This study investigated the use of an ionic liquid for designing polymorphs of the active pharmaceutical ingredient adefovir dipivoxil (AD) in drowning-out crystallization. Because of the influence of 1-ally-3-ethylimidazolium tetrafluoroborate (AEImBF4) on the formation of the intermolecular interaction of AD in the solution, new anhydrous (N-II) and hemihydrate (N-I) crystals of AD were produced when varying the ionic liquid fraction and crystallization temperature. The polymorphic structure and number of hydrate crystals were determined using X-ray diffraction and thermogravimetric analysis, respectively. Also, AEImBF4 had a significant influence on the thermal stability of the AD molecules in the AEImBF4−water mixture, as there was no hydrolysis of the AD molecules up to a temperature of 90 °C. According to a differential scanning calorimetry thermal scan, the N-I and N-II crystals were uniquely transformed into other crystal phases in a solid state. That is, the N-I crystals underwent three polymorphic changes: N-I → amorphous → form-V → liquid, while the N-II crystals underwent two polymorphic changes: N-II → form-V → liquid.
The applicability of ionic liquids to the polymorphic design of the active pharmaceutical ingredient adefovir dipivoxil (AD) was investigated in the case of antisolvent crystallization. When using 1-allyl-3-ethylimidazolium tetrafluoroborate (AEImBF 4 ) as the solvent and 1-butyl-2,3dimethylimidazolium tetrafluoroborate (BDMImBF 4 ) as the antisolvent (AEImBF 4 /BDMImBF 4 ), a new form (NF) of AD crystal was obtained at a crystallization temperature below 50 °C and initial solute concentration of 25.6 mg/mL. However, when using 1-allyl-3-ethylimidazolium tetrafluoroborate/1,3-diallylimidazolium tetrafluoroborate (AEImBF 4 / AAImBF 4 ) and 1-allyl-3-ethylimidazolium tetrafluoroborate/1-ethyl-3-methylimidazolium ethylsulfate (AEImBF 4 /EMImEtSO 4 ), the conventional form-I polymorph was directly crystallized. No crystallization occurred in the ionic solutions of 1-allyl-3ethylimidazolium tetrafluoroborate/1-allyl-3-ethylimidazolium bromide (AEImBF 4 /AEImBr) and 1-allyl-3-ethylimidazolium tetrafluoroborate/1,3-diallylimidazolium bromide (AEImBF 4 /AAImBr). According to a spectroscopic analysis, the polymorphs were predominantly determined by the preorientation of the solute molecules in the ionic liquid solution (AEImBF 4 / BDMImBF 4 ), and this preorientation varied according to the crystallization temperature. Thus, the pure form-X polymorph was nucleated at a crystallization temperature above 80 °C. Plus, the polymorphic nucleation depending on the crystallization temperature was also combined with the crystallization concentration. Thus, the minimum crystallization temperature for the nucleation of the pure form-X polymorph was reduced to 40 °C when decreasing the crystallization concentration to 15 mg/mL. The relationship between the polymorphic nucleation and the crystallization conditions was effectively predicted by a polymorphic supersaturation level diagram (S NF −S form-X diagram), where the formation of the metastable polymorph (NF crystals) was favored at a high supersaturation level (S NF > 2.1), while the stable polymorph (form-X crystals) was preferentially nucleated at a low supersaturation level (S NF < 1.6). Differental scanning calorimetry thermal analysis confirmed that the NF polymorph was the metastable phase and the form-X polymorph was the stable phase, and there was a monotropic relationship between the two polymorphs.
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.
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