Febuxostat (FB) is a poorly water-soluble drug that belongs to BCS class II. The drug is employed for the treatment of inflammatory disease arthritis urica (gout), and the free base, FB form-A, is most preferred for drug formulation. In order to achieve a goal of improving the water solubility of FB form-A, this study was carried out using the cocrystallization technique called the liquid-assisted grinding method to produce FB cocrystals. Here, five amino acids containing amine (NH), oxygen (O), and hydroxyl (OH) functional groups, and possessing difference of pKa less than 3 with FB, were selected as coformers. Then, solvents including methanol, ethanol, isopropyl alcohol, n-hexane, dichloromethane, and acetone were used for the cocrystal screening. As a result, a cocrystal was obtained when acetone and L-pyroglutamic acid (PG) of 0.5 eq. were employed as solvent and coformer, respectively. The ratio of 2:1, which is the ratio of FB to PG within FB-PG cocrystal, was predicted by means of solid-state CP/MAS 13 C-NMR, solution-state NMR ( 1 H, 13 C, and 2D) and FT-IR. Moreover, Powder X-ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC), and Thermogravimetric Analysis (TGA) were used to investigate the characteristics of FB-PG cocrystal. In addition, comparative solubility tests between FB-PG cocrystal and FB form-A were conducted in deionized water and under simulated gastrointestinal pH (1.2, 4, and 6.8) conditions. The result revealed that FB-PG cocrystal has a solubility of four-fold higher than FB form-A in deionized water and two-fold and five-fold greater than FB form-A at simulated gastrointestinal pH 1.2 and pH 4, respectively. Besides, solubilities of FB-PG cocrystal and FB form-A at pH 6.8 were similar to the results measured in deionized water. Therefore, it is postulated that FB-PG cocrystal has a potential overcoming the limitations related to the low aqueous solubility of FB form-A. Accordingly, FB-PG cocrystal is suggested as an alternative active pharmaceutical ingredient of the currently used FB form-A.

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.

Since ionic liquids (ILs), salts with a melting point below 100 °C, have unique physicochemical properties, they have been spotlighted as novel alternatives to organic solvents. However, studies relating to polymorph control using IL as solvent have not yet been performed due to the numerous (10 18 ) available IL types with unknown effects on the control of polymorphic transformation, and the extremely high unit price compared with conventional organic solvents. Presently, the pharmaceutical industry highly prefers the high soluble form-I polymorph among several polymorphs of the active pharmaceutical ingredients (APIs), clopidogrel bisulfate (CLP). However, as form-I polymorphs are metastable crystals, their phase transformation to stable form-II crystals occurs only within 5 min in the organic solvent. Therefore, the present study was performed in order to control the phenomenon that induces the rapid phase transformation from form-I to form-II. Ethanol was used as solvent, ILs including 1-allyl-3-ethylimidazolium tetrafluoroborate (AEImBF 4 ), 1-butyl-2,3dimethylimidazolium tetrafluoroborate (BDMImBF 4 ), and 1,3-diallylimidazolium tetrafluoroborate (AAImBF 4 ) were used as antisolvents, and drowning-out crystallization was the method applied. Among three ILs used in this experiment, only AEImBF 4 could induce crystals precipitation. Therefore, AEImBF 4 was used as antisolvent for further studies. The thermodynamic factor, the temperature, was set in the range of 25 to 50 °C; then the phase transformation phenomenon from form-I to form-II under temperature variation was studied. In order to illustrate the quantitative analysis of the polymorphic transformation under the new IL solvent, the nucleation and mass transfer equations were used.

Ionic liquids (ILs) are defined as salts with a melting point below 100 °C. ILs have received increasing attention as new alternative to organic solvents because of their unique physicochemical properties. Therefore, this study was conducted in the purpose to present the efficacy of ILs as new solvents capable to control the Polymorphic transformation phenomenon. Here, the polymorphic transformation phenomenon of adefovir dipivoxil, an efficient antiviral active pharmaceutical ingredient on human immunodeficiency virus, was investigated. The phase transformation phenomenon from the metastable polymorph, new form (NF) to the stable polymorph, Form-X in 1-allyl-3-ethylimidazolium tetrafluoroborate (AEImBF4) and 1-butyl-2,3-dimethylimidazolium tetrafluoroborate (BDMImBF4) ILs solutions was observed utilizing the solvent-mediated phase transformation method The thermodynamic factors, AEImBF4/BDMImBF4 solvent composition ratio of 3:7-6:4 and the temperature in range of 25-100 °C, as well as the dynamic factor, the rational speed in range of 300-1000 rpm were parameters studied in this experiment. The thermodynamic and dynamic equations involving nucleation and mass transfer were applied for the quantitative analysis. The result of the present study confirmed the use of ILs as substitute solvent for volatile organic solvents, and demonstrated the efficacy of ILs as potential solvent-media to control the polymorphic transformation.

Clopidogrel bisulfate (CLP) form-I crystals are irregular, rectangular-shaped crystals. Because of their poor compressibility, flowability and their strong surface tension, manufacturers apply spherical crystallization methods to produce CLP form-I spherical agglomerates with a uniform particle size distribution. Consequently, manufacturers primarily synthesize CLP form-I crystal salts utilizing very complex methods, which produces form-I spherical agglomerates by means of spherical crystallization. In this study, spherical crystals of CLP Form-I were directly prepared from CLP Form-II, the most stable polymorph at room temperature, by using ethanol as solvent and a mixture of isopropyl alcohol (IPA)/n-Hexane (Hex) as an anti-solvent. To provide systematic inputs for the development of spherical agglomerates of optimal morphology, size, particle size distribution (PSD), and polymorphic form, processing parameters such as anti-solvent type, a mixture of IPA/Hex, pure Hex, or pure acetone; stirring speeds of 500, 600, 700, or 800 rpm; and temperatures ranging from 25 to 40 °C were explored. The effects of these parameters on spherical crystallization and polymorphic form were studied in terms of supersaturation, a driving force for polymorphic transformation, and the crystallization solution. Notably, our method does not require a large volume of anti-solvent which is the main complication of conventional anti-solvent crystallization methods.