Patent Publication Number: US-2023133435-A1

Title: Cocrystals derivatives of apixaban

Description:
CROSS REFERENCE TO RELATED APPLICATION 
     This application is a national stage entry of PCT/162021/055434 filed Jun. 21, 2021, under the International Convention and claiming priority over U.S. provisional Patent Application No. 63/042,692 filed Jun. 23, 2020. 
    
    
     FIELD OF THE INVENTION 
     The present application pertains to the field of pharmaceutical solid forms of Apixaban, particularly pharmaceutical forms that provide Apixaban with higher solubility, more particularly the pharmaceutical forms are Apixaban cocrystals obtained with pharmaceutical acceptable organic acids as coformers. 
     BACKGROUND OF THE INVENTION 
     The present application refers to derivatives of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4c] pyridine-3-carboxamide (Apixaban). 
     Regarding the Apixaban polymorphism landscape, several patents and papers report on the synthesis and the interconversion of anhydrous and solvated Apixaban forms. In addition, several polymorphs were described. Although, the nomenclature employed and the accompanying characterization data are often unclear and incomplete, leading to a situation in which apparently the same form has been reported by different authors or claimed by different inventors. 
     A tentative rationalization of all the data reported in literature was performed by Barbas and coworker in 2018 (Mol. Pharmaceutics 2018, 15, 1909): an experimental screening, along with the comparison of the collected data with those from literature was carried out and up to 23 crystal forms were identified. 
     In the following Table 1 the comprehensive nomenclature rationalization for the polymorph and pseudo-polymorph landscape was reported: 
     
       
         
           
               
               
               
             
               
                   
               
               
                   
                   
                 Native 
               
               
                 Adopted 
                   
                 nomen- 
               
               
                 nomenclature 
                 Reference Patent (Papers) 
                 clature 
               
               
                   
               
             
            
               
                 I (anhydrous form) 
                 (Mol. Pharmaceutics 2018, 15, 1909) 
                 I 
               
               
                   
                 (RSC Adv. 2015, 5, 81696-81706) 
                 N-1 
               
               
                   
                 (World Journal of Pharmaceutical 
                 N-1 
               
               
                   
                 Sciences, 2015, 3 (3), 663-677) 
               
               
                   
                 WO2007001385 
                 N-1 
               
               
                   
                 WO2014108919 
                 M 
               
               
                   
                 CN103539795 
                 I 
               
               
                   
                 WO2014111954 
                 “form” 
               
               
                   
                 WO2014056434 
                 I 
               
               
                   
                 WO2015021902 
                 A 
               
               
                   
                 CN103539795 
                 III 
               
               
                   
                 CN104788448 
                 X 
               
               
                 II (anhydrous 
                 (Mol. Pharmaceutics 2018, 15, 1909) 
                 II 
               
               
                 form) 
                 WO2013119328 
                 III 
               
               
                   
                 EP2752414 
                 A 
               
               
                 III (hydrate) 
                 (Mol. Pharmaceutics 2018, 15, 1909) 
                 III 
               
               
                   
                 WO2013119328 
                 DF-1 
               
               
                   
                 WO2012168364 
                 α 
               
               
                   
                 EP2752414 
                 H-3 
               
               
                   
                 CN103539795 
                 IV 
               
               
                   
                 WO2014108919 
                 N 
               
               
                   
                 CN103833755 
                 B 
               
               
                   
                 WO2014173377 
                 AP3 
               
               
                   
                 WO2014173377 
                 AP5 
               
               
                   
                 IPCOM000216902D 
                 A 
               
               
                   
                 WO2014203275 
                 “form” 
               
               
                 IV (hydrate) 
                 (Mol. Pharmaceutics 2018, 15, 1909) 
                 IV 
               
               
                 V (hydrate) 
                 (Mol. Pharmaceutics 2018, 15, 1909) 
                 V 
               
               
                   
                 US2006/0069258 A1 
                 H2-2 
               
               
                   
                 CN103539795 
                 II 
               
               
                   
                 CN104086544 
                 monohydrate 
               
               
                   
                 WO2014108919 
                 S 
               
               
                 VI 
                 (Mol. Pharmaceutics 2018, 15, 1909) 
                 VI 
               
               
                   
                 WO2014173377 
                 AP4 
               
               
                 VII 
                 (Mol. Pharmaceutics 2018, 15, 1909) 
                 VII 
               
               
                 VIII (hemibenzyl 
                 (Mol. Pharmaceutics 2018, 15, 1909) 
                 VIII 
               
               
                 alcohol solvate) 
               
               
                 IX (DMSO 
                 (Mol. Pharmaceutics 2018, 15, 1909) 
                 IX 
               
               
                 solvate) 
                 PCOM000216902D 
                 D 
               
               
                   
                 CN103360391 
                 β 
               
               
                 X (isopropanol 
                 (Mol. Pharmaceutics 2018, 15, 1909) 
                 X 
               
               
                 solvate) 
               
               
                 XI (amorphous) 
                 (Mol. Pharmaceutics 2018, 15, 1909) 
                 XI 
               
               
                   
                 U.S. Pat. No. 9,045,473 
                 amorphous 
               
               
                   
                 WO2014203275 
                 amorphous 
               
               
                   
                 CN103539795 
                 amorphous 
               
               
                   
                 US20150018386 
                 amorphous 
               
               
                 XII 
                 (Mol. Pharmaceutics 2018, 15, 1909) 
                 XII 
               
               
                 XIII (unclear) 
                 (Mol. Pharmaceutics 2018, 15, 1909) 
                 XIII 
               
               
                   
                 WO2013119328 
                 I 
               
               
                   
                 IPCOM000216217D 
                 I 
               
               
                   
                 IPCOM000216902D 
                 B 
               
               
                 XIV (DMF solvate) 
                 US20070203178 
                 DMF-5 
               
               
                 XV (formamide 
                 US20070203178 
                 FA-2 
               
               
                 solvate) 
               
               
                 XVI (unclear) 
                 WO2013119328 
                 II 
               
               
                   
                 IPCOM000216217D 
                 II 
               
               
                 XVII 
                 IPCOM000216902D 
                 C 
               
               
                 XVIII 
                 PCOM000227611D 
                 “form” 
               
               
                 XIX 
                 CN103539795 
                 V 
               
               
                 XX 
                 CN104672233 
                 Y 
               
               
                 XXI 
                 CN104650074 
                 “form” 
               
               
                 XXII 
                 CN104910147 
                 I 
               
               
                 XXIII 
                 CN104910147 
                 II 
               
               
                   
               
            
           
         
       
     
     According to the literature research, the XRPD calculated pattern (necessary for the crystalline phase determination) was available (from research in CSD—crystalline structure reported within) only for: 
     Apixaban anhydrous phase (named Form I—crystalline phase of the starting material); 
     Apixaban dimethyl formamide solvate (named Form XIV); 
     Apixaban formamide solvate (named Form XV); 
     Apixaban-Oxalic acid cocrystal ( Cryst. Growth Des.  2016, 16, 2923-2930). 
     For all the remaining isolated Apixaban and its derivatives, crystalline phases and observed from literature research it was not possible to retrieve, nor the XRPD calculated pattern (the crystal structure not reported in CSD) neither the raw data of the experimental XRPD analysis (only images were available). In this sense, from the perspective of a cocrystal investigation, the resulting crystalline phases obtained were assessed by direct comparison with available reference XRPD calculated patterns as well as with XRPD experimental patterns images. 
     Moving to cocrystal derivatives of Apixaban, patent CN 106986868 firstly reported the preparation methods of eutectic crystals of Apixaban with oxalic acid, isonicotine, 3-aminopyridine and urea, along with their XRPD. Moreover, further derivatives were reported and characterized in two different papers. 
     In detail, Apixaban derivatives with Fumaric, Succinic and D,L-malic acids were prepared and characterized in  Appl. Spectrosc.  2014, 68, 758; these derivatives were described as isostructural polymorphs, and XRPD of the described species are reported. Furthermore, in  Cryst. Growth Des.  2016, 16, 2923, even an Apixaban/oxalic acid cocrystal was described. In the same article, even other coformers were tested, such as Malonic acid, Succinic acid, Maleic acid, Adipic acid, Glycolic acid, Salicylic acid, 4-hydroxybenzoic acid, L-malic acid and L-tartaric acid. Nevertheless, no cocrystals with these coformers were reported. 
     In the Table 2 below, the results on the cocrystal derivatives of Apixaban in the literature are reported. 
     
       
         
           
               
               
               
               
               
               
               
               
               
               
             
               
                   
               
               
                   
                   
                   
                   
                   
                   
                 Com- 
                   
                 Analytical 
                   
               
               
                   
                 Patent 
                   
                 Author/ 
                   
                 Patent 
                 pound 
                   
                 techniques 
               
               
                 Title 
                 Number 
                 DOI 
                 Applicants 
                 Journal 
                 Type 
                 Name 
                 Date 
                 and notes 
                 Notes 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
            
               
                 Patents 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Eutectic 
                 CN106986868A 
                   
                 / 
                   
                 Preparation 
                 Apixaban 
                 2017 
                 XRPD of 
                 Eutectic crystals and 
               
               
                 crystals 
                   
                   
                   
                   
                 of eutectic 
                   
                 Jul. 
                 Apixaban 
                 preparation methods 
               
               
                 containing 
                   
                   
                   
                   
                 crystals 
                   
                 28 
                 derivatives 
                 of: 
               
               
                 apixaban, and 
                   
                   
                   
                   
                 of 
                   
                   
                   
                 apixaban/oxalic acid 
               
               
                 preparation 
                   
                   
                   
                   
                 Apixaban 
                   
                   
                   
                 apixaban/isonicotine 
               
               
                 methods 
                   
                   
                   
                   
                   
                   
                   
                   
                 apixaban/3- 
               
               
                 thereof 
                   
                   
                   
                   
                   
                   
                   
                   
                 aminopyridine 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 apixaban/urea 
               
            
           
           
               
            
               
                 Papers 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Polymorph 
                   
                 10.1366/ 
                 Peter J. 
                 Applied 
                   
                 Apixaban 
                 Volume 
                 Low 
                 Coformer tested: 
               
               
                 Characteriza- 
                   
                 13-07329 
                 Larkin, 
                 Spectroscopy 
                   
                   
                 68, 
                 frequency 
                 Fumaric acid 
               
               
                 tion of Active 
                   
                   
                 Marta 
                   
                   
                   
                 Number 
                 Raman, 
                 Succinic acid 
               
               
                 Pharmaceutical 
                   
                   
                 Dabros, 
                   
                   
                   
                 7, 2014 
                 XRPD 
                 D,L malic acid 
               
               
                 Ingredients 
                   
                   
                 Beth 
                   
                   
                   
                   
                 and SC 
                 Isostructural 
               
               
                 (APIs) 
                   
                   
                 Sarsfield, 
                   
                   
                   
                   
                 XRD 
                 CoCrystals 
               
               
                 using Low- 
                   
                   
                 Eric Chan, 
                   
                   
                   
                   
                 (not 
                 (crystalline 
               
               
                 Frequency 
                   
                   
                 James T. 
                   
                   
                   
                   
                 reported 
                 structure 
               
               
                 Raman 
                   
                   
                 Carriere, 
                   
                   
                   
                   
                 in CSD) 
                 determined). 
               
               
                 Spectroscopy 
                   
                   
                 Brian C. 
                   
                   
                   
                   
                   
                 From CSD research 
               
               
                   
                   
                   
                 Smith 
                   
                   
                   
                   
                   
                 not found. 
               
               
                 Improving the 
                   
                 10.1021/ 
                 Young 
                 Crystal 
                   
                 Apixaban 
                 Mar. 
                 XRPD 
                 Other coformer tested: 
               
               
                 Solubility and 
                   
                 ac s.c 
                 Chen, 
                 Growth &amp; 
                   
                   
                 31, 
                 DSC on 
                 Malonic acid 
               
               
                 Bioavailability 
                   
                 gd.6b00266 
                 Long Li, 
                 Design 
                   
                   
                 2016 
                 oxalic 
                 Succinic acid 
               
               
                 of Apixaban 
                   
                   
                 Jia Yao, 
                   
                   
                   
                   
                 apixaban 
                 Maleic acid 
               
               
                 via Apixaban- 
                   
                   
                 Yu-Yu Ma, 
                   
                   
                   
                   
                 cocrystal 
                 Adipic acid 
               
               
                 Oxalic 
                   
                   
                 Jia-Mei 
                   
                   
                   
                   
                 hydrate. 
                 Glycolic acid 
               
               
                 Acid Cocrystal 
                   
                   
                 Chen and 
                   
                   
                   
                   
                 CSD ref. 
                 Salicylic acid 
               
               
                   
                   
                   
                 Tong-Bu 
                   
                   
                   
                   
                 OKAWEE 
                 4-hydroxybenzoic acid 
               
               
                   
                   
                   
                 Lu 
                   
                   
                   
                   
                   
                 L-malic acid 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 L-tartaric acid 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 No cocrystal with 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 these coformers 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 are reported. 
               
