US 20160045483A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0045483 A1 STAHLY et al. (43) Pub. Date: Feb. 18, 2016 (54) SOLID FORMS COMPRISING Related U.S. Application Data 3-(4-AMINO-1-OXO-1,3-DIHYDRO ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE (60) Eyal application No. 61/805.425, filed on Mar. AND ACOFORMER, COMPOSITIONS AND s METHODS OF USE THEREOF (71) Applicant: CELGENE CORPORATION, Summit, Publication Classification NJ (US) (51) Int. Cl. (72) Inventors: G. Patrick STAHLY, West Lafayette, IN A613 L/454 (2006.01) (US); David JONAITIS, Brookston, IN A 6LX3/573 (2006.01) (US); Ho-Wah HUI, Basking Ridge, NJ (52) U.S. Cl. (US); Kevin J. KLOPFER, Flemington, CPC ............. A6 IK3I/454 (2013.01); A61 K3I/573 NJ (US) (2013.01) (73) Assignee: CELGENE CORPORATION, Summit, NJ (US) (57) ABSTRACT (21) Appl. No.: 14/780,495 Provided herein are solid forms comprising (a) 3-(4-amino (22) PCT Filed: Mar. 25, 2014 1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (Le nalidomide) and (b) a coformer. Pharmaceutical composi (86). PCT No.: PCT/US2O14/O31689 tions comprising the Solid forms and methods for treating, S371 (c)(1), preventing and managing various disorders are also dis (2) Date: Sep. 25, 2015 closed. Patent Application Publication Feb. 18, 2016 Sheet 1 of 35 US 2016/0045483 A1 5e004 4e--004 1. O S 3e--004 2e--004 1e--004 Oe--000 10 20 30 40 2-Theta (deg) FIG. 1 Patent Application Publication Feb. 18, 2016 Sheet 2 of 35 US 2016/0045483 A1 1.5e004 1.0e--004 s 5.0e--004 0.0e--000 10 20 50 to 2-Theta (deg) FIG. 2 Patent Application Publication Feb. 18, 2016 Sheet 3 of 35 US 2016/0045483 A1 5.0e--004 14.0e--004 O s ae 2 3.0e--004 2.0e--004 1.0e--004 0,0e--000 10 20 30 40 2-Theta (deg) FIG. 3 Patent Application Publication Feb. 18, 2016 Sheet 4 of 35 US 2016/0045483 A1 6.0e--004 5.0e--004 3. SS 4.0e+004 2Y 23.0e--004 9 2.0e--004 1,0e--004 0.0e--000 10 20 30 40 2-Theta (deg) FIG. 4 Patent Application Publication Feb. 18, 2016 Sheet 5 of 35 US 2016/0045483 A1 1S 2.0e--005 C i 10e--005 0.0e--000 10 20 30 40 2-Theta (deg) FIG. 5 Patent Application Publication Feb. 18, 2016 Sheet 6 of 35 US 2016/0045483 A1 2,0e--005 1 5 e - O O 5 'r 1,0e--005 5,0e--004 2-Theta (deg) FIG. 6 Patent Application Publication Feb. 18, 2016 Sheet 7 of 35 US 2016/0045483 A1 S000 lenalidomide/magnesium bromide cocrystal 2500 2000 1500 1000- w ? . Wyf 500- w Wy Now. 5 10 15 20 25 SO 35 40 Degrees Two Theta FIG. 7B Patent Application Publication Feb. 18, 2016 Sheet 8 of 35 US 2016/0045483 A1 DSC2.0075 110 TC2.0130 15.52%. 70-20O'C (1.056mg) se 60N 122,840 lenalidomide/magnesium bromide cocrystal 209.71C O O 50 100 150 200 250 300 350 ExO Up Temperature (C) FIG. 8 Patent Application Publication Feb. 18, 2016 Sheet 9 of 35 US 2016/0045483 A1 lenalidomide/magnesium bromide cocrystal 4.O 5 O 2 O O O 20 40 60 80 100 Percent Relative Humidity FIG. 9 Patent Application Publication Feb. 18, 2016 Sheet 10 of 35 US 2016/0045483 A1 lenalidomide/magnesium bromide COCrystal E | 3500 3000 2500 2000 1500 1000 500 Raman shift (cm-1) FIG. 10 Patent Application Publication Feb. 18, 2016 Sheet 11 of 35 US 2016/0045483 A1 N W lenolidomidel/magnesium bromide cocrystal 11 10 FIG. 11 Patent Application Publication Feb. 18, 2016 Sheet 12 of 35 US 2016/0045483 A1 FIG. 12 Patent Application Publication Feb. 18, 2016 Sheet 13 of 35 US 2016/0045483 A1 1.0e--005 E. e 5.0e+004 Oe--000 e O 20 30 40 2-Theta (deg) FIG. 13A 4. 3.53 10?O lenalidomide/malonic acid cocrystal 5 O 15 20 25 50 35 40 Degrees Two Theta FIG. 13B Patent Application Publication Feb. 18, 2016 Sheet 14 of 35 US 2016/0045483 A1 DSC20074 43.13%. 