(12) Patent Application Publication (10) Pub. No.: US 2016/0045483 A1 STAHLY Et Al

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 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

3 O desorption 2O

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

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

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. 31 Patent Application Publication Feb. 18, 2016 Sheet 33 of 35 US 2016/0045483 A1

magnesium bromide

5 10 15 20 25 30 35 40 Degrees Two-Theta FIG. 32 Patent Application Publication Feb. 18, 2016 Sheet 34 of 35 US 2016/0045483 A1

lenoidomide form D

5 10 15 20 25 50 35 40 Degrees Two-Theta FIG. 33 Patent Application Publication Feb. 18, 2016 Sheet 35 of 35 US 2016/0045483 A1

benzoic acid

5 O 15 20 25 30 35 40 Degrees Two-Theta FIG. 34 US 2016/0045483 A1 Feb. 18, 2016

SOLID FORMS COMPRISING ponent solids that may potentially offer other property 3-(4-AMINO-1-OXO-1,3-DIHYDRO improvements for a pharmaceutical compound or salt thereof ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE include, e.g., hydrates, Solvates, co-crystals and clathrates, AND ACOFORMER, COMPOSITIONS AND among others (see, e.g., S. R. Byrnet al., Solid State Chem METHODS OF USE THEREOF istry of Drugs, (1999) SSCI, West Lafayette). Moreover, mul tiple-component crystal forms may potentially be susceptible 0001. This application claims priority to U.S. Provisional to polymorphism, whereina given multiple-component com Application No. 61/805.425, filed Mar. 26, 2013, the entirety position may exist in more than one three-dimensional crys of which is incorporated herein by reference. talline arrangement. 0006 Cocrystals are crystalline molecular complexes of 1. FIELD two or more non-volatile compounds bound together in a 0002 Provided herein are solid forms comprising 3-(4- crystal lattice by non-ionic interactions. Pharmaceutical coc amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-di rystals are cocrystals of a therapeutic compound, e.g., an one and a coformer. Pharmaceutical compositions compris active pharmaceutical ingredient (API), and one or more non ing Such solid forms (e.g., cocrystals) and methods of use for volatile compound(s) (referred to herein as coformer). A treating, preventing, and managing various disorders are also coformer in a pharmaceutical cocrystal is typically a non provided herein. toxic pharmaceutically acceptable molecule, such as, for example, food additives, preservatives, pharmaceutical 2. BACKGROUND excipients, or other APIs. In recent years, pharmaceutical cocrystals have emerged as a possible alternative approach to 2.1 Solid Forms of Pharmaceutical Compounds enhance physicochemical properties of drug products. 0007. The variety of possible solid forms creates potential 0003. The identification and selection of a solid form of a diversity in physical and chemical properties for a given pharmaceutical compound are complex, given that a change pharmaceutical compound. The discovery and selection of in solid form may affect a variety of physical and chemical properties, which may provide benefits or drawbacks in pro Solid forms are of great importance in the development of an cessing, formulation, stability, bioavailability, storage, han effective, stable and marketable pharmaceutical product. dling (e.g., shipping), among other important pharmaceutical 2.2 Lenalidomide characteristics. Useful pharmaceutical Solids include crystal 0008 Lenalidomide has a chemical name of 3-(4-amino line solids and amorphous solids, depending on the product 1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione and and its mode of administration. Amorphous Solids are char is marketed as Revlimid R. It is an immunomodulatory agent acterized by a lack of long-range structural order, whereas with antiangiogenic and antineoplastic properties. Lenalido crystalline solids are characterized by structural periodicity. mide is a 4-amino-glutamyl analogue of thalidomide that The desired class of pharmaceutical Solid depends upon the lacks neurological side effects such as sedation and neuropa specific application; amorphous solids are sometimes thy commonly associated with thalidomide. Lenalidomide is selected on the basis of, e.g., an enhanced dissolution profile, an immunomodulator and has been shown to affect the cel while crystalline solids may be desirable for properties such lular and humoral limbs of the immune system. It has also as, e.g., physical or chemical stability (see, e.g., S. R. Vippa been shown to have anti-antigenic properties wherein it has gunta et al., Adv. Drug. Deliv Rev., (2001) 48:3-26: L. Yu, been shown to act across a spectrum of neoplastic conditions. Adv. Drug. Deliv Rev., (2001) 48:27-42). 