               
                   
               
            
           
         
       
     
     Therefore, it is desirable to provide new derivatives of Apixaban with good solubility in water, a defined chemical structure and no observed adverse effect level (NOAEL). The new derivatives of Apixaban must have good stability and compressibility, useful for preparing pharmaceutical compositions in the form of tablets. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The features and advantages of certain embodiments will be more readily appreciated when considered in conjunction with the accompanying figures. The figures are not to be construed as limiting any of the preferred embodiments. 
         FIG.  1    is the XRPD pattern comparison between TRQ01-Apixaban (black line) and the solid isolated from KN experiment using MOA (red line). XRPD pattern of Malonic Acid (green line) is reported as reference. 
         FIG.  2    is the XRPD pattern comparison between TRQ01-Apixaban (black line) and the solid isolated from KN experiment using KGL (red line). XRPD pattern of α-Ketoglutaric Acid (green line) is reported as reference. 
         FIG.  3    is the XRPD pattern comparison between TRQ01-Apixaban (black line) and the solid isolated from KN experiment using GAL (red line). XRPD pattern of Gallic Acid (green line) is reported as reference. 
         FIG.  4    is the XRPD pattern comparison between TRQ01-Apixaban (black line) and the solid isolated from KN experiment using MEA (red line). XRPD pattern of Maleic Acid (green line) is reported as reference. 
         FIG.  5    is the XRPD pattern comparison between TRQ01-Apixaban (black line) and the solid isolated from KN experiment using GLY (red line). XRPD pattern of Glycolic Acid (green line) is reported as reference. 
         FIG.  6    is the XRPD pattern comparison between TRQ01-Apixaban (black line) and the solid isolated from KN experiment using LTA (red line). XRPD pattern of L-Tartaric Acid (green line) is reported as reference. 
         FIG.  7    is the XRPD pattern comparison between TRQ01-Apixaban (black line) and the solid isolated from KN experiment using CIA (red line). XRPD pattern of Citric acid (green line) is reported as reference. 
         FIG.  8    is the XRPD pattern comparison between TRQ01-Apixaban (black line) and the solid isolated from KN experiment using GTR (red line). XRPD pattern of Glutaric acid (green line) is reported as reference. 
         FIG.  9    is the XRPD pattern comparison between TRQ01-Apixaban (black line) and the solid isolated from KN experiment using DCBA (red line). XRPD pattern of 2,4-Dichlorobenzyl Alcohol (green line) is reported as reference. 
         FIG.  10    is the XRPD pattern comparison between TRQ01-Apixaban (black line) and the solid isolated from KN experiment using ITA (red line). XRPD pattern of Itaconic acid (green line) is reported as reference. 
         FIG.  11    is the XRPD pattern comparison between TRQ01-Apixaban (black line) and the solid isolated from KN experiment using COU (red line). XRPD pattern of Coumaric acid (green line) is reported as reference. 
         FIG.  12    is the XRPD pattern comparison between TRQ01-Apixaban (black line) and the solid isolated from KN experiment using DHB (red line). XRPD pattern of Gentisic acid (green line) is reported as reference. 
         FIG.  13    is the XRPD pattern comparison between TRQ01-Apixaban (black line) and the solid isolated from KN experiment using FER (red line). XRPD pattern of Ferulic acid (green line) is reported as reference. 
         FIG.  14    is the XRPD pattern comparison between TRQ01-Apixaban (black line) and the solid isolated from KN experiment using TRI (red line). XRPD pattern of Trimesic acid (green line) is reported as reference. 
         FIG.  15    is the XRPD pattern comparison between TRQ01-Apixaban (black line) and the solid isolated from KN experiment using VAN (red line). XRPD pattern of Vanillic acid (green line) is reported as reference. 
         FIG.  16    is the XRPD pattern of sample TRQ01-API-MOA-ssSL-H 2 O-200 mg-dried. 
         FIG.  17    shows the DSC profile of sample TRQ01-API-MOA-ssSL-H2O-200 mg-dried. 
         FIG.  18    shows the TG (black line) and dTG (red line) profiles of sample TRQ01-API-MOA-ssSL-H2O-200 mg-dried. 
         FIG.  19    shows the 3D-EGA profile of sample TRQ01-API-MOA-ssSL-H2O-200 mg-dried. 
         FIG.  20    is the FT-IR spectrum of sample TRQ01-API-MOA-ssSL-H 2 O-200 mg-dried. 
         FIG.  21    is the FT-Raman spectrum of sample TRQ01-API-MOA-ssSL-H 2 O-200 mg-dried. 
         FIG.  22    is the 1H-NMR spectrum of sample TRQ01-API-MOA-ssSL-H 2 O-200 mg-dried. 
         FIG.  23    is the XRPD pattern of sample TRQ01-API-KGL-1-1-SL-ETA-200 mg-dried. 
         FIG.  24    shows the DSC profile of sample TRQ01-API-KGL-1-1-SL-ETA-200 mg-dried. 
         FIG.  25    shows the TG (black line) and dTG (red line) profiles of sample TRQ01-API-KGL-1-1-SL-ETA-200 mg-dried. 
         FIG.  26    shows the 3D-EGA profile of sample TRQ01-API-KGL-1-1-SL-ETA-200 mg-dried. 
         FIG.  27    is the FT-IR spectrum of sample TRQ01-API-KGL-1-1-SL-ETA-200 mg-dried. 
         FIG.  28    is the FT-Raman spectrum of sample TRQ01-API-KGL-1-1-SL-ETA-200 mg-dried. 
         FIG.  29    is the 1H-NMR spectrum of sample TRQ01-API-KGL-1-1-SL-ETA-200 mg-dried. 
         FIG.  30    is the XRPD pattern of sample TRQ01-API-GAL-1-1-SL-H2O-50C-R01-filtered. 
         FIG.  31    shows the DSC profile of sample TRQ01-API-GAL-NP01b. 
         FIG.  32    shows the TG (black line) and dTG (red line) profiles of sample TRQ01-API-GAL-NP01b. 
         FIG.  33    shows the 3D-EGA profile of sample TRQ01-API-GAL-NP01b. 
         FIG.  34    is the FT-IR spectrum of sample TRQ01-API-GAL-NP01b. 
         FIG.  35    is the FT-Raman spectrum of sample TRQ01-API-GAL-NP01b. 
         FIG.  36    is the 1H-NMR spectrum of sample TRQ01-API-GAL-NP01b. 
         FIG.  37    is the XRPD pattern of sample TRQ01-API-MEA-1-3-SL-ETA-200 mg-dried. 
         FIG.  38    shows the DSC profile of sample TRQ01-API-MEA-1-3-SL-ETA-200 mg-dried. 
         FIG.  39    shows the TG (black line) and dTG (red line) profiles of sample TRQ01-API-MEA-1-3-SL-ETA-200 mg-dried. 
         FIG.  40    shows the 3D-EGA profile of sample TRQ01-API-MEA-1-3-SL-ETA-200 mg-dried. 
         FIG.  41    is the FT-IR spectrum of sample TRQ01-API-MEA-1-3-SL-ETA-200 mg-dried. 
         FIG.  42    is the FT-Raman spectrum of sample TRQ01-API-MEA-1-3-SL-ETA-200 mg-dried. 
         FIG.  43    is the 1H-NMR spectrum of sample TRQ01-API-MEA-1-3-SL-ETA-200 mg-dried. 
         FIG.  44    is the XRPD pattern of sample TRQ01-API-LTA-1-1-SL-ACN-200 mg-dried. 
         FIG.  45    shows the DSC profile of sample TRQ01-API-LTA-1-1-SL-ACN-200 mg-dried. 
         FIG.  46    shows the TG (black line) and dTG (red line) profiles of sample TRQ01-API-LTA-1-1-SL-ACN-200 mg-dried. 
         FIG.  47    shows the 3D-EGA profile of sample TRQ01-API-LTA-1-1-SL-ACN-200 mg-dried. 
         FIG.  48    is the FT-IR spectrum of sample TRQ01-API-LTA-1-1-SL-ACN-200 mg-dried. 
         FIG.  49    is the FT-Raman spectrum of sample TRQ01-API-LTA-1-1-SL-ACN-200 mg-dried. 
         FIG.  50    is the 1H-NMR spectrum of sample TRQ01-API-LTA-1-1-SL-ACN-200 mg-dried. 
         FIG.  51    is the XRPD pattern of sample TRQ01-API-CIA-1-1,1-SL-ETA-200 mg-dried. 
         FIG.  52    shows the DSC profile of sample TRQ01-API-CIA-1-1,1-SL-ETA-200 mg-dried. 
         FIG.  53    shows the TG (black line) and dTG (red line) profiles of sample TRQ01-API-CIA-1-1,1-SL-ETA-200 mg-dried. 
         FIG.  54    shows the 3D-EGA profile of sample TRQ01-API-CIA-1-1,1-SL-ETA-200 mg-dried. 
         FIG.  55    is the FT-IR spectrum of sample TRQ01-API-CIA-1-1,1-SL-ETA-200 mg-dried. 
         FIG.  56    is the FT-Raman spectrum of sample TRQ01-API-CIA-1-1,1-SL-ETA-200 mg-dried. 
         FIG.  57    is the 1H-NMR spectrum of sample TRQ01-API-CIA-1-1,1-SL-ETA-200 mg-dried. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     For the sake of clarity and comprehension of the description, the following Table comprises a Glossary of terms used along the same. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Glossary: Abbreviation table 
               
            
           
           
               
               
            
               
                 Abbreviation 
                 Definition 
               
               
                   
               
               
                 ABZ 
                 Benzyl alcohol 
               
               
                 ACT 
                 Acetone 
               
               
                 API 
                 Apixaban 
               
               
                 CAN 
                 Acetonitrile 
               
               
                 CIA 
                 Citric Acid 
               
               
                 Class 1 
                 Unrestricted salt-formers used because physiologically 
               
               
                   
                 ubiquitous ions or intermediate metabolites in 
               
               
                   
                 biochemical pathways 
               
               
                 Class 2 
                 Not naturally occurring salt-formers but profusely 
               
               
                   
                 employed due to their low toxicity and good tolerability 
               
               
                 Class 3 
                 No prohibitive adverse salt-formers but some of these 
               
               
                   
                 have their own pharmacological activity or less 
               
               
                   
                 frequently used in the past 
               
               
                 COU 
                 p-Coumaric Acid 
               
               
                 CSD 
                 Cambridge Structure Database 
               
               
                 DCBA 
                 2,4-Dichlorobenzyl Alcohol 
               
               
                 DHB 
                 2,5-Dihydroxybenzoic Acid 
               
               
                 DMA 
                 Dimethylacetamide 
               
               
                 DSC 
                 Differential Scanning Calorimetry 
               
               
                 EGA 
                 Evolved Gas Analysis 
               
               
                 ETA 
                 Ethyl acetate 
               
               
                 ETH 
                 Ethanol 
               
               
                 FER 
                 Ferulic Acid 
               
               
                 FT-IR 
                 Fourier Transform Infrared Spectroscopy 
               
               
                 FT-Raman 
                 Fourier Transform Raman Spectroscopy 
               
               
                 GAL 
                 Gallic Acid 
               
               
                 GLY 
                 Glycolic Acid 
               
               
                 GRAS 
                 Generally Recognized as Safe 
               
               
                 GTR 
                 Glutaric Acid 
               
               
                 H 2 O 
                 Water 
               
               
                 Iidg 
                 Inactive ingredients Database Guide 
               
               
                 ITA 
                 Itaconic Acid 
               
               
                 KGL 
                 α-Ketoglutaric Acid 
               
               
                 KN 
                 Kneading 
               
               
                 LTA 
                 L-Tartaric Acid 
               
               
                 MEA 
                 Maleic Acid 
               
               
                 MET 
                 Methanol 
               
               
                 MOA 
                 Malonic Acid 
               
               
                 MPR 
                 2-Methyl-1-Propanol 
               
               
                 NMR 
                 Nuclear Magnetic Resonance 
               
               
                 NP 
                 New pattern 
               
               
                 NS 
                 Not sieved 
               
               
                 1PR 
                 1-Propanol 
               
               
                 S 
                 Sieved 
               
               
                 SL 
                 Slurry 
               
               
                 ssSL 
                 Slurry from Saturated Solution 
               
               
                 TGA 
                 Thermal Gravimetric Analysis 
               
               
                 THF 
                 Tetrahydrofuran 
               
               
                 TRI 
                 Trimesic Acid 
               
               
                 VAN 
                 Vanillic Acid 
               
               
                 XRPD 
                 X-Ray Powder Diffraction 
               
               
                   
               
            
           
         
       
     
