV-1 and HSV-2

“…The co-amorphous systems involve combining drug and low molecular weight organic excipient (the co-former) in an equimolar ratio using suitable methods to yield a homogenous amorphous single phase [27][28][29]. It should be noted that several studies have established the ability of citric acid and tartaric acid to form co-amorphous systems with weakly basic drugs [30][31][32][33], which corroborates our results on the formation of BX795-tartaric acid/citric acid co-amorphous systems. Furthermore, our PXRD analyses showed that BX795-tartaric acid/citric acid co-amorphous mixtures were stable for at least 1 month at room temperature (Figure S18).…”

Pterostilbene Nanoparticles Downregulate Hypoxia-Inducible Factors in Hepatoma Cells Under Hypoxic Conditions

“…Therefore, conversion of a crystalline drug into an amorphous form could improve its water solubility. 34 As shown in Figure 3 , EE- and PVA-encapsulated PTS changed the crystalline nature of raw PTS to the amorphous form. Additionally, it is well known that the formation of hydrogen bonds between nanocarriers and lipophilic bioactive compounds could effectively enhance the water solubility of the raw compound.…”

Co-Amorphous Drug Formulations in Numbers: Recent Advances in Co-Amorphous Drug Formulations with Focus on Co-Formability, Molar Ratio, Preparation Methods, Physical Stability, In Vitro and In Vivo Performance, and New Formulation Strategies

“…Drug–organic acid CAMS form the third largest class of the reported CAMS with 12.9%. Organic acids have been applied as co-formers in CAMS mainly as acidic excipients to form strong molecular interactions with basic drugs (for example in [ 25 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]). The organic acids used as co-formers differ in their number of carboxylic acid groups, which was hypothesized to lead to salt formation with a basic drug at different molar ratios.…”