0009 Lenalidomide is approved by the Food and Drug 0004. Whether crystalline or amorphous, solid forms of a Administration (FDA) for use in combination with dexam pharmaceutical compound include single-component and ethasone for the treatment of multiple myeloma (MM) multiple-component Solids. Single-component solids consist patients who have received at least one prior therapy and for essentially of the pharmaceutical compound or active ingre patients with transfusion-dependent anemia due to Low- or dient in the absence of other compounds. Variety among Intermediate-1-risk myelodysplastic syndromes (MDS) single-component crystalline materials may potentially arise associated with a deletion 5q cytogenetic abnormality with or from the phenomenon of polymorphism, wherein multiple without additional cytogenetic abnormalities (Revlimid(R) three-dimensional arrangements exist for a particular phar webpage). maceutical compound (see, e.g., S. R. Byrnet al., Solid State 0010 Lenalidomide is an off-white to pale-yellow solid Chemistry of Drugs, (1999) SSCI, West Lafayette). The powder. It is soluble in organic solvent/water mixtures, and importance of discovering polymorphs was underscored by buffered aqueous solvents. Lenalidomide is more soluble in the case of RitonavirTM. an HIV protease inhibitor that was organic solvents and low pH solutions. Solubility was signifi formulated as Soft gelatin capsules. About two years after the cantly lower in less acidic buffers, ranging from about 0.4 to product was launched, the unanticipated precipitation of a 0.5 mg/ml. Lenalidomide has an asymmetric carbonatom and new, less soluble polymorph in the formulation necessitated can exist as the optically active forms S(-) and R(+), and is the withdrawal of the product from the market until a more produced as a racemic mixture with a net optical rotation of consistent formulation could be developed (see S. R. Chem ZO. burkar et al., Org. Process Res. Dev., (2000) 4:413-417). 0011. The mechanism of action of lenalidomide remains 0005 Additional diversity among the potential solid to be fully characterized. Lenalidomide possesses immuno forms of a pharmaceutical compound may arise from the modulatory, antiangiogenic, and antineoplastic properties. possibility of multiple-component solids. Crystalline solids Experiments have demonstrated that lenalidomide inhibits comprising two or more ionic species may be termed salts the growth of cells derived from patients with multiple (see, e.g., Handbook of Pharmaceutical Salts. Properties, myeloma and del (5q) myelodysplastic syndromes in vitro. Selection and Use, P. H. Stahl and C. G. Wermuth, Eds., Lenalidomide causes a delay in tumor growth in some in vivo (2002), Wiley, Weinheim). Additional types of multiple-com nonclinical hematopoietic tumor models, including multiple US 2016/0045483 A1 Feb. 18, 2016 myeloma. Lenalidomide inhibits the secretion of pro-inflam (0023 FIG. 5 provides a representative XRPD pattern of a matory cytokines such as tumor necrosis factor alpha (TNF Solid form comprising lenalidomide and glycolic acid. C.), from peripheral blood mononuclear cells. Lenalidomide (0024 FIG. 6 provides a representative XRPD pattern of a also inhibited the expression of cyclooxygenase-2 (COX-2) Solid form comprising lenalidomide and sodium lauryl Sul but not COX-1 in vitro. fate. 0012 Citation of any references in this Section is not to be (0025 FIGS. 7A & 7B provide representative XRPD pat construed as an admission that Such references are prior art to terns of a Solid form comprising lenalidomide and magne the present application. sium bromide. 0026 FIG. 8 provides a representative DSC thermogram 3. SUMMARY and a representative TGA thermogram of a solid form com 0013 Provided herein are solid forms (e.g., crystal forms prising lenalidomide and magnesium bromide. or amorphous forms, or mixtures thereof) comprising lenali (0027 FIG.9 provides a representative DVS plot of a solid domide, or pharmaceutically acceptable salts, Stereoisomers, form comprising lenalidomide and magnesium bromide. Solvates (including, hydrates), prodrugs, or clathrates thereof, 0028 FIG. 10 provides a representative Raman spectrum and a coformer. Also provided are methods of preparing, of a solid form comprising lenalidomide and magnesium isolating, and characterizing the solid forms. bromide. 