     With regards to the cocrystal screening protocol, solid state kneading was tested as a first approach. The kneading methodology was found to be an extremely powerful technique to discover new derivatives. Moreover, the performed experiments confirmed the high tendency of Apixaban to form new derivatives with the selected coformers. Based on the collected results, and taking into account the solubility of the tested coformer in water, fifteen coformers such as MOA, KGL, GAL, MEA, GLY, LTA, CIA, GTR, DCBA, ITA, COU, DHB, FER, TRI and VAN were identified. 
     From the results collected from kneading experiments, the isolation of the observed derivatives was attempted through liquid-based methods such as slurry. Slurry in coformer saturated solutions were performed, the isolated species was characterized by means of thermal (DSC and TGA/EGA) and spectroscopic analyses (FT-IR, FTRaman and 1H-NMR). 
     The isolated derivatives are summarized below, and a brief description of each was reported. 
     API-KGL derivative NP02: it was synthesized from a slurry of API and 1 equivalent of KGL in ETA. The stoichiometry of the species could be quantified as API:KGL 1:1. 
     API-GAL derivative NP01b: it was synthesized by dissolution of API and 1 equivalent of GAL in H 2 O at 50° C. NMR spectrum disclosed the stoichiometry of the isolated species as API:GAL 1:0.35. 
     API-MEA derivative NP01: it was synthesized from a slurry of API and 3 equivalents of MEA in ETA. A complete characterization of the species was carried out. 1H-NMR spectrum showed the presence of both API and MEA in a stoichiometric ratio of API:MEA 1:0.5. 
     API-LTA derivative NP01: it was synthesized from a slurry of API and 1 equivalent of LTA in ACN. A complete characterization of the species was carried out. NMR spectrum showed the presence of both API and LTA in a stoichiometric ratio of API:LTA 1:0.5. 
     API-CIA derivative NP02: it was synthesized from a slurry of API and 1.1 equivalent of CIA in ETA. A complete characterization of the species was carried out. NMR spectrum showed the presence of both API and CIA in a stoichiometric ratio of API:CIA 1:0.5. 
     API-MOA derivative NP01: it was synthesized by ssSL reaction in H 2 O. A complete characterization of the species was carried out. NMR spectrum showed the presence of both API and MOA in a stoichiometric ratio of API:MOA 1:0.25. 
     EXPERIMENTAL 
     Prescreening 
     Cocrystals Synthesis 
     Generally, cocrystals were prepared by solid and liquid based methods; the reactivity of the substrate was initially investigated by solid state reactions (Kneading) and then confirmed and explored by solution reactions: slurry maturation, crystallization from solution and solvent evaporation. 
     Solid State Kneading 
     As a first step of the Cocrystal synthesis, solid state Kneading was tested. 
     Apixaban (50 mg) and the chosen coformer (1.0 equivalent) were accurately weighed and transferred in a stainless jar equipped with stainless ball. The mixture was ground by ball milling in a Retsch MM 200 grinder for 15 minutes at a frequency of 30 Hz with a catalytic amount of H 2 O (10 μl). The recovered powders were analyzed by XRPD and the patterns compared with that of Apixaban and coformer. 
     Moreover, the performed experiments using the kneading methodology provided new derivatives of Apixaban with selected coformers, wherein the latter have been selected from the group consisting of MOA, KGL, GAL, MEA, GLY, LTA, CIA, GTR, DCBA, ITA, COU, DHB, FER, TRI and VAN. 
     Based on the collected results and taking into account the solubility of the tested coformer in water, a new more restricted group of six coformers was selected. These new derivatives were obtained using the following coformers: MOA, KGL, GAL, MEA, LTA and CIA, and their derivatives were in depth studied. 
     As a first step, XRPD pattern comparisons between TRQ01-Apixaban (black line), the solid isolated from KN experiment using each coformer (red line), and the used coformer (green line) were performed, wherein these comparisons are shown as follows: MOA ( FIG.  1   ), KGL ( FIG.  2   ), GAL ( FIG.  3   ), MEA ( FIG.  4   ), LTA ( FIG.  6   ) and CIA ( FIG.  7   ). 
     In turn, probable new derivatives were observed from experiments carried out with the following coformers GLY, GTR, DCBA, ITA, COU, DHB, FER, TRI and VAN, but at the moment, only XRPD pattern comparisons between TRQ01-Apixaban (black line), the solid isolated from KN experiment using each coformer (red line), and the coformer (green line) were performed. 
     These XRPD pattern comparisons are shown as follows: GLY ( FIG.  5   ), GTR ( FIG.  8   ), DCBA ( FIG.  9   ), ITA ( FIG.  10   ), COU ( FIG.  11   ), DHB ( FIG.  12   ), FER ( FIG.  13   ), TRI ( FIG.  14   ) and VAN ( FIG.  15   ). 
     Hereafter, the studies performed on the six derivatives obtained with the coformers MOA, KGL, GAL, MEA, LTA and CIA are provided. 
     Apixaban—Malonic Acid Derivative 
     A new derivative of Apixaban and Malonic Acid was firstly observed from Kneading experiment. In detail, the recovered powder showed a new XRPD pattern, labeled as NP01. 
     Characterization of API-MOA Derivative NP01 (200 mg Scale) 
     A saturated solution of MOA was prepared by adding solid coformer to 4.0 ml of H 2 O until no further dissolution. The resulting solution was so filtered using a 0.45 mm syringe filter to remove any excess solid. The filtered solution was then added to Apixaban (200 mg) and the resulting mixture was stirred at room temperature for 24 hours. 
     After this time, the formed solid was isolated by vacuum filtration and washed with 1 ml of H 2 O, analyzed by XRPD and dried at 40° C. and 30 mbar for 20 hours. After the drying step, XRPD analysis was performed again. 
     XRPD 
     In  FIG.  16    was reported the XRPD pattern and the peaks list of sample TRQ01-API-MOA-ssSL-H 2 O-200 mg-dried was reported below. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 XRPD peak list of sample TRQ01- 
               
               
                 API-MOA-ssSL-H 2 O-200 mg-dried. 
               
            
           
           
               
               
               
               
               
            
               
                 Pos. 
                 Height 
                 FWHM 
                 d-spacing 
                 Rel. Int. 
               
               
                 [°2Th.] 
                 [cts] 
                 [°2Th.] 
                 [Å] 
                 [%] 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 5.8511 
                 5657.28 
                 0.0984 
                 15.10497 
                 100.00 
               
               
                 7.3923 
                 1011.77 
                 0.1279 
                 11.95894 
                 17.88 
               
               
                 8.9234 
                 207.91 
                 0.1378 
                 9.91014 
                 3.68 
               
               
                 9.4742 
                 22.94 
                 0.2362 
                 9.33523 
                 0.41 
               
               
                 11.6320 
                 4342.78 
                 0.0984 
                 7.60786 
                 76.76 
               
               
                 11.6988 
                 3437.19 
                 0.0295 
                 7.56457 
                 60.76 
               
               
                 13.0254 
                 58.97 
                 0.1181 
                 6.79700 
                 1.04 
               
               
                 13.4915 
                 1345.49 
                 0.1181 
                 6.56317 
                 23.78 
               
               
                 13.8324 
                 345.83 
                 0.1574 
                 6.40219 
                 6.11 
               
               
                 16.0239 
                 1571.88 
                 0.1082 
                 5.53121 
                 27.79 
               
               
                 16.8694 
                 320.98 
                 0.0689 
                 5.25582 
                 5.67 
               
               
                 17.1156 
                 94.19 
                 0.0590 
                 5.18079 
                 1.66 
               
               
                 17.4169 
                 554.89 
                 0.0394 
                 5.09185 
                 9.81 
               
               
                 17.8718 
                 2481.25 
                 0.1476 
                 4.96324 
                 43.86 
               
               
                 18.6649 
                 666.28 
                 0.0480 
                 4.75017 
                 11.78 
               
               
                 18.7282 
                 959.10 
                 0.0689 
                 4.73818 
                 16.95 
               
               
                 19.3150 
                 30.91 
                 0.1181 
                 4.59551 
                 0.55 
               
               
                 19.7416 
                 169.58 
                 0.1574 
                 4.49717 
                 3.00 
               
               
                 20.0703 
                 1282.82 
                 0.0984 
                 4.42427 
                 22.68 
               
               
                 20.4507 
                 760.68 
                 0.0480 
                 4.33922 
                 13.45 
               
               
                 20.5330 
                 574.48 
                 0.0590 
                 4.32560 
                 10.15 
               
               
                 20.7370 
                 327.45 
                 0.1378 
                 4.28350 
                 5.79 
               
               
                 21.1204 
                 62.95 
                 0.1181 
                 4.20660 
                 1.11 
               
               
                 21.4909 
                 261.50 
                 0.0984 
                 4.13491 
                 4.62 
               
               
                 21.7183 
                 515.62 
                 0.1181 
                 4.09213 
                 9.11 
               
               
                 22.0213 
                 2113.35 
                 0.0840 
                 4.03315 
                 37.36 
               
               
                 22.0907 
                 2987.37 
                 0.0720 
                 4.02064 
                 52.81 
               
               
                 22.1738 
                 2336.03 
                 0.0480 
                 4.01572 
                 41.29 
               
               
                 23.0031 
                 148.22 
                 0.1920 
                 3.86320 
                 2.62 
               
               
                 23.3901 
                 2203.82 
                 0.1680 
                 3.80014 
                 38.96 
               
               
                 23.4842 
                 1963.19 
                 0.0600 
                 3.79453 
                 34.70 
               
               
                 24.6527 
                 287.46 
                 0.1680 
                 3.60830 
                 5.08 
               
               
                 25.0185 
                 973.66 
                 0.0840 
                 3.55637 
                 17.21 
               
               
                 25.6952 
                 433.00 
                 0.0840 
                 3.46421 
                 7.65 
               
               
                 26.5882 
                 326.43 
                 0.0600 
                 3.34986 
                 5.77 
               
               
                 27.1361 
                 30.98 
                 0.2400 
                 3.28346 
                 0.55 
               
               
                 27.7045 
                 119.77 
                 0.1200 
                 3.21737 
                 2.12 
               
               
                 28.5968 
                 191.18 
                 0.1920 
                 3.11897 
                 3.38 
               
               
                 29.2290 
                 667.22 
                 0.0960 
                 3.05294 
                 11.79 
               
               
                 29.9914 
                 502.86 
                 0.1200 
                 2.97704 
                 8.89 
               
               
                 30.8194 
                 292.56 
                 0.2160 
                 2.89892 
                 5.17 
               
               
                 31.1427 
                 128.03 
                 0.1440 
                 2.86956 
                 2.26 
               
               
                 31.7752 
                 27.95 
                 0.1440 
                 2.81387 
                 0.49 
               
               
                 32.2029 
                 199.36 
                 0.1200 
                 2.77747 
                 3.52 
               
               
                 32.9913 
                 167.56 
                 0.1680 
                 2.71287 
                 2.96 
               
               
                 34.1007 
                 40.84 
                 0.2880 
                 2.62711 
                 0.72 
               
               
                 35.0668 
                 72.70 
                 0.1200 
                 2.55691 
                 1.29 
               
               
                 35.3827 
                 134.26 
                 0.1680 
                 2.53480 
                 2.37 
               
               
                 36.1242 
                 47.43 
                 0.2160 
                 2.48445 
                 0.84 
               
               
                 37.0876 
                 38.64 
                 0.2880 
                 2.42210 
                 0.68 
               
               
                 38.2364 
                 183.08 
                 0.2160 
                 2.35193 
                 3.24 
               
               
                 38.9506 
                 97.20 
                 0.0720 
                 2.31043 
                 1.72 
               
               
                   
               
            
           
         
       
     
     DSC/TGA/EGA 
       FIGS.  17 ,  18  and  19    correspond to DSC, TG and EGA analyses of sample TRQ01-API-MOA-ssSL-H 2 O-200 mg-dried, respectively. 
     The DSC showed an endothermic event at 58.7° C. (Onset 29.0° C.) imputable to sample dehydration. A second complex endothermic event was observed at 161.8° C. (Onset 149.9° C.) and it could be tentatively assigned to multiple events partially overlapped ascribable to melting and degradation process (range 170-190° C.) of Malonic Acid. 
     The dehydration step was confirmed by TG/EG analysis, since a weight loss of 3.6% w/w was recorded in correspondence with this event. In addition, a second weight loss of 4.6% w/w was observed at follows. 150° C., confirming the nature of the second endothermic event in the DSC profile. The degradation was confirmed even by EG analysis, where the evolution of Acetic Acid was recorded after 15 minutes of analysis, revealing the presence of Malonic Acid in the sample. 
     Finally, as follows, 240° C., melting of Apixaban was observed, while its decomposition occurred above 340° C. 
     FT-IR 
       FIG.  20    reports the FT-IR spectrum of API-MOA derivative NP01 and its peak list is provided. A comparison with FT-IR spectrum of Apixaban suggested the formation of a new species. In detail, the band at 1733 cm −1  could be associated to the presence of the coformer in the new derivative. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 FT-IR peak list of TRQ01-API-MOA-ssSL-H 2 O-200 mg-dried. 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Position (cm −1 ) 
                 Intensity 
                 Position (cm −1 ) 
                 Intensity 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 428.30 
                 54.721 
                 1147.83 
                 50.292 
               
               
                   
                 465.01 
                 58.715 
                 1165.90 
                 52.569 
               
               
                   
                 518.68 
                 38.557 
                 1207.93 
                 63.871 
               
               
                   
                 538.06 
                 46.899 
                 1229.95 
                 53.088 
               
               
                   
                 557.88 
                 43.071 
                 1254.22 
                 35.891 
               
               
                   
                 606.30 
                 51.556 
                 1296.66 
                 40.725 
               
               
                   
                 649.18 
                 59.281 
                 1335.56 
                 52.236 
               
               
                   
                 665.25 
                 57.482 
                 1373.00 
                 73.148 
               
               
                   
                 702.42 
                 53.192 
                 1400.48 
                 67.151 
               
               
                   
                 757.27 
                 64.309 
                 1440.02 
                 61.786 
               
               
                   
                 789.06 
                 62.222 
                 1461.54 
                 53.588 
               
               
                   
                 797.47 
                 70.325 
                 1512.24 
                 33.177 
               
               
                   
                 815.12 
                 53.583 
                 1543.66 
                 77.903 
               
               
                   
                 831.01 
                 33.289 
                 1590.99 
                 44.893 
               
               
                   
                 898.25 
                 79.813 
                 1628.87 
                 56.170 
               
               
                   
                 936.71 
                 70.899 
                 1662.42 
                 38.302 
               
               
                   
                 981.44 
                 60.612 
                 1732.73 
                 85.748 
               
               
                   
                 1003.58 
                 57.832 
                 2943.54 
                 86.275 
               
               
                   
                 1019.93 
                 57.548 
                 3177.68 
                 83.513 
               
               
                   
                 1030.12 
                 61.473 
                 3238.49 
                 83.203 
               
               
                   
                 1091.35 
                 71.522 
                 3444.34 
                 83.381 
               
               
                   
                 1112.00 
                 62.437 
               
               
                   