100-180C TG20129 (1.717mg) 159.44C 102.11C 110.75°C lenalidomide/malonic acid cocrystal "() 50 100 150 200 250 300 350 EXO Up Temperature (C) FIG. 14 Patent Application Publication Feb. 18, 2016 Sheet 15 of 35 US 2016/0045483 A1 lenalidomide/malonic acid cocrystal 5 O 4O 3 O desorption 2 O O O 20 40 60 80 100 Percent Relative Humidity FIG. 15 Patent Application Publication Feb. 18, 2016 Sheet 16 of 35 US 2016/0045483 A1 lenolidomide/molonic acid cocrystal 5.5- 5.0- 45 40 3.5- 91199||-!!!!!!!-- 3.0- 2.5- 2.0- 15 10 !===== 0.5- 0.0 3500 3000 2500 2000 1500 1000 500 Raman shift (cm-1) FIG. 16 Patent Application Publication Feb. 18, 2016 Sheet 17 of 35 US 2016/0045483 A1 cN do on N. cn or r n N - - r c Cn C on N d - C - no do N. r o or N d C C C N v Co do N. Cd N C N n c Cn oc C C Co od N. cn v. Cd Cod N N A C C CN c Cn Oce L. N. N. N. CN CN C C C. v- N. s. s. co co co co r r s s n an on on on an on on can on can on Siss SNNN \ | // --92 is is Sisar lenalidomidel/molonic acid COCrystal - N -e-2 - u-au-24 - 2-/Nils ty- e- addened r Cond nonr n w v- w we wor-ged we wr-y- 13 11 11 10 9 8 7 6 5 4 3 2 1 ppm Patent Application Publication Feb. 18, 2016 Sheet 18 of 35 US 2016/0045483 A1 lenalidomidel/molonic acid cocrystal 11 10 ppm FIG. 17B Patent Application Publication Feb. 18, 2016 Sheet 19 Of 35 US 2016/0045483 A1 SS SS &S & 888 :8 SS : S 8 8 SS S& &S : 8 & 8 3. & &š :8: 88:8: & /molonic acid cocrystal Patent Application Publication Feb. 18, 2016 Sheet 20 of 35 US 2016/0045483 A1 5e--004 2e--004 1e--004 Oe--000 2-Theta (deg) FIG. 19A lenalidomide/L-tartaric acid cocrystal 5 10 15 20 25 30 35 40 Degrees Two Theta FIG. 19B Patent Application Publication Feb. 18, 2016 Sheet 21 of 35 US 2016/0045483 A1 0.5 DSC20082 110 11.85% start-2000 TC2.0137 -100 0.0 N (0.5568mg) 90 80 g-5 70 Ne 60S a -1.0 E LL- 50.5 a- S E-15 40 30 -20 20 148.29C 10 -25 O 50 100 150 200 250 300 35 Exo Up Temperature (C) FIG. 20 Patent Application Publication Feb. 18, 2016 Sheet 22 of 35 US 2016/0045483 A1 lenalidomide/L-tartaric acid cocrystal 2 5 2 O 1 5 10 desorption 5 absorption O 20 40 60 80 100 Percent Relative Humidity FIG. 21 Patent Application Publication Feb. 18, 2016 Sheet 23 of 35 US 2016/0045483 A1 8 en N en N en - to No Lo N. c. oo No N- - - to No en O N en - c to cond or ob is ced as or c s - d do do or d is ad is no dry d oc - od at as od on s- ad is . o. oO N N C C CN CN C N o os oo to L. N. N. CN C C C. - N is s. cae cad ad go r r r s r. No ind a on CN can can can can on on can ea lenalidomidel/L-tortoric acid cocrystal 's- -- % - --- d - C L l N Nado v- son conce cans v- N Non N v- corr an on can s 13 12 11 10 9 8 7 6 5 4. 3 2 1 ppm Patent Application Publication Feb. 18, 2016 Sheet 24 of 35 US 2016/0045483 A1 ric dicid cocrystol FIG. 23 Patent Application Publication Feb. 18, 2016 Sheet 25 of 35 US 2016/0045483 A1 2.0e--004 1.5e+004 2-Theta (deg) FIG. 24 Patent Application Publication Feb. 18, 2016 Sheet 26 of 35 US 2016/0045483 A1 6,0e--005 g e 4.0e+003 2.0e--003 0.0e--000 2-Theta (deg) FIG. 25 Patent Application Publication Feb. 18, 2016 Sheet 27 of 35 US 2016/0045483 A1 5.0e--003 0.0e--000 10 20 30 40 2-Theta (deg) FIG. 26 Patent Application Publication Feb. 18, 2016 Sheet 28 of 35 US 2016/0045483 A1 gallic acid 5 O 15 20 25 30 35 40 Degrees Two-Theta FIG. 27 Patent Application Publication Feb. 18, 2016 Sheet 29 of 35 US 2016/0045483 A1 enolidomide form D 5 10 15 20 25 30 35 40 Degrees Two-Theta FIG. 28 Patent Application Publication Feb. 18, 2016 Sheet 30 of 35 US 2016/0045483 A1 engidomide form D 5 10 15 20 25 30 35 40 Degrees Two-Theta FIG. 29 Patent Application Publication Feb. 18, 2016 Sheet 31 of 35 US 2016/0045483 A1 enolidomide form A glycolic acid 5 10 15 20 25 30 35 40 Degrees Two-Theta FIG. 30 Patent Application Publication Feb. 18, 2016 Sheet 32 of 35 US 2016/0045483 A1 enolidomide form A 5 O 15 20 25 30 35 40 Degrees Two-Theta FIG.