0014. Also provided herein are pharmaceutical composi 0029 FIG. 11 provides a representative 'H-NMR spec tions and single unit dosage forms, which comprise one or trum of a solid form comprising lenalidomide and magne more solid forms provided herein. sium bromide. 0015. Also provided herein are methods of treating and 0030 FIG. 12 provides a representative crystal habit of a managing various diseases or disorders. The methods com Solid form comprising lenalidomide and magnesium bro prise administering to a patient in need of Such treatment or mide. management a therapeutically effective amount of a Solid 0031 FIGS. 13A & 13B provide representative XRPD form provided herein. patterns of a solid form comprisinglenalidomide and malonic 0016. Also provided herein are methods of preventing acid. various diseases and disorders, which comprise administer 0032 FIG. 14 provides a representative DSC thermogram ing to a patient in need of such prevention a prophylactically and a representative TGA thermogram of a solid form com effective amount of a solid form provided herein. prising lenalidomide and malonic acid. 0017 Also provided herein are methods of treating and 0033 FIG. 15 provides a representative DVS plot of a managing various diseases or disorders with a therapeutically Solid form comprising lenalidomide and malonic acid. effective amount of a solid form provided herein and a sec 0034 FIG. 16 provides a representative Raman spectrum ond, third, or fourth agent. of a solid form comprising lenalidomide and malonic acid. 0.018. The various diseases and disorders include, but are 0035 FIGS. 17A and 17B provides a representative not limited to: cancer, including hematologic cancer or Solid H-NMR spectrum of a solid form comprising lenalidomide tumor, for example, multiple myeloma; leukemia including and malonic acid. but not limited to acute lymphoblastic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, cchronic 0036 FIG. 18 provides a representative crystal habit of a lymphocytic leukemia, chronic myelogenous leukemia: lym Solid form comprising lenalidomide and malonic acid. phoma including but not limbited to Hodgkins and Non 0037 FIGS. 19A & 19B provide representative XRPD Hodgkins lymphoma (B-cell and T-cell lymphomas, includ patterns of a solid form comprising lenalidomide and L-tar ing follicular lymphoma, mantle cell lymphoma, Burkitt taric acid. lymphoma, indolent lymphomas and others), sarcoma, pros 0038 FIG. 20 provides a representative DSC thermogram tate cancer, or Small cell lung cancer, glioma, neuroblastoma, and a representative TGA thermogram of a solid form com Scleroderma; amyloidosis; pain; myelofibrosis; myeloprolif prising lenalidomide and L-tartaric acid. erative disease, for example, myelofibrosis with myeloid 0039 FIG. 21 provides a representative DVS plot of a metaplasia (MMM); myelodysplastic syndromes; diffuse Solid form comprising lenalidomide and L-tartaric acid. systemic sclerosis; macular degeneration; an immunodefi 0040 FIG. 22 provides a representative 'H-NMR spec ciency disorder; a CNS disorder; a CNS injury; atherosclero trum of a solid form comprising lenalidomide and L-tartaric sis; hemoglobinopathy; anemia, for example, sickle cell ane acid. mia; an inflammatory disease; an autoimmune disease; a viral 0041 FIG. 23 provides a representative crystal habit of a disease; a genetic disease; an allergic disease; a bacterial Solid form comprising lenalidomide and L-tartaric acid. disease; an ocular neovascular disease; a choroidal neovas 0042 FIG. 24 provides a representativeXRPD pattern of a cular disease; a retina neovascular disease; and rubeosis. Solid form comprising lenalidomide and hippuric acid. 0043 FIG.25 provides a representativeXRPD pattern of a 4. BRIEF DESCRIPTION OF THE DRAWINGS Solid form comprising lenalidomide and Zinc chloride. 0019 FIG. 1 provides a representative XRPD pattern of a 0044 FIG. 26 provides a representativeXRPD pattern of a Solid form comprising lenalidomide and gallic acid. Solid form comprising lenalidomide and benzoic acid. 0020 FIG. 2 provides a representative XRPD pattern of a 004.5 FIG. 27 provides a representative overlay plot of the Solid form comprising lenalidomide and Vanillin. XRPD pattern of a solid form comprising lenalidomide and 0021 FIG.3 provides a representative XRPD pattern of a gallic acid with a pattern from gallic acid. Solid form comprising lenalidomide and oxalic acid. 0046 FIG. 28 provides a representative overlay plot of the 0022 FIG. 4 provides a representative XRPD pattern of a XRPD pattern of a solid form comprising lenalidomide and Solid form comprising lenalidomide and propyl gallate. oxalic acid with a pattern from lenalidomide form D. US 2016/0045483 A1 Feb. 18, 2016