                   
               
            
           
         
       
     
     FT-Raman 
     In the  FIG.  21    was reported the FT-Raman spectrum of API-MOA derivative NP01 which peak list was provided as follows. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 FT-Raman peak list of TRQ01-API-MOA-ssSL-H 2 O-200 mg-dried 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Position (cm −1 ) 
                 Intensity 
                 Position (cm −1 ) 
                 Intensity 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 97.08 
                 136.228 
                 1337.85 
                 22.031 
               
               
                   
                 407.84 
                 10.329 
                 1374.16 
                 26.455 
               
               
                   
                 634.89 
                 8.889 
                 1423.51 
                 29.397 
               
               
                   
                 701.88 
                 21.953 
                 1450.24 
                 56.073 
               
               
                   
                 734.98 
                 8.081 
                 1463.30 
                 44.531 
               
               
                   
                 758.22 
                 11.109 
                 1515.48 
                 43.834 
               
               
                   
                 798.70 
                 14.151 
                 1612.06 
                 78.667 
               
               
                   
                 937.81 
                 10.152 
                 1663.28 
                 55.618 
               
               
                   
                 1001.87 
                 12.970 
                 2940.46 
                 30.162 
               
               
                   
                 1174.98 
                 16.531 
                 2971.75 
                 27.726 
               
               
                   
                 1239.27 
                 27.192 
                 3073.28 
                 23.429 
               
               
                   
                 1303.34 
                 15.498 
               
               
                   
                   
               
            
           
         
       
     
     1H-NMR 
     1H-NMR spectrum ( FIG.  22   ) of sample TRQ01-Anin the stoichiometric ratio API:MOA approximately 1:0.25 (in agreement with TG analysis). PI-MOA-ssSL-H 2 O-200 mg-dried showed the presence of Apixaban and Malonic Acid. 
     The characteristic peaks of the 1H-NMR spectrum are as follows: (400 MHz, DMSO-d6) δ: 7.71 (bs, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.43 (bs, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.27 (d, J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz, 2H), 4.05 (t, J=6.4 Hz, 2H), 3.80 (s, 3H), 3.59 (t, J=5.6 Hz, 2H), 3.22 (s, 0.25H), 3.20 (t, J=6.4 Hz, 2H), 2.38 (t, J=6.4 Hz, 2H), 1.90-1.78 (m, 4H). 
     Apixaban-α-Ketoglutaric Acid Derivative 
     A new derivative labeled as NP01 was recovered from kneading experiment between API and 1 equivalent of coformer. 
     A second derivative of Apixaban and α-Ketoglutaric Acid was isolated from ssSL experiments in ETA. This new derivative was labeled as NP02. 
     Characterization of API-KGL Derivative NP02 (200 mg Scale) 
     Synthesis 
     63.6 mg of α-Ketoglutaric Acid were accurately weighed in an 8 ml glass vial equipped with a magnetic stirring bar and dissolved in 4 ml of ETA. When the complete dissolution of the coformer occurred, 200 mg of Apixaban were added to the solution and the resulting mixture was stirred for 48 hours at room temperature. After this time, the formed solid was isolated by vacuum filtration and washed with 2 ml of ETA, analyzed by XRPD and dried at 40° C. and 30 mbar for 72 hours. After the drying step, XRPD analysis was performed again. 
     The so isolated derivative NP02 was fully characterized. 
     XRPD 
     XRPD pattern ( FIG.  23   ) and peaks list of sample TRQ01-API-KGL-1-1-SL-ETA-200 mg-dried were reported below. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 XRPD peak list of sample TRQ01- 
               
               
                 API-KGL-1-1-SL-ETA-200 mg-dried. 
               
            
           
           
               
               
               
               
               
            
               
                 Pos. 
                 Height 
                 FWHM 
                 d-spacing 
                 Rel. Int. 
               
               
                 [°2Th.] 
                 [cts] 
                 [°2Th.] 
                 [Å] 
                 [%] 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 3.2265 
                 18.82 
                 0.2362 
                 27.38412 
                 0.67 
               
               
                 5.5285 
                 37.32 
                 0.1574 
                 15.98567 
                 1.34 
               
               
                 6.3659 
                 1448.05 
                 0.0984 
                 13.88457 
                 51.91 
               
               
                 8.5284 
                 345.71 
                 0.0394 
                 10.36826 
                 12.39 
               
               
                 10.9701 
                 48.68 
                 0.1574 
                 8.06539 
                 1.74 
               
               
                 12.4024 
                 417.06 
                 0.0492 
                 7.13698 
                 14.95 
               
               
                 13.5989 
                 646.45 
                 0.0689 
                 6.51159 
                 23.17 
               
               
                 13.9609 
                 660.42 
                 0.0600 
                 6.33829 
                 23.67 
               
               
                 14.0013 
                 781.77 
                 0.0590 
                 6.32534 
                 28.02 
               
               
                 15.0356 
                 418.58 
                 0.0394 
                 5.89248 
                 15.00 
               
               
                 15.6675 
                 238.04 
                 0.0787 
                 5.65623 
                 8.53 
               
               
                 15.9813 
                 37.52 
                 0.0984 
                 5.54584 
                 1.35 
               
               
                 16.3741 
                 293.88 
                 0.0689 
                 5.41367 
                 10.53 
               
               
                 17.0420 
                 413.85 
                 0.0480 
                 5.19869 
                 14.84 
               
               
                 17.1107 
                 369.93 
                 0.0492 
                 5.18225 
                 13.26 
               
               
                 17.3416 
                 640.01 
                 0.0787 
                 5.11376 
                 22.94 
               
               
                 17.8078 
                 126.84 
                 0.0590 
                 4.98092 
                 4.55 
               
               
                 18.1972 
                 243.69 
                 0.0689 
                 4.87523 
                 8.74 
               
               
                 18.4765 
                 65.12 
                 0.1181 
                 4.80216 
                 2.33 
               
               
                 19.0027 
                 68.08 
                 0.1574 
                 4.67035 
                 2.44 
               
               
                 19.5763 
                 80.73 
                 0.1181 
                 4.53478 
                 2.89 
               
               
                 19.9861 
                 745.13 
                 0.0689 
                 4.44271 
                 26.71 
               
               
                 20.3443 
                 197.83 
                 0.0984 
                 4.36529 
                 7.09 
               
               
                 20.9534 
                 348.54 
                 0.0590 
                 4.23974 
                 12.49 
               
               
                 21.5680 
                 393.25 
                 0.0394 
                 4.12030 
                 14.10 
               
               
                 22.3222 
                 1123.84 
                 0.1378 
                 3.98277 
                 40.29 
               
               
                 23.4517 
                 2789.71 
                 0.1279 
                 3.79343 
                 100.00 
               
               
                 24.0583 
                 42.17 
                 0.0984 
                 3.69916 
                 1.51 
               
               
                 24.6482 
                 263.89 
                 0.1181 
                 3.61193 
                 9.46 
               
               
                 24.8508 
                 201.50 
                 0.1181 
                 3.58295 
                 7.22 
               
               
                 25.6615 
                 335.51 
                 0.1771 
                 3.47157 
                 12.03 
               
               
                 26.1885 
                 107.14 
                 0.1181 
                 3.40289 
                 3.84 
               
               
                 26.8581 
                 533.74 
                 0.0984 
                 3.31955 
                 19.13 
               
               
                 27.2819 
                 99.45 
                 0.1378 
                 3.26894 
                 3.56 
               
               
                 28.0618 
                 196.45 
                 0.0590 
                 3.17985 
                 7.04 
               
               
                 28.4363 
                 99.94 
                 0.1181 
                 3.13881 
                 3.58 
               
               
                 29.8395 
                 74.72 
                 0.1574 
                 2.99433 
                 2.68 
               
               
                 30.2508 
                 128.90 
                 0.1378 
                 2.95455 
                 4.62 
               
               
                 30.5052 
                 93.31 
                 0.0984 
                 2.93048 
                 3.34 
               
               
                 30.8588 
                 74.25 
                 0.1181 
                 2.89771 
                 2.66 
               
               
                 31.3648 
                 44.90 
                 0.1968 
                 2.85210 
                 1.61 
               
               
                 32.9322 
                 38.13 
                 0.3936 
                 2.71986 
                 1.37 
               
               
                 33.8768 
                 53.11 
                 0.1574 
                 2.64614 
                 1.90 
               
               
                 34.2951 
                 68.77 
                 0.1968 
                 2.61482 
                 2.47 
               
               
                 35.4351 
                 68.02 
                 0.1574 
                 2.53327 
                 2.44 
               
               
                 35.6866 
                 60.94 
                 0.2362 
                 2.51599 
                 2.18 
               
               
                 37.2404 
                 34.78 
                 0.1968 
                 2.41451 
                 1.25 
               
               
                 37.8218 
                 47.69 
                 0.1968 
                 2.37872 
                 1.71 
               
               
                 38.7662 
                 39.48 
                 0.2362 
                 2.32292 
                 1.42 
               
               
                   
               
            
           
         
       
     
     DSC/TGA/EGA 
       FIGS.  24 ,  25  and  26    correspond to DSC,TG and EGA analyses performed on sample TRQ01-API-KGL-1-1-SL-ETA-200 mg-dried, respectively. 
     The DSC profile showed an endothermic event at 174.3° C. (Onset 172.8° C.) imputable to sample melting and decomposition. 
     The melting/decomposition step was confirmed by TG/EG analysis, since a weight loss of 11.8% w/w was recorded in correspondence with this event. Combined TG/EG analysis even showed the presence of a small quantity of ETA trapped in the crystalline lattice of the new derivative. Indeed, this solvent was released immediately before the melting/decomposition of the sample. The amount of the solvent could not be unambiguously determined using this technique. 
     In addition, EGA confirmed the presence of KGL in the new derivative, since the massive CO2 evolution during the decomposition step, imputable to the α-Ketoglutaric Acid moiety. 
     FT-IR 
     In  FIG.  27    was reported the FT-IR spectrum of API-KGL derivative NP02 along with its peak list in the table below. The comparison with FT-IR spectrum of Apixaban suggested the formation of a new species. In detail, the band at 1727 cm −1  could be associated to the presence of the coformer in the new derivative. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 FT-IR peak list of TRQ01-API-KGL-1-1-SL-ETA-200 mg-dried. 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Position (cm −1 ) 
                 Intensity 
                 Position (cm −1 ) 
                 Intensity 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 414.10 
                 57.872 
                 1092.61 
                 60.446 
               
               
                   
                 431.13 
                 75.013 
                 1114.84 
                 74.669 
               
               
                   
                 459.64 
                 69.854 
                 1146.56 
                 42.417 
               
               
                   
                 489.44 
                 51.917 
                 1170.15 
                 40.671 
               
               
                   
                 513.92 
                 67.845 
                 1201.05 
                 60.109 
               
               
                   
                 523.10 
                 70.306 
                 1223.09 
                 53.537 
               
               
                   
                 545.30 
                 56.641 
                 1254.44 
                 29.844 
               
               
                   
                 560.14 
                 51.149 
                 1283.15 
                 46.228 
               
               
                   
                 593.14 
                 71.971 
                 1298.52 
                 38.450 
               
               
                   
                 606.42 
                 58.161 
                 1318.94 
                 60.773 
               
               
                   
                 615.38 
                 63.322 
                 1334.02 
                 59.826 
               
               
                   
                 630.45 
                 53.109 
                 1396.63 
                 55.785 
               
               
                   
                 680.94 
                 52.539 
                 1417.43 
                 63.590 
               
               
                   
                 708.33 
                 49.761 
                 1429.59 
                 63.784 
               
               
                   
                 760.99 
                 58.516 
                 1444.04 
                 63.563 
               
               
                   
                 801.53 
                 71.012 
                 1465.06 
                 59.570 
               
               
                   
                 813.17 
                 59.162 
                 1511.32 
                 30.726 
               
               
                   
                 831.59 
                 32.729 
                 1591.26 
                 43.785 
               
               
                   
                 926.04 
                 74.704 
                 1611.32 
                 59.949 
               
               
                   
                 945.21 
                 71.822 
                 1671.37 
                 39.205 
               
               
                   
                 983.93 
                 62.417 
                 1726.59 
                 43.194 
               
               
                   
                 1004.41 
                 56.681 
                 2892.04 
                 87.999 
               
               
                   
                 1017.51 
                 51.583 
                 3241.29 
                 90.525 
               
               
                   
                 1052.29 
                 73.051 
                 3381.30 
                 90.114 
               
               
                   
                   
               
            
           
         
       
     
     FT-Raman 
     In  FIG.  28    below was reported the FT-Raman spectrum of API-KGL derivative NP02 along with its peak list. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 FT-Raman peak list of TRQ01-API- 
               
               
                 KGL-1-1-SL-ETA-200 mg-dried. 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Position (cm −1 ) 
                 Intensity 
                 Position (cm −1 ) 
                 Intensity 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 106.57 
                 216.689 
                 1286.79 
                 60.348 
               
               
                   
                 218.27 
                 28.397 
                 1335.38 
                 43.432 
               
               
                   
                 257.68 
                 23.743 
                 1361.42 
                 45.116 
               
               
                   
                 404.18 
                 24.203 
                 1383.61 
                 80.404 
               
               
                   
                 637.76 
                 16.910 
                 1448.42 
                 105.022 
               
               
                   
                 708.88 
                 45.366 
                 1515.14 
                 63.409 
               
               
                   
                 762.09 
                 31.139 
                 1607.96 
                 167.686 
               
               
                   
                 797.29 
                 21.029 
                 1672.50 
                 82.915 
               