0047 FIG. 29 provides a representative overlay plot of the 0056. Unless otherwise specified, the term “crystalline' XRPD pattern of a solid form comprising lenalidomide and and related terms used herein, when used to describe a sub propyl gallate with a pattern from lenalidomide form D. stance, component, product, or form, mean that the Substance, 0048 FIG.30 provides a representative overlay plot of the component, product, or form is Substantially crystalline, for XRPD pattern of a solid form comprising lenalidomide and example, as determined by X-ray diffraction. (see, e.g., Rem glycolic acid with a pattern from glycolic acid. ington's Pharmaceutical Sciences, 18" ed., Mack Publish 0049 FIG.31 provides a representative overlay plot of the ing, Easton Pa., 173 (1990); The United States Pharma XRPD pattern of a solid form comprising lenalidomide and copeia, 23" ed., 1843-1844 (1995)). sodium lauryl sulfate with a pattern from lenalidomide form A. 0057. Unless otherwise specified, the term “crystal form.” 0050 FIG.32 provides a representative overlay plot of the “crystal forms, and related terms herein refer to crystalline XRPD patterns of a solid form comprising lenalidomide and modifications comprising a given Substance, including magnesium bromide with a pattern from magnesium bro single-component crystal forms and multiple-component mide. crystal forms, and including, but not limited to, polymorphs, 0051 FIG.33 provides a representative overlay plot of the Solvates, hydrates, co-crystals, other molecular complexes, XRPD pattern of a solid form comprising lenalidomide and salts, Solvates of salts, hydrates of salts, co-crystals of salts, hippuric acid with a pattern from lenalidomide form D. and other molecular complexes of salts, and polymorphs 0052 FIG.34 provides a representative overlay plot of the thereof. In some embodiments, a crystal form of a Substance may be substantially free of amorphous forms and/or other XRPD pattern of a solid form comprising lenalidomide and crystal forms. In other embodiments, a crystal form of a benzoic acid with a pattern from benzoic acid. substance may contain less than about 1%, 2%. 3%, 4%. 5%, 5. DETAILED DESCRIPTION 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% of one or more amorphous form(s) and/or other crystal form(s) on a 5.1 Definitions weight basis. Crystal forms of a substance may be obtained by a number of methods. Such methods include, but are not 0053 As used herein, and in the specification and the limited to, melt recrystallization, melt cooling, Solvent accompanying claims, the indefinite articles “a” and “an and recrystallization, recrystallization in confined spaces such as, the definite article “the include plural as well as single ref e.g., in nanopores or capillaries, recrystallization on Surfaces erents, unless the context clearly indicates otherwise. or templates such as, e.g., on polymers, recrystallization in 0054 As used herein, and unless otherwise specified, the the presence of additives, such as, e.g., co-crystal counter compound referred to herein by the namelenalidomide, 3-(4- molecules, desolvation, dehydration, rapid evaporation, rapid amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-di cooling, slow cooling, vapor diffusion, Sublimation, grinding, one, or Revlimid R, corresponds to chemical structure (I), and solvent-drop grinding. depicted below. In certain embodiments, the term lenalido mide, 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperi 0058. Unless otherwise specified, the terms “polymorph.” dine-2,6-dione, may be used herein to refer to either a free "polymorphic form.” “polymorphs.” “polymorphic forms.” base form or an ionized form of a compound of formula (I) and related terms herein refer to two or more crystal forms that consist essentially of the same molecule, molecules or (e.g., the molecule is protonated at one or more basic centers). ions. Different polymorphs may have different physical prop erties, such as, for example, melting temperatures, heats of fusion, Solubilities, dissolution rates, and/or vibrational spec (I) tra as a result of a different arrangement or conformation of the molecules or ions in the crystal lattice. The differences in physical properties exhibited by polymorphs may affect phar maceutical parameters, such as storage stability, compress ibility and density (important in formulation and product manufacturing), and dissolution rate (an important factor in bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, 0055. Unless otherwise specified, the terms “solid