               
                   
                 945.36 
                 19.812 
                 1736.89 
                 19.867 
               
               
                   
                 1005.82 
                 22.576 
                 2891.14 
                 44.257 
               
               
                   
                 1086.06 
                 32.451 
                 2921.22 
                 51.791 
               
               
                   
                 1147.98 
                 24.916 
                 2967.87 
                 68.067 
               
               
                   
                 1177.51 
                 39.878 
                 3083.06 
                 30.101 
               
               
                   
                 1225.93 
                 43.981 
               
               
                   
                   
               
            
           
         
       
     
     1H-NMR 
     The 1H-NMR spectrum ( FIG.  29   ) of TRQ01-API-KGL-1-1-SL-ETA-200 mg-dried revealed the presence of both Apixaban and α-Ketoglutaric Acid. Since the observed integrals, the stoichiometric ratio could be calculated as API:KGL approx. 1:0.8. Only one peak related to KGL was clearly visible in the spectrum, while the second peak could be observed very close to the signal of DMSO, so an unambiguously integration could not be done. 
     The structural integrity of the molecule was confirmed. Small traces of ETA were observed, as already seen in TG/EG analysis; the amount of ETA could be quantified as 0.02 mol/mol. 
     The 1H-NMR spectrum particulars are as follows: (400 MHz, DMSO-d6) δ: 7.71 (bs, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.43 (bs, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.27 (d, J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz, 2H), 4.05 (t, J=6.4 Hz, 2H), 3.80 (s, 3H), 3.59 (t, J=5.6 Hz, 2H), 3.20 (t, J=6.4 Hz, 2H), 2.99 (bs, 1.6H), 2.38 (t, J=6.4 Hz, 2H), 1.90-1.78 (m, 4H). 
     Apixaban—Gallic Acid Derivative 
     A new derivative was isolated from Kneading experiment using Apixaban and 1, 2 or 3 equivalents of Gallic Acid coformer. This derivative was recovered in mixture with Apixaban Form I and free coformer using, H2O, 
     Characterization of API-GAL Derivative NP01b (1 g Scale) 
     Synthesis 
     370.2 mg of Gallic Acid were accurately weighed in a 100 mL glass reactor equipped with a magnetic stirring bar and dissolved in 20 mL of H 2 O at 50° C. When the complete dissolution of the coformer occurred, 1 g of Apixaban was added to the solution and the resulting mixture was stirred for 72 hours. 
     After this time, the formed solid was isolated by vacuum filtration and washed with 4 mL of H 2 O, analyzed by XRPD and dried at 40° C. and 30 mbar for 20 hours. After the drying step, XRPD analysis was performed again. 1.0544 g of the desired derivative were isolated (Y=93.4%). 
     The solid recovered from slurry experiment in H 2 O at 50° C. with 1 equivalent of Gallic Acid was characterized as reported below. The new isolated pattern was labeled as NP01b. 
     XRPD 
     The XRPD spectrum pattern is shown in  FIG.  30    and the list of peaks of sample TRQ01-API-GAL-1-1-SL-H2O-500-1G-R01-filtered was reported in the table below. 
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 XRPD peak list of sample TRQ01- 
               
               
                 API-GAL-1-1-SL-H2O-50C-R01-filtered. 
               
            
           
           
               
               
               
               
               
            
               
                 Pos. 
                 Height 
                 FWHM 
                 d-spacing 
                 Rel. Int. 
               
               
                 [°2Th.] 
                 [cts] 
                 [°2Th.] 
                 [Å] 
                 [%] 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 5.9749 
                 1769.86 
                 0.1279 
                 14.79230 
                 34.04 
               
               
                 7.3416 
                 279.13 
                 0.1181 
                 12.04144 
                 5.37 
               
               
                 8.9285 
                 668.18 
                 0.0689 
                 9.90445 
                 12.85 
               
               
                 10.6140 
                 27.44 
                 0.1181 
                 8.33516 
                 0.53 
               
               
                 11.1048 
                 146.52 
                 0.1968 
                 7.96787 
                 2.82 
               
               
                 11.8026 
                 5198.59 
                 0.1771 
                 7.49827 
                 100.00 
               
               
                 13.5195 
                 1895.36 
                 0.1082 
                 6.54965 
                 36.46 
               
               
                 13.6781 
                 1009.06 
                 0.0787 
                 6.47406 
                 19.41 
               
               
                 13.8554 
                 322.05 
                 0.0787 
                 6.39162 
                 6.19 
               
               
                 15.8383 
                 880.39 
                 0.0787 
                 5.59559 
                 16.94 
               
               
                 16.1363 
                 1639.20 
                 0.1181 
                 5.49291 
                 31.53 
               
               
                 16.6162 
                 318.35 
                 0.0787 
                 5.33535 
                 6.12 
               
               
                 16.8321 
                 583.66 
                 0.0787 
                 5.26739 
                 11.23 
               
               
                 17.0836 
                 108.72 
                 0.0590 
                 5.19042 
                 2.09 
               
               
                 17.7424 
                 1428.56 
                 0.0984 
                 4.99914 
                 27.48 
               
               
                 17.9839 
                 818.75 
                 0.0689 
                 4.93257 
                 15.75 
               
               
                 18.8133 
                 487.95 
                 0.0295 
                 4.71693 
                 9.39 
               
               
                 19.8963 
                 1552.98 
                 0.0492 
                 4.46256 
                 29.87 
               
               
                 20.5276 
                 1294.39 
                 0.0984 
                 4.32673 
                 24.90 
               
               
                 21.5745 
                 859.97 
                 0.1181 
                 4.11907 
                 16.54 
               
               
                 21.8798 
                 4371.56 
                 0.1082 
                 4.06229 
                 84.09 
               
               
                 22.1464 
                 3153.68 
                 0.1181 
                 4.01398 
                 60.66 
               
               
                 23.2397 
                 3180.87 
                 0.1673 
                 3.82756 
                 61.19 
               
               
                 23.4956 
                 2076.09 
                 0.0600 
                 3.78332 
                 39.94 
               
               
                 23.5487 
                 1876.75 
                 0.0590 
                 3.77802 
                 36.10 
               
               
                 24.7497 
                 1246.05 
                 0.0492 
                 3.59735 
                 23.97 
               
               
                 25.0601 
                 662.24 
                 0.1378 
                 3.55350 
                 12.74 
               
               
                 25.4391 
                 1024.03 
                 0.0960 
                 3.49851 
                 19.70 
               
               
                 25.5055 
                 1143.87 
                 0.0600 
                 3.49823 
                 22.00 
               
               
                 25.7702 
                 646.07 
                 0.1440 
                 3.45431 
                 12.43 
               
               
                 26.3869 
                 495.47 
                 0.0840 
                 3.37495 
                 9.53 
               
               
                 26.6722 
                 265.56 
                 0.1440 
                 3.33950 
                 5.11 
               
               
                 27.4787 
                 129.44 
                 0.3360 
                 3.24329 
                 2.49 
               
               
                 27.8067 
                 99.91 
                 0.2400 
                 3.20578 
                 1.92 
               
               
                 28.2145 
                 120.45 
                 0.1680 
                 3.16036 
                 2.32 
               
               
                 28.5579 
                 396.07 
                 0.1680 
                 3.12313 
                 7.62 
               
               
                 28.8364 
                 286.66 
                 0.1440 
                 3.09360 
                 5.51 
               
               
                 29.1536 
                 86.97 
                 0.1440 
                 3.06065 
                 1.67 
               
               
                 29.5143 
                 154.17 
                 0.0840 
                 3.02407 
                 2.97 
               
               
                 29.7622 
                 110.69 
                 0.0960 
                 2.99944 
                 2.13 
               
               
                 30.2691 
                 813.92 
                 0.0840 
                 2.95036 
                 15.66 
               
               
                 30.5186 
                 984.99 
                 0.1200 
                 2.92680 
                 18.95 
               
               
                 30.9882 
                 376.82 
                 0.2400 
                 2.88351 
                 7.25 
               
               
                 31.8213 
                 87.58 
                 0.2880 
                 2.80990 
                 1.68 
               
               
                 32.1956 
                 203.76 
                 0.2160 
                 2.77807 
                 3.92 
               
               
                 32.8198 
                 128.70 
                 0.0960 
                 2.72665 
                 2.48 
               
               
                 33.2383 
                 147.29 
                 0.1440 
                 2.69327 
                 2.83 
               
               
                 33.9793 
                 108.86 
                 0.1680 
                 2.63622 
                 2.09 
               
               
                 34.3316 
                 50.43 
                 0.1440 
                 2.60997 
                 0.97 
               
               
                 34.7398 
                 24.48 
                 0.1440 
                 2.58023 
                 0.47 
               
               
                 35.2696 
                 180.75 
                 0.1680 
                 2.54267 
                 3.48 
               
               
                 35.8821 
                 59.87 
                 0.1440 
                 2.50066 
                 1.15 
               
               
                 36.3703 
                 131.30 
                 0.1200 
                 2.46821 
                 2.53 
               
               
                 36.8791 
                 81.09 
                 0.1440 
                 2.43531 
                 1.56 
               
               
                 37.9636 
                 60.39 
                 0.3840 
                 2.36820 
                 1.16 
               
               
                 38.5792 
                 141.74 
                 0.1680 
                 2.33182 
                 2.73 
               
               
                 39.2389 
                 35.80 
                 0.1920 
                 2.29412 
                 0.69 
               
               
                   
               
            
           
         
       
     
     DSC/TGA/EGA 
     DSC and TG/EG analyses of sample TRQ01-API-GAL-1-1-SL-H2O-50C-1G-R01-filtered were reported below. 
     The DSC profile showed a first complex endothermic event at 99.2° C. (Onset 80.8° C.-57.6 J/g), ascribable to dehydration of the sample. A second weak broad endothermic event was recorded immediately before the melting of the sample. This event, observed at 202.8° C. (Onset 196.7° C.-7.1 J/g) could be tentatively explained by the presence of some impurities in the analyzed sample and eutectic trace. The third sharp endothermic peak at 215.9° C. (Onset 214.6° C.-76.8 J/g) was indeed imputable to congruent melting of anhydrous derivative ( FIG.  31   ). 
     Combined TG/EG analysis confirmed the nature of the first event: in fact, between approx. 40 and 110° C., a weight loss of 1.4% w/w was registered (approx. 0.4 water molecule each API molecule ( FIG.  32   ). EGA did not recorded any solvent evolution, so the presence of Water in the sample was supposed ( FIG.  33   ). In addition, a second weight loss of 12.4% w/w was recorded in the range approx. 200÷340° C. Since the evolution of Carbon Dioxide highlighted by EG analysis, this event could be assigned to the decomposition of Gallic acid. Moreover, TGA highlighted the starting of decomposition of the Apixaban moiety above approx. 340° C. ( FIG.  32   ). 
     FT-IR 
     The FT-IR spectrum pattern of API-GAL derivative NP01 b is shown in  FIG.  34    and the list of peaks was reported in the table below. 
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 FT-IR peak list of sample TRQ01-API-GAL-NP01b-dried. 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Position (cm −1 ) 
                 Intensity 
                 Position (cm −1 ) 
                 Intensity 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 407.34 
                 65.792 
                 1032.15 
                 55.691 
               
               
                   
                 425.61 
                 58.790 
                 1091.29 
                 76.902 
               
               
                   
                 459.19 
                 65.478 
                 1114.60 
                 67.670 
               
               
                   
                 500.46 
                 47.674 
                 1149.25 
                 46.653 
               
               
                   
                 518.64 
                 42.383 
                 1164.07 
                 45.046 
               
               
                   
                 536.52 
                 48.111 
                 1207.20 
                 55.288 
               
               
                   
                 555.02 
                 42.379 
                 1231.16 
                 46.678 
               
               
                   
                 607.11 
                 55.245 
                 1253.82 
                 33.029 
               
               
                   
                 648.58 
                 64.619 
                 1298.66 
                 41.639 
               
               
                   
                 668.70 
                 60.748 
                 1329.89 
                 54.496 
               
               
                   
                 702.51 
                 55.327 
                 1337.24 
                 50.294 
               
               
                   
                 757.85 
                 68.126 
                 1400.92 
                 73.808 
               
               
                   
                 775.72 
                 73.283 
                 1440.22 
                 57.792 
               
               
                   
                 788.72 
                 65.726 
                 1460.62 
                 55.503 
               
               
                   
                 797.28 
                 75.377 
                 1513.16 
                 32.875 
               
               
                   
                 815.67 
                 56.653 
                 1543.37 
                 78.448 
               
               
                   
                 832.16 
                 33.598 
                 1593.56 
                 46.993 
               
               
                   
                 869.63 
                 84.712 
                 1630.31 
                 46.196 
               
               
                   
                 896.72 
                 86.493 
                 1662.39 
                 43.837 
               
               
                   
                 938.21 
                 77.542 
                 1686.10 
                 75.407 
               
               
                   
                 982.21 
                 66.000 
                 2944.67 
                 88.649 
               
               
                   
                 1004.55 
                 61.832 
                 3179.46 
                 86.705 
               
               
                   
                 1021.00 
                 60.585 
                 3450.24 
                 91.895 
               
               
                   
                   
               
            
           
         
       
     
     FT-Raman 
     In  FIG.  35    was reported the FT-Raman spectrum of API-GAL derivative NP01b along with its peak list in the following table. 
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 FT-Raman peak list of sample TRQ01-API-GAL-NP01b dried. 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Position (cm −1 ) 
                 Intensity 
                 Position (cm −1 ) 
                 Intensity 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 97.08 
                 1107.265 
                 1339.47 
                 174.626 
               
               
                   
                 422.97 
                 78.852 
                 1373.67 
                 187.169 
               
               
                   
                 701.92 
                 154.781 
                 1424.46 
                 226.803 
               
               
                   
                 759.12 
                 85.058 
                 1450.37 
                 369.905 
               
               
                   
                 799.29 
                 98.137 
                 1516.09 
                 289.631 
               
               
                   
                 939.86 
                 65.807 
                 1613.65 
                 520.486 
               
               
                   
                 1003.52 
                 79.785 
                 1661.63 
                 358.883 
               
               
                   
                 1177.20 
                 123.127 
                 2971.41 
                 127.522 
               
               
                   
                 1239.57 
                 215.047 
                 3077.08 
                 113.567 
               
               
                   
                 1305.62 
                 120.165 
               
               
                   
                   
               
            
           
         
       
     
     1H-NMR 
     The 1H-NMR spectrum ( FIG.  36   ) of TRQ01-API-GAL-NP01b dried confirmed the presence of Apixaban and Gallic Acid in the stoichiometric ratio API:GAL approx. 1:0.35 (in agreement with TG analysis). The structural integrity of the molecule was even confirmed. 
     The spectrum 1H-NMR data are as follows: (400 MHz, DMSO-d6) δ: 7.71 (bs, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.43 (bs, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.27 (d, J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz, 2H), 6.90 (s, 0.7H), 4.05 (t, J=6.4 Hz, 2H), 3.80 (s, 3H), 3.59 (t, J=5.6 Hz, 2H), 3.20 (t, J=6.4 Hz, 2H), 2.99 (bs, 1.6H), 2.38 (t, J=6.4 Hz, 2H), 1.90-1.78 (m, 4H). 
     Apixaban-Maleic Acid Derivative 
     A new derivative of Apixaban and Maleic Acid was firstly observed from Kneading experiment. In detail, the recovered powder showed a new XRPD pattern, labeled as NP01. 
     Characterization of API-MEA Derivative NP01 
     Synthesis 
     151.6 mg of Maleic Acid were accurately weighed in an 8 ml glass vial equipped with a magnetic stirring bar and 4 ml of ETA were added. After complete dissolution of the coformer, 200 mg of Apixaban were added and the resulting mixture was stirred for 48 hours at room temperature. 
     After this time, the formed solid was isolated by vacuum filtration and washed with 2 ml of ETA, analyzed by XRPD and dried at 40° C. and 30 mbar for 20 hours. After the drying step, XRPD analysis was performed again. 
     The desired derivative API-MEA-NP01 was successfully recovered and it was fully characterized. 
     XRPD 
     The XRPD spectrum pattern is shown in  FIG.  37    and the list of peaks of sample TRQ01-API-MEA-1-3-SL-ETA-200 mg-dried was reported in the table below. 
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 XRPD peak list of sample TRQ01- 
               
               
                 API-MEA-1-3-SL-ETA-200 mg-dried. 
               
            
           
           
               
               
               
               
               
            
               
                 Pos. 
                 Height 
                 FWHM 
                 d-spacing 
                 Rel. Int. 
               
               
                 [°2Th.] 
                 [cts] 
                 [°2Th.] 
                 [Å] 
                 [%] 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 5.8998 
                 1213.66 
                 0.0886 
                 14.98057 
                 23.30 
               
               
                 7.4007 
                 78.73 
                 0.1574 
                 11.94547 
                 1.51 
               
               
                 8.9837 
                 262.73 
                 0.1574 
                 9.84372 
                 5.04 
               
               
                 11.1559 
                 91.84 
                 0.1378 
                 7.93143 
                 1.76 
               
               
                 11.7367 
                 2279.27 
                 0.0984 
                 7.54022 
                 43.75 
               
               
                 13.5746 
                 588.46 
                 0.1279 
                 6.52321 
                 11.30 
               
               
                 13.8724 
                 397.51 
                 0.1082 
                 6.38385 
                 7.63 
               
               
                 15.8783 
                 1229.81 
                 0.1279 
                 5.58159 
                 23.61 
               
               
                 16.1507 
                 1503.92 
                 0.0886 
                 5.48805 
                 28.87 
               
               
                 16.7330 
                 757.45 
                 0.1082 
                 5.29838 
                 14.54 
               
               
                 17.5935 
                 145.85 
                 0.1181 
                 5.04112 
                 2.80 
               
               
                 17.9244 
                 1317.13 
                 0.1181 
                 4.94879 
                 25.28 
               
               
                 18.8560 
                 468.23 
                 0.1574 
                 4.70635 
                 8.99 
               
               
                 19.7301 
                 264.22 
                 0.0984 
                 4.49976 
                 5.07 
               
               
                 20.0562 
                 2632.42 
                 0.1476 
                 4.42734 
                 50.53 
               
               
                 20.3800 
                 728.03 
                 0.0886 
                 4.35772 
                 13.97 
               
               
                 20.5308 
                 766.61 
                 0.0984 
                 4.32606 
                 14.72 
               
               
                 20.7282 
                 366.70 
                 0.0984 
                 4.28530 
                 7.04 
               
               
                 21.6841 
                 616.78 
                 0.1181 
                 4.09850 
                 11.84 
               
               
                 22.1329 
                 5209.72 
                 0.0984 
                 4.01640 
                 100.00 
               
               
                 23.4653 
                 1795.83 
                 0.1181 
                 3.79127 
                 34.47 
               
               
                 24.7378 
                 600.84 
                 0.0590 
                 3.59906 
                 11.53 
               
               
                 25.0424 
                 1680.48 
                 0.0886 
                 3.55598 
                 32.26 
               
               
                 25.7246 
                 521.96 
                 0.0590 
                 3.46320 
                 10.02 
               
               
                 26.3569 
                 323.17 
                 0.0689 
                 3.38153 
                 6.20 
               
               
                 26.5691 
                 635.97 
                 0.0590 
                 3.35500 
                 12.21 
               
               
                 27.2507 
                 58.88 
                 0.1574 
                 3.27262 
                 1.13 
               
               
                 27.7423 
                 219.34 
                 0.1378 
                 3.21573 
                 4.21 
               
               
                 28.6235 
                 320.25 
                 0.1378 
                 3.11871 
                 6.15 
               
               
                 29.1758 
                 139.79 
                 0.1378 
                 3.06091 
                 2.68 
               
               
                 29.4759 
                 50.72 
                 0.1574 
                 3.03043 
                 0.97 
               
               
                 30.2284 
                 532.79 
                 0.0689 
                 2.95668 
                 10.23 
               
               
                 30.6680 
                 504.47 
                 0.0492 
                 2.91530 
                 9.68 
               
               
                 31.6419 
                 162.79 
                 0.0689 
                 2.82775 
                 3.12 
               
               
                 32.2493 
                 277.95 
                 0.1181 
                 2.77587 
                 5.34 
               
               
                 32.8438 
                 82.60 
                 0.1574 
                 2.72697 
                 1.59 
               
               
                 33.1759 
                 216.44 
                 0.1771 
                 2.70043 
                 4.15 
               
               
                 34.2036 
                 83.66 
                 0.1181 
                 2.62161 
                 1.61 
               
               
                 34.9640 
                 63.78 
                 0.1574 
                 2.56632 
                 1.22 
               
               
                 35.4362 
                 241.33 
                 0.1181 
                 2.53320 
                 4.63 
               
               
                 36.2119 
                 66.23 
                 0.1181 
                 2.48069 
                 1.27 
               
               
                 36.7192 
                 5.39 
                 0.1181 
                 2.44758 
                 0.10 
               
               
                 37.1149 
                 35.52 
                 0.1181 
                 2.42239 
                 0.68 
               
               
                 37.4936 
                 3.94 
                 0.1181 
                 2.39878 
                 0.08 
               
               
                 37.8032 
                 67.42 
                 0.1968 
                 2.37985 
                 1.29 
               
               
                 38.3632 
                 102.90 
                 0.1378 
                 2.34639 
                 1.98 
               
               
                   
               
            
           
         
       
     
     DSC/TGA/EGA 
       FIGS.  38 ,  39  and  40    correspond to DSC, TG and EGA analyses performed on sample TRQ01-API-MEA-1-3-SL-ETA-200 mg-dried were performed, respectively. 
     The DSC profile showed two endothermic events: the first broad endothermic event at 189.1° C. (Onset 179.5° C.) could be imputable to melting/degradation of the sample. A second sharp endothermic peak was recorded at 237.5° C. (Onset 236.1° C.), ascribable to the melting of Apixaban. 
     The nature of the first event was disclosed by combined TG/EG analysis. In fact, TG highlights a significant weight loss (11.2% w/w) starting from approx. 150° C., in correspondence with the broad endothermic event recorded in DSC. In addition, EGA confirmed the evolution of Maleic Anhydride in correspondence with the recorded weight loss. The evolution of Maleic Anhydride also unambiguously confirms the presence of the coformer in the isolated species. 
     In addition, TGA highlights the recovery of an anhydrous derivative and the degradation of the Apixaban moiety above approx. 340° C. 
     FT-IR 
     The FT-IR spectrum pattern of API-MEA derivative NP01 is shown in  FIG.  41    and the list of peaks was reported in the table below. The comparison with FT-IR spectrum of Apixaban suggested the formation of a new species. In detail, the two bands at 1737 cm −1  and 1706 cm −1  could be associated to the presence of the coformer in the new derivative. 
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 FT-IR peak list of sample TRQ01- 
               
               
                 API-MEA-1-3-SL-ETA-200 mg-dried. 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Position (cm −1 ) 
                 Intensity 
                 Position (cm −1 ) 
                 Intensity 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 429.94 
                 68.782 
                 1164.29 
                 49.428 
               
               
                   
                 465.54 
                 80.585 
                 1202.24 
                 50.132 
               
               
                   
                 519.41 
                 44.310 
                 1231.28 
                 64.984 
               
               
                   
                 558.37 
                 69.585 
                 1253.58 
                 38.537 
               
               
                   
                 583.28 
                 56.819 
                 1290.75 
                 53.947 
               
               
                   
                 606.42 
                 58.561 
                 1303.76 
                 48.732 
               
               
                   
                 633.45 
                 80.962 
                 1336.73 
                 55.380 
               
               
                   
                 648.78 
                 78.606 
                 1351.97 
                 75.437 
               
               
                   
                 665.87 
                 69.818 
                 1401.23 
                 76.848 
               
               
                   
                 702.47 
                 65.680 
                 1440.68 
                 62.960 
               
               
                   
                 758.16 
                 72.176 
                 1461.55 
                 61.018 
               
               
                   
                 788.29 
                 67.606 
                 1512.87 
                 34.419 
               
               
                   
                 797.93 
                 78.365 
                 1543.97 
                 83.101 
               
               
                   
                 816.06 
                 55.110 
                 1595.76 
                 48.822 
               
               
                   
                 831.28 
                 35.348 
                 1625.51 
                 37.348 
               
               
                   
                 898.11 
                 86.364 
                 1661.91 
                 46.126 
               
               
                   
                 937.17 
                 77.191 
                 1683.03 
                 67.345 
               
               
                   
                 963.87 
                 81.560 
                 1705.91 
                 68.435 
               
               
                   
                 982.32 
                 71.575 
                 1737.03 
                 80.729 
               
               
                   
                 1003.91 
                 66.820 
                 2948.08 
                 94.638 
               
               
                   
                 1020.66 
                 67.637 
                 3158.12 
                 96.931 
               
               
                   
                 1032.02 
                 69.135 
                 3315.76 
                 97.919 
               
               
                   
                 1091.70 
                 83.284 
                 3428.63 
                 100.947 
               
               
                   
                 1113.20 
                 73.640 
                 3464.46 
                 102.116 
               
               
                   
                 1148.79 
                 58.386 
               
               
                   
                   
               
            
           
         
       
     
     FT-Raman 
     In  FIG.  42    was reported the FT-Raman spectrum of API-MEA derivative NP01 along with its peak list in the following table. 
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 FT-Raman peak list of sample TRQ01- 
               
               
                 API-MEA-1-3-SL-ETA-200 mg-dried. 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Position (cm −1 ) 
                 Intensity 
                 Position (cm −1 ) 
                 Intensity 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 97.08 
                 426.006 
                 1338.47 
                 65.286 
               
               
                   
                 407.04 
                 32.605 
                 1357.56 
                 78.820 
               
               
                   
                 702.11 
                 66.381 
                 1423.61 
                 91.169 
               
               
                   
                 758.89 
                 36.028 
                 1449.79 
                 156.931 
               
               
                   
                 798.89 
                 41.076 
                 1515.52 
                 124.922 
               
               
                   
                 938.57 
                 29.679 
                 1612.00 
                 224.792 
               
               
                   
                 1001.85 
                 39.490 
                 1662.69 
                 141.645 
               
               
                   
                 1089.84 
                 25.079 
                 2943.26 
                 72.372 
               
               
                   
                 1176.80 
                 56.555 
                 2975.47 
                 71.638 
               
               
                   
                 1240.36 
                 76.326 
                 3072.68 
                 66.023 
               
               
                   
                 1304.85 
                 49.818 
               
               
                   
                   
               
            
           
         
       
     
     1H-NMR 
     The 1H-NMR spectrum ( FIG.  43   ) of TRQ01-API-MEA-1-3-SL-ETA-200 mg-dried revealed the presence of Apixaban and Maleic Acid in the stoichiometric ratio API:MEA of approx. 1:0.5. The structural integrity of the molecule was confirmed. 
     The spectrum 1H-NMR data are as follows: (400 MHz, DMSO-d6) δ: 7.71 (bs, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.43 (bs, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.27 (d, J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz, 2H), 6.26 (s, 1H), 4.05 (t, J=6.4 Hz, 2H), 3.80 (s, 3H), 3.59 (t, J=5.6 Hz, 2H), 3.20 (t, J=6.4 Hz, 2H), 2.38 (t, J=6.4 Hz, 2H), 1.90-1.78 (m, 4H). 
     Apixaban-L-Tartaric Acid Derivative 
     A new derivative of Apixaban and L-Tartaric Acid was firstly observed from kneading experiment in Water. This new derivative was labeled as NP01. 
     Characterization of API-LTA Derivative NP01 (200 mg Scale) 
     Synthesis 
     65.3 mg of L-Tartaric Acid were accurately weighed in a 20 ml glass vial equipped with a magnetic stirring bar and 18 ml of ACN were added. After complete dissolution of the coformer, 200 mg of Apixaban were added and the resulting mixture was stirred for 24 hours at room temperature. 
     After this time, the formed solid was isolated by vacuum filtration and washed with 2 ml of ACN, analyzed by XRPD and dried at 40° C. and 30 mbar for 20 hours. After the drying step, XRPD analysis was performed again. 
     The desired derivative API-LTA-NP01 was successfully isolated and it was fully characterized. 
     XRPD 
     The XRPD spectrum pattern is shown in  FIG.  44    and the list of peaks of sample TRQ01-API-LTA-1-1-SL-ACN-200 mg-dried was reported in the table below. 
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 XRPD peak list of sample TRQ01- 
               
               
                 API-LTA-1-1-SL-ACN-200 mg-dried. 
               