form.” Such that a dosage form discolors more rapidly when com “solid forms, and related terms, when used herein to refer a prised of one polymorph than when comprised of another physical form comprising lenalidomide, which is not pre polymorph) or mechanical changes (e.g., tablets crumble on dominantly in a liquid or a gaseous state. As used herein, the storage as a kinetically favored polymorph converts to ther terms "solid form” and “solid forms' encompass semi-solids. modynamically a more stable polymorph) or both (e.g., tab Solid forms may be crystalline, amorphous, partially crystal lets of one polymorph are more susceptible to breakdown at line, partially amorphous, or mixtures of forms. A 'single high humidity). As a result of solubility/dissolution differ component solid form comprising lenalidomide consists ences, in the extreme case, some polymorphic transitions may essentially of lenalidomide. A "multiple-component solid result in lack of potency or, at the other extreme, toxicity. In form comprising lenalidomide comprises a significant quan addition, the physical properties of the crystal may be impor tity of one or more additional species, such as ions and/or tant in processing; for example, one polymorph might be molecules, within the solid form. For example, in particular more likely to form solvates or might be difficult to filter and embodiments, a crystalline multiple-component Solid form wash free of impurities (e.g., particle shape and size distribu comprising lenalidomide further comprises one or more spe tion might be different between polymorphs). cies non-covalently bonded at regular positions in the crystal 0059. Unless otherwise specified, the term “cocrystal” or lattice. “co-crystal. as used herein, refers to a crystalline material US 2016/0045483 A1 Feb. 18, 2016 comprised of two or more non-volative compounds bond quantitative analysis, particle size analysis (PSA), Surface together in a crystal lattice by non-covalent interactions. area analysis, Solubility studies, and dissolution studies. 0060. Unless otherwise specified, the term “pharmaceuti 0065. In certain embodiments, the terms “about' and cal cocrystal' or “cocrystal of an active pharmaceutical “approximately, when used in this context, indicate that the ingredient (API), as used herein, refers to a crystalline mate numeric value or range of values may vary within 30%, 20%, rial comprised of an API and one or more non-volative com 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, pound(s) (refered herein as a coformer). The API and the 0.5%, or 0.25% of the recited value or range of values. For coformer interact through non-covalent forces in a crystal example, in some embodiments, the value of an XRPD peak lattice. position may vary by up to +0.2 degrees two theta while still 0061 Unless otherwise specified, the term “amorphous.” describing the particular XRPD peak. “amorphous form.” and related terms used herein mean that 0066. As used herein, and unless otherwise specified, a the Substance, component, or product referred to is not Sub crystalline or amorphous form that is "pure, i.e., Substan stantially crystalline as determined by X-ray diffraction. In tially free of other crystalline or amorphous forms, contains certain embodiments, an amorphous form of a Substance may less than about 10% by weight of one or more other crystal be substantially free of crystal forms. In other embodiments, line or amorphous forms, less than about 5% by weight of one an amorphous form of a Substance may contain less than or more other crystalline or amorphous forms, less than about about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 3% by weight of one or more other crystalline or amorphous 35%, 40%, 45% or 50% of one or more crystal forms on a forms, or less than about 1% by weight of one or more other weight basis. In other embodiments, an amorphous form of a crystalline or amorphous forms. Substance may comprise additional components or ingredi 0067. As used herein, and unless otherwise specified, a ents (for example, an additive, a polymer, or an excipient that solid form that is “substantially physically pure' is substan may serve to further stabilize the amorphous form). In some tially free from other solid forms. In certain embodiments, a embodiments, amorphous form may be a solid solution. crystal form that is Substantially physically pure contains less Amorphous forms of a Substance can be obtained by a number than about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, of methods. Such methods include, but are not limited to, 10%, 9%, 8%, 7%, 6%. 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, heating, melt cooling, rapid melt cooling, solvent evapora 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% of one or more other tion, rapid solvent evaporation, desolvation, Sublimation, solid forms on a weight basis. The detection of other solid grinding, ball-milling, cryo-grinding, spray drying, and forms can be accomplished by any method apparent to a freeze drying. person of ordinary skill in the art, including, but not limited to, 0062. As used herein, and unless otherwise specified, the diffraction analysis, thermal analysis, elemental combustion terms “about and “approximately, when used in connection analysis and/or spectroscopic analysis. with doses, amounts, or weight percents of ingredients of a 0068. As used herein, and unless otherwise specified, a composition or a dosage form, mean a dose, amount, or solid form that is “substantially chemically pure' is substan weight percent that is recognized by one of ordinary skill in tially free from other chemical compounds (i.e., chemical the art to provide a pharmacological effect equivalent to that impurities). In certain embodiments, a Solid form that is Sub obtained from the specified dose, amount, or weight percent. stantially chemically pure contains less than about 50%, 45%, In certain embodiments, the terms “about and “approxi 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, mately, when used in this context, contemplate a dose, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, amount, or weight percent within 30%, within 20%, within or 0.01% of one or more other chemical compounds on a 15%, within 10%, or within 5%, of the specified dose, weight basis. The detection of other chemical compounds can amount, or weight percent. be accomplished by any method apparent to a person of 0063 As used herein, and unless otherwise specified, the ordinary skill in the art, including, but not limited to, methods terms “about and “approximately, when used in connection of chemical analysis, such as, e.g., mass spectrometry analy with a numeric value or range of values which is provided to sis, spectroscopic analysis, thermal analysis, elemental com characterize a particular solid form, e.g., a specific tempera bustion analysis and/or chromatographic analysis. ture or temperature range. Such as, for example, that describes 0069. As used herein, and unless otherwise indicated, a a melting, dehydration, desolvation, or glass transition tem chemical compound, Solid form, or composition that is “sub perature; a mass change. Such as, for example, a mass change stantially free” of another chemical compound, solid form, or as a function of temperature or humidity; a solvent or water composition means that the compound, Solid form, or com content, in terms of for example, mass or a percentage; or a position contains, in certain embodiments, less than about peak position, Such as, for example, in analysis by, for 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, example, IR or Raman spectroscopy or XRPD; indicate that 7%, 6%. 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2% the value or range of values may deviate to an extent deemed 0.1%, 0.05%, or 0.01% by weight of the other compound, reasonable to one of ordinary skill in the art while still Solid form, or composition. describing the solid form. 0070. As used herein, and unless otherwise specified, the 0064. Techniques for characterizing crystal forms and term “pharmaceutically acceptable salts' refers to salts pre amorphous forms include, but are not limited to, thermal pared from pharmaceutically acceptable, relatively non-toxic gravimetric analysis (TGA), differential scanning calorim acids, including inorganic acids and organic acids. In some etry (DSC), X-ray powder diffractometry (XRPD), single embodiments, suitable acids include, but are not limited to, crystal X-ray diffractometry, vibrational spectroscopy, e.g., acetic, benzenesulfonic, benzoic, camphorsulfonic, carbonic, infrared (IR) and Raman spectroscopy, Solid-state and Solu citric, dihydrogenphosphoric, ethenesulfonic, fumaric, tion nuclear magnetic resonance (NMR) spectroscopy, opti galactunoric, gluconic, glucuronic, glutamic, hydrobromic, cal microscopy, hot stage optical microscopy, Scanning elec hydrochloric, hydriodic, isobutyric, isethionic, lactic, maleic, tron microscopy (SEM), electron crystallography and malic, malonic, mandelic, methanesulfonic, monohydrogen US 2016/0045483 A1 Feb. 18, 2016

carbonic, monohydrogen-phosphoric, monohydrogensulfu 0074 As used herein, and unless otherwise specified, the ric, mucic, nitric, pamoic, pantothenic, phosphoric, phthalic, terms “manage.” “managing” and “management” refer to propionic, Suberic, succinic, Sulfuric, tartaric, toluene preventing or slowing the progression, spread, or worsening Sulfonic acid (including p-toluenesulfonic, m-toluene of a disease or disorder, or of one or more symptoms thereof. Sulfonic, and o-toluenesulfonic acids), and the like (see, e.g., Often, the beneficial effects that a subject derives from a S. M. Berge et al., J. Pharm. Sci., 66:1-19 (1977); and Hand prophylactic and/ortherapeutic agent do not resultina cure of book of Pharmaceutical Salts. Properties, Selection and Use, the disease or disorder. In this regard, the term “managing P. H. Stahl and C. G. Wermuth, Eds. (2002), Wiley, Wein encompasses treating a patient who had suffered from the heim). In some embodiments, suitable acids are strong acids particular disease in an attempt to prevent or minimize the (e.g., with pKa less than about 1), including, but not limited recurrence of the disease or one or more symptoms thereof. to, hydrochloric, hydrobromic, Sulfuric, nitric, methane 0075. As used herein, and unless otherwise specified, a Sulfonic, benzene Sulfonic, toluene Sulfonic, naphthalene Sul “therapeutically effective amount of a compound is an fonic, naphthalene disulfonic, pyridine-Sulfonic, or other amount sufficient to provide a therapeutic benefit in the treat substituted sulfonic acids. Also included are salts of other ment or management of a disease or disorder, or to delay or relatively non-toxic compounds that possess acidic character, minimize one or more symptoms associated with the disease including amino acids, such as aspartic acid and the like, and or disorder. A therapeutically effective amount of a com other compounds, such as aspirin, ibuprofen, Saccharin, and pound means an amount of therapeutic agent, alone or in the like. Acid addition salts can be obtained by contacting the combination with other therapies, that provides a therapeutic neutral form of a compound with a sufficient amount of the benefit in the treatment or management of the disease or desired acid, either neat or in a suitable solvent. As Solids, disorder. The term “therapeutically effective amount can salts can exist in crystalline or amorphous forms, or mixtures encompass an amount that improves overall therapy, reduces thereof. Salts can also exist in polymorphic forms. or avoids symptoms or causes of disease or disorder, or 0071. Unless otherwise specified, the terms “solvate” and enhances the therapeutic efficacy of another therapeutic “solvated as used herein, refer to a solid form of a substance agent. which contains solvent. The terms “hydrate” and “hydrated 0076. As used herein, and unless otherwise specified, a refer to a solvate wherein the solventis water. “Polymorphs of “prophylactically effective amount of a compound is an solvates' refer to the existence of more than one solid form for amount Sufficient to prevent a disease or disorder, or one or a particular Solvate composition. Similarly, "polymorphs of more symptoms thereof, or prevent the recurrence of the hydrates' refer to the existence of more than one solid form disease or disorder, or one or more symptoms thereof. A for a particular hydrate composition. The term "desolvated prophylactically effective amount of a compound means an solvate, as used herein, refers to a solid form of a substance amount of therapeutic agent, alone or in combination with which can be made by removing the solvent from a solvate. other agents, that provides a prophylactic benefit in the pre The terms “solvate” and “solvated as used herein, can also vention of the disease or disorder. The term “prophylactically refer to a solvate of a salt, co-crystal, or molecular complex. effective amount' can encompass an amount that improves The terms “hydrate” and “hydrated,” as used herein, can also overall prophylaxis or enhances the prophylactic efficacy of refer to a hydrate of a salt, co-crystal, or molecular complex. another prophylactic agent. 