            
           
           
               
               
               
               
               
            
               
                 Pos. 
                 Height 
                 FWHM 
                 d-spacing 
                 Rel. Int. 
               
               
                 [°2Th.] 
                 [cts] 
                 [°2Th.] 
                 [Å] 
                 [%] 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 5.8131 
                 752.45 
                 0.1082 
                 15.20373 
                 7.24 
               
               
                 8.7755 
                 664.66 
                 0.0590 
                 10.07687 
                 6.39 
               
               
                 8.8260 
                 600.22 
                 0.0394 
                 10.01931 
                 5.77 
               
               
                 10.8696 
                 220.01 
                 0.0492 
                 8.13969 
                 2.12 
               
               
                 11.5197 
                 2480.87 
                 0.1082 
                 7.68179 
                 23.87 
               
               
                 13.3065 
                 1298.04 
                 0.0984 
                 6.65403 
                 12.49 
               
               
                 13.5494 
                 974.75 
                 0.0886 
                 6.53528 
                 9.38 
               
               
                 14.4069 
                 90.73 
                 0.0984 
                 6.14817 
                 0.87 
               
               
                 15.8124 
                 1117.04 
                 0.1082 
                 5.60469 
                 10.75 
               
               
                 16.0214 
                 463.43 
                 0.0492 
                 5.53204 
                 4.46 
               
               
                 16.2975 
                 103.84 
                 0.1181 
                 5.43897 
                 1.00 
               
               
                 16.7908 
                 378.16 
                 0.0689 
                 5.28027 
                 3.64 
               
               
                 17.0372 
                 74.96 
                 0.0590 
                 5.20445 
                 0.72 
               
               
                 17.2872 
                 92.47 
                 0.0787 
                 5.12974 
                 0.89 
               
               
                 17.5279 
                 1622.08 
                 0.1082 
                 5.05984 
                 15.60 
               
               
                 18.0021 
                 62.60 
                 0.0984 
                 4.92762 
                 0.60 
               
               
                 18.2033 
                 72.21 
                 0.0787 
                 4.87360 
                 0.69 
               
               
                 18.5016 
                 763.26 
                 0.0886 
                 4.79570 
                 7.34 
               
               
                 19.5465 
                 401.86 
                 0.0787 
                 4.54162 
                 3.87 
               
               
                 20.0038 
                 2517.43 
                 0.1181 
                 4.43882 
                 24.22 
               
               
                 20.2332 
                 321.64 
                 0.0590 
                 4.38900 
                 3.09 
               
               
                 20.6511 
                 56.15 
                 0.0787 
                 4.30112 
                 0.54 
               
               
                 21.6550 
                 10395.27 
                 0.1378 
                 4.10394 
                 100.00 
               
               
                 22.5771 
                 56.96 
                 0.1181 
                 3.93837 
                 0.55 
               
               
                 22.9515 
                 1691.87 
                 0.0984 
                 3.87497 
                 16.28 
               
               
                 24.2245 
                 74.54 
                 0.1378 
                 3.67414 
                 0.72 
               
               
                 24.5250 
                 450.43 
                 0.1082 
                 3.62981 
                 4.33 
               
               
                 24.8308 
                 879.54 
                 0.0492 
                 3.58579 
                 8.46 
               
               
                 25.0061 
                 589.88 
                 0.0492 
                 3.56105 
                 5.67 
               
               
                 25.5117 
                 276.54 
                 0.0886 
                 3.49161 
                 2.66 
               
               
                 26.0350 
                 101.16 
                 0.0787 
                 3.42261 
                 0.97 
               
               
                 26.2977 
                 394.07 
                 0.0787 
                 3.38900 
                 3.79 
               
               
                 26.6413 
                 30.81 
                 0.1181 
                 3.34607 
                 0.30 
               
               
                 27.1736 
                 35.13 
                 0.1378 
                 3.28172 
                 0.34 
               
               
                 27.8987 
                 478.01 
                 0.0492 
                 3.19806 
                 4.60 
               
               
                 28.3776 
                 69.95 
                 0.1181 
                 3.14517 
                 0.67 
               
               
                 28.7663 
                 180.85 
                 0.0590 
                 3.10355 
                 1.74 
               
               
                 28.9528 
                 317.10 
                 0.1181 
                 3.08398 
                 3.05 
               
               
                 29.6991 
                 251.58 
                 0.0787 
                 3.00816 
                 2.42 
               
               
                 30.1333 
                 423.21 
                 0.0787 
                 2.96580 
                 4.07 
               
               
                 30.5511 
                 124.72 
                 0.1378 
                 2.92619 
                 1.20 
               
               
                 31.1063 
                 62.49 
                 0.0590 
                 2.87522 
                 0.60 
               
               
                 31.7806 
                 408.88 
                 0.0394 
                 2.81573 
                 3.93 
               
               
                 32.2082 
                 26.43 
                 0.1181 
                 2.77932 
                 0.25 
               
               
                 32.6486 
                 108.21 
                 0.0689 
                 2.74283 
                 1.04 
               
               
                 33.4789 
                 161.08 
                 0.0590 
                 2.67668 
                 1.55 
               
               
                 33.8272 
                 66.46 
                 0.1574 
                 2.64991 
                 0.64 
               
               
                 34.4406 
                 57.61 
                 0.0590 
                 2.60411 
                 0.55 
               
               
                 34.8017 
                 58.46 
                 0.0787 
                 2.57791 
                 0.56 
               
               
                 35.2706 
                 114.97 
                 0.0590 
                 2.54471 
                 1.11 
               
               
                 35.7538 
                 40.30 
                 0.1574 
                 2.51141 
                 0.39 
               
               
                 37.1881 
                 154.39 
                 0.1181 
                 2.41778 
                 1.49 
               
               
                 37.8891 
                 127.37 
                 0.0886 
                 2.37465 
                 1.23 
               
               
                 38.5847 
                 59.73 
                 0.0787 
                 2.33342 
                 0.57 
               
               
                 39.5967 
                 76.20 
                 0.1378 
                 2.27609 
                 0.73 
               
               
                   
               
            
           
         
       
     
     DSC/TGA/EGA 
       FIGS.  45 ,  46  and  47    correspond to DSC, TG and EGA analyses performed on sample TRQ01-API-LTA-1-1-SL-ACN-200 mg-dried were reported below. 
     The DSC profile showed a sharp endothermic peak at 220.2° C. (Onset 218.7° C.) imputable to sample melting and decomposition. 
     TG/EG analysis highlighted the recovery of an anhydrous compound and confirmed the presence of L-Tartaric Acid in the isolated species. In fact, at approx. 210° C., in correspondence with the sharp endothermic peak observed in DSC, a weight loss of 12.9% w/w was registered and the massive evolution of Carbon Dioxide was highlighted, imputable to the presence of the coformer in the analyzed sample. 
     In addition, TGA confirmed the decomposition of the Apixaban moiety above approx. 320° C. 
     FT-IR 
     In the  FIG.  48    was reported the FT-IR spectrum of API-LTA derivative NP01 and the peaks list can be found in the table below. 
     The comparison with FT-IR spectrum of Apixaban suggested the formation of a new species. In detail, the band at 1716 cm −1  could be associated to the presence of the coformer in the new derivative. 
     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                 FT-IR peak list of sample TRQ01- 
               
               
                 API-LTA-1-1-SL-ACN-200 mg-dried. 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Position (cm −1 ) 
                 Intensity 
                 Position (cm −1 ) 
                 Intensity 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 406.48 
                 82.105 
                 1077.79 
                 83.328 
               
               
                   
                 429.92 
                 73.782 
                 1091.95 
                 82.493 
               
               
                   
                 499.95 
                 80.911 
                 1112.55 
                 74.571 
               
               
                   
                 521.34 
                 66.773 
                 1148.20 
                 72.692 
               
               
                   
                 540.54 
                 72.697 
                 1167.62 
                 71.309 
               
               
                   
                 571.50 
                 68.957 
                 1184.28 
                 81.326 
               
               
                   
                 607.06 
                 79.214 
                 1208.54 
                 76.830 
               
               
                   
                 650.67 
                 84.891 
                 1229.02 
                 67.133 
               
               
                   
                 660.49 
                 86.427 
                 1256.59 
                 57.924 
               
               
                   
                 676.82 
                 80.931 
                 1300.04 
                 61.824 
               
               
                   
                 703.17 
                 76.904 
                 1337.32 
                 73.293 
               
               
                   
                 759.48 
                 85.954 
                 1380.23 
                 87.062 
               
               
                   
                 788.24 
                 84.191 
                 1401.14 
                 81.318 
               
               
                   
                 798.13 
                 89.432 
                 1438.26 
                 81.077 
               
               
                   
                 816.26 
                 75.641 
                 1463.73 
                 74.530 
               
               
                   
                 832.24 
                 56.297 
                 1512.93 
                 54.197 
               
               
                   
                 842.80 
                 80.435 
                 1544.05 
                 85.843 
               
               
                   
                 880.40 
                 91.273 
                 1589.50 
                 69.351 
               
               
                   
                 938.28 
                 87.606 
                 1623.89 
                 57.885 
               
               
                   
                 966.89 
                 84.269 
                 1663.64 
                 66.135 
               
               
                   
                 983.78 
                 80.692 
                 1715.95 
                 84.836 
               
               
                   
                 1003.26 
                 77.511 
                 2948.22 
                 93.582 
               
               
                   
                 1019.09 
                 76.939 
                 3179.06 
                 93.455 
               
               
                   
                 1030.56 
                 76.802 
                 3441.59 
                 93.237 
               
               
                   
                   
               
            
           
         
       
     
     FT-Raman 
     In the  FIG.  49    was reported the FT-Raman spectrum of API-LTA derivative NP01 and its peak list can be found in the table below. 
     
       
         
           
               
             
               
                 TABLE 18 
               
             
            
               
                   
               
               
                 FT-Raman peak list of sample TRQ01- 
               
               
                 API-LTA-1-1-SL-ACN-200 mg-dried. 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Position (cm −1 ) 
                 Intensity 
                 Position (cm −1 ) 
                 Intensity 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 98.96 
                 165.565 
                 1327.37 
                 26.966 
               
               
                   
                 422.68 
                 14.101 
                 1382.26 
                 38.691 
               
               
                   
                 634.70 
                 12.357 
                 1424.39 
                 37.177 
               
               
                   
                 702.56 
                 26.411 
                 1451.02 
                 66.594 
               
               
                   
                 759.91 
                 16.330 
                 1465.56 
                 56.221 
               
               
                   
                 799.09 
                 16.558 
                 1515.03 
                 44.721 
               
               
                   
                 939.15 
                 13.239 
                 1611.52 
                 93.247 
               
               
                   
                 999.32 
                 14.398 
                 1664.72 
                 56.656 
               
               
                   
                 1081.74 
                 11.264 
                 2940.87 
                 34.703 
               
               
                   
                 1174.37 
                 21.100 
                 2971.84 
                 33.510 
               
               
                   
                 1239.74 
                 34.121 
                 3074.14 
                 32.451 
               
               
                   
                 1303.30 
                 24.448 
               
               
                   
                   
               
            
           
         
       
     
     1H-NMR 
     The 1H-NMR spectrum ( FIG.  50   ) of TRQ01-API-LTA-1-1-SL-ACN-200 mg-dried revealed the presence of Apixaban and L-Tartaric Acid in the stoichiometric ratio API:LTA approx. 1:0.5. The structural integrity of the molecule was confirmed. No traces of residual solvents were visible. 
     Spectrum 1H-NMR data are as follows: (400 MHz, DMSO-d6) δ: 7.71 (bs, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.43 (bs, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.27 (d, J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz, 2H), 4.31 (s, 1H), 4.05 (t, J=6.4 Hz, 2H), 3.80 (s, 3H), 3.59 (t, J=5.6 Hz, 2H), 3.20 (t, J=6.4 Hz, 2H), 2.38 (t, J=6.4 Hz, 2H), 1.90-1.78 (m, 4H). 
     Apixaban—Citric Acid Derivative 
     A new derivative of Apixaban and Citric Acid was observed from Kneading experiment using Water as solvent, although in mixture with Apixaban Form I. 
     Characterization of API-CIA Derivative NP02 (200 mg Scale) 
     Synthesis 
     92.0 mg of Citric Acid (1.1 equivalents) were accurately weighed in a 20 ml glass vial equipped with a magnetic stirring bar and 6.8 ml of ETA were added. After complete dissolution of the coformer, 200 mg of Apixaban were added and the resulting mixture was stirred for 48 hours at room temperature. 
     After this time, the formed solid was isolated by vacuum filtration and washed with 4 ml of ETA, analyzed by XRPD and dried at 40° C. and 30 mbar for 70 hours. After the drying step, XRPD analysis was performed again. 
     The desired derivative API-CIA-NP02 was successfully isolated and it was fully characterized. 
     XRPD 
     The XRPD spectrum pattern is shown in  FIG.  51    and the list of peaks of sample TRQ01-API-CIA-1-1,1-SL-ETA-200 mg-dried was reported in the table below. 
     
       
         
           
               
             
               
                 TABLE 19 
               
             
            
               
                   
               
               
                 XRPD peak list of sample TRQ01-API- 
               
               
                 CIA-1-1,1-SL-ETA-200 mg-dried. 
               
            
           
           
               
               
               
               
               
            
               
                 Pos. 
                 Height 
                 FWHM 
                 d-spacing 
                 Rel. Int. 
               
               
                 [°2Th.] 
                 [cts] 
                 [°2Th.] 
                 [Å] 
                 [%] 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 3.8685 
                 2229.91 
                 0.1279 
                 22.84065 
                 100.00 
               
               
                 3.9307 
                 1623.10 
                 0.0492 
                 22.47934 
                 72.79 
               
               
                 7.5922 
                 63.97 
                 0.1181 
                 11.64457 
                 2.87 
               
               
                 8.5810 
                 242.76 
                 0.1378 
                 10.30475 
                 10.89 
               
               
                 9.8526 
                 395.46 
                 0.0590 
                 8.97751 
                 17.73 
               
               
                 10.1712 
                 753.26 
                 0.0787 
                 8.69701 
                 33.78 
               
               
                 10.7764 
                 45.24 
                 0.1574 
                 8.20989 
                 2.03 
               
               
                 11.5998 
                 181.37 
                 0.1378 
                 7.62889 
                 8.13 
               
               
                 12.3210 
                 81.78 
                 0.1574 
                 7.18397 
                 3.67 
               
               
                 12.7613 
                 337.26 
                 0.1771 
                 6.93702 
                 15.12 
               
               
                 13.1062 
                 251.35 
                 0.1181 
                 6.75526 
                 11.27 
               
               
                 14.0074 
                 958.57 
                 0.0689 
                 6.32259 
                 42.99 
               
               
                 15.8536 
                 108.08 
                 0.1378 
                 5.59025 
                 4.85 
               
               
                 16.4175 
                 772.57 
                 0.0590 
                 5.39948 
                 34.65 
               
               
                 16.8933 
                 1508.14 
                 0.0960 
                 5.24410 
                 67.63 
               
               
                 16.9610 
                 1808.15 
                 0.0480 
                 5.23631 
                 81.09 
               
               
                 17.2488 
                 1106.84 
                 0.0720 
                 5.13683 
                 49.64 
               
               
                 17.6078 
                 931.54 
                 0.0480 
                 5.03289 
                 41.77 
               
               
                 17.6506 
                 1048.69 
                 0.0480 
                 5.02078 
                 47.03 
               
               
                 18.3421 
                 902.66 
                 0.1440 
                 4.83302 
                 40.48 
               
               
                 18.9738 
                 26.79 
                 0.1440 
                 4.67352 
                 1.20 
               
               
                 19.6218 
                 29.55 
                 0.1440 
                 4.52062 
                 1.33 
               
               
                 20.0190 
                 466.66 
                 0.1440 
                 4.43180 
                 20.93 
               
               
                 20.5845 
                 346.89 
                 0.1680 
                 4.31131 
                 15.56 
               
               
                 21.1303 
                 265.00 
                 0.1920 
                 4.20117 
                 11.88 
               
               
                 21.4897 
                 383.39 
                 0.1200 
                 4.13172 
                 17.19 
               
               
                 21.9106 
                 359.88 
                 0.0360 
                 4.05328 
                 16.14 
               
               
                 22.4050 
                 710.33 
                 0.0600 
                 3.96495 
                 31.85 
               
               
                 22.4783 
                 938.46 
                 0.0960 
                 3.95219 
                 42.09 
               
               
                 22.8080 
                 273.90 
                 0.1440 
                 3.89579 
                 12.28 
               
               
                 23.4822 
                 133.42 
                 0.1440 
                 3.78545 
                 5.98 
               
               
                 24.0102 
                 2099.98 
                 0.1320 
                 3.70338 
                 94.17 
               
               
                 24.5732 
                 1044.01 
                 0.1200 
                 3.61979 
                 46.82 
               
               
                 24.6510 
                 813.74 
                 0.0720 
                 3.61751 
                 36.49 
               
               
                 25.2201 
                 226.43 
                 0.1680 
                 3.52839 
                 10.15 
               
               
                 25.5677 
                 73.76 
                 0.1440 
                 3.48120 
                 3.31 
               
               
                 26.0148 
                 498.36 
                 0.0360 
                 3.42238 
                 22.35 
               
               
                 26.8588 
                 656.92 
                 0.0960 
                 3.31672 
                 29.46 
               
               
                 27.2099 
                 132.73 
                 0.1440 
                 3.27472 
                 5.95 
               
               
                 27.5676 
                 63.95 
                 0.1440 
                 3.23303 
                 2.87 
               
               
                 28.1638 
                 571.29 
                 0.0960 
                 3.16593 
                 25.62 
               
               
                 28.6910 
                 399.98 
                 0.1200 
                 3.10894 
                 17.94 
               
               
                 29.0331 
                 103.54 
                 0.1440 
                 3.07309 
                 4.64 
               
               
                 29.7234 
                 195.49 
                 0.0960 
                 3.00327 
                 8.77 
               
               
                 30.0797 
                 103.48 
                 0.1440 
                 2.96851 
                 4.64 
               
               
                 30.4811 
                 340.39 
                 0.0720 
                 2.93032 
                 15.26 
               
               
                 30.8720 
                 182.48 
                 0.2160 
                 2.89410 
                 8.18 
               
               
                 31.3219 
                 170.50 
                 0.1920 
                 2.85355 
                 7.65 
               
               
                 32.0824 
                 17.53 
                 0.2880 
                 2.78762 
                 0.79 
               
               
                 33.4259 
                 78.17 
                 0.1200 
                 2.67858 
                 3.51 
               
               
                 34.2182 
                 276.39 
                 0.0840 
                 2.61836 
                 12.39 
               
               
                 35.4066 
                 68.20 
                 0.1920 
                 2.53315 
                 3.06 
               
               
                 36.1864 
                 32.93 
                 0.2880 
                 2.48033 
                 1.48 
               
               
                 36.7237 
                 56.04 
                 0.1440 
                 2.44526 
                 2.51 
               
               
                 37.0014 
                 87.12 
                 0.1920 
                 2.42754 
                 3.91 
               
               
                 38.3233 
                 76.99 
                 0.2880 
                 2.34680 
                 3.45 
               
               
                 38.8273 
                 68.62 
                 0.1440 
                 2.31748 
                 3.08 
               
               
                 39.3128 
                 52.21 
                 0.1920 
                 2.28998 
                 2.34 
               
               
                   
               
            
           
         
       
     
     DSC/TGA/EGA 
       FIGS.  52 ,  53  and  54    correspond to DSC,TG and EGA analyses performed on sample TRQ01-API-CIA-1-1,1-SL-ETA-200 mg-dried were performed. 
     The DSC profile showed an endothermic peak at 218.4° C. (Onset 217.2° C.) imputable to sample melting and decomposition. 
     TG/EG analysis highlighted the recovery of an anhydrous compound and confirmed the presence of the coformer in the isolated species. In fact, at approx. 210° C., in correspondence with the endothermic peak observed in DSC, a weight loss of 16.6% w/w was registered and the evolution of Citraconic Anhydride was highlighted. This evidence confirmed the presence of Citric Acid in the analyzed sample. 
     In addition, TGA confirmed the decomposition of the Apixaban moiety above approx. 340° C. 
     FT-IR 
     In the  FIG.  55    was reported the FT-IR spectrum of API-CIA derivative NP02 and the its peak list was provided in the table below. The comparison with FT-IR spectrum of Apixaban suggested the formation of a new species. In detail, the band at 1748 cm −1  could be associated to the presence of the coformer in the new derivative. 
     
       
         
           
               
             
               
                 TABLE 20 
               
             
            
               
                   
               
               
                 FT-IR peak list of sample TRQ01-API- 
               
               
                 CIA-1-1,1-SL-ETA-200 mg-dried. 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Position (cm −1 ) 
                 Intensity 
                 Position (cm −1 ) 
                 Intensity 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 423.58 
                 63.221 
                 1143.86 
                 49.050 
               
               
                   
                 463.07 
                 67.332 
                 1167.43 
                 39.626 
               
               
                   
                 529.72 
                 38.185 
                 1195.34 
                 63.016 
               
               
                   
                 550.64 
                 49.890 
                 1223.55 
                 58.226 
               
               
                   
                 609.35 
                 64.935 
                 1248.77 
                 38.746 
               
               
                   
                 653.41 
                 71.496 
                 1298.60 
                 42.848 
               
               
                   
                 666.79 
                 78.477 
                 1333.12 
                 62.962 
               
               
                   
                 686.15 
                 74.331 
                 1381.92 
                 64.893 
               
               
                   
                 705.42 
                 62.940 
                 1403.82 
                 62.688 
               
               
                   
                 734.43 
                 83.539 
                 1440.64 
                 62.872 
               
               
                   
                 761.21 
                 62.261 
                 1474.16 
                 68.995 
               
               
                   
                 794.52 
                 64.664 
                 1486.10 
                 74.551 
               
               
                   
                 814.96 
                 60.157 
                 1512.77 
                 35.688 
               
               
                   
                 832.37 
                 39.455 
                 1543.78 
                 80.195 
               
               
                   
                 896.95 
                 81.762 
                 1592.79 
                 55.847 
               
               
                   
                 943.56 
                 81.387 
                 1611.93 
                 60.934 
               
               
                   
                 980.58 
                 73.980 
                 1668.81 
                 55.030 
               
               
                   
                 1003.13 
                 72.963 
                 1684.72 
                 40.530 
               
               
                   
                 1016.84 
                 67.591 
                 1748.33 
                 67.446 
               
               
                   
                 1027.88 
                 63.784 
                 2961.56 
                 89.148 
               
               
                   
                 1078.51 
                 77.617 
                 3150.99 
                 84.348 
               
               
                   
                 1112.08 
                 69.360 
                 3459.17 
                 88.956 
               
               
                   
                   
               
            
           
         
       
     
     FT-Raman 
     In the  FIG.  56    below was reported the FT-Raman spectrum of API-CIA derivative NP02 along with its peak list. 
     
       
         
           
               
             
               
                 TABLE 21 
               
             
            
               
                   
               
               
                 FT-Raman peak list of sample TRQ01- 
               
               
                 API-CIA-1-1,1-SL-ETA-200 mg-dried. 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Position (cm −1 ) 
                 Intensity 
                 Position (cm −1 ) 
                 Intensity 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 97.08 
                 505.607 
                 1235.17 
                 93.272 
               
               
                   
                 220.13 
                 80.522 
                 1325.68 
                 105.989 
               
               
                   
                 257.43 
                 62.864 
                 1358.56 
                 123.395 
               
               
                   
                 412.07 
                 75.562 
                 1388.39 
                 181.961 
               
               
                   
                 705.62 
                 115.915 
                 1455.60 
                 259.337 
               
               
                   
                 762.76 
                 59.003 
                 1514.82 
                 159.147 
               
               
                   
                 799.98 
                 68.979 
                 1589.44 
                 216.235 
               
               
                   
                 945.48 
                 56.201 
                 1611.45 
                 358.690 
               
               
                   
                 1004.08 
                 54.745 
                 1665.80 
                 180.082 
               
               
                   
                 1029.15 
                 53.520 
                 2908.22 
                 103.979 
               
               
                   
                 1083.70 
                 39.432 
                 2964.56 
                 134.478 
               
               
                   
                 1145.50 
                 50.522 
                 3017.21 
                 63.534 
               
               
                   
                 1175.12 
                 87.176 
                 3077.05 
                 87.312 
               
               
                   
                   
               
            
           
         
       
     
     1H-NMR 
     The 1H-NMR spectrum ( FIG.  57   ) of TRQ01-API-CIA-1-1,1-SL-ETA-200 mg-dried revealed the presence of Apixaban and Citric Acid in the stoichiometric ratio API:CIA of approx. 1:0.5. Moreover, the structural integrity of the molecule was confirmed. 
     Spectrum 1H-NMR data are as follows: (400 MHz, DMSO-d6) δ: 7.71 (bs, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.43 (bs, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.27 (d, J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz, 2H), 4.05 (t, J=6.4 Hz, 2H), 3.80 (s, 3H), 3.59 (t, J=5.6 Hz, 2H), 3.20 (t, J=6.4 Hz, 2H), 2.76 (d, J=15.4 Hz, 1H), 2.65 (d, J=15.4 Hz, 1H), 2.38 (t, J=6.4 Hz, 2H), 1.90-1.78 (m, 4H).