0072. As used herein, and unless otherwise specified, the terms “treat,” “treating and “treatment” refer to the eradica 0077. Unless otherwise specified, the term “composition' tion oramelioration of a disease or disorder, or of one or more as used herein is intended to encompass a product comprising symptoms associated with the disease or disorder. In certain the specified ingredient(s) (and in the specified amount(s), if embodiments, the terms refer to minimizing the spread or indicated), as well as any product which results, directly or worsening of the disease or disorder resulting from the indirectly, from combination of the specified ingredient(s) in administration of one or more prophylactic or therapeutic the specified amount(s). By “pharmaceutically acceptable it agents to a subject with Such a disease or disorder. In some is meant a diluent, excipient, or carrier in a formulation must embodiments, the terms refer to the administration of a com be compatible with the other ingredient(s) of the formulation pound provided herein, with or without other additional and not deleterious to the recipient thereof. active agent, after the onset of symptoms of a particular (0078. Unless otherwise specified, the term “subject” is disease. defined herein to include animals, such as mammals, includ 0073. As used herein, and unless otherwise specified, the ing, but not limited to, primates (e.g., humans), cows, sheep, terms “prevent,” “preventing and “prevention” refer to the goats, horses, dogs, cats, rabbits, rats, mice, and the like. In prevention of the onset, recurrence or spread of a disease or specific embodiments, the Subject is a human. disorder, or of one or more symptoms thereof. In certain 0079. As used herein, and unless otherwise specified, the embodiments, the terms refer to the treatment with or admin terms 'symptom of a hemoglobinopathy' and 'symptom of istration of a compound provided herein, with or without anemia' mean any physiological or biological symptom asso other additional active compound, prior to the onset of symp ciated with any hemoglobinopathy or anemia, including, but toms, particularly to patients at risk of a disease or disorder not limited to, dizziness, shortness of breath, loss of con provided herein. The terms encompass the inhibition or sciousness, tiredness, weakness, hemolysis, pains associated reduction of a symptom of a particular disease. Patients with with abnormal hemoglobin, reduced erythrocyte counts (i.e., familial history of a disease in particular are candidates for reduced hematocrit), a reduced ability of a given volume of preventive regimens in certain embodiments. In addition, blood to carry oxygen, as compared with a Volume of normal patients who have a history of recurring symptoms are also blood, deformities of erythrocytes visible under a micro potential candidates for the prevention. In this regard, the Scope, etc. The terms also include negative psychological term “prevention” may be interchangeably used with the term symptoms such as depression, low self-esteem, perception of “prophylactic treatment.” illness, perception of limited physical capability, etc. US 2016/0045483 A1 Feb. 18, 2016

0080 Unless otherwise specified, to the extent that there is cyclamic acid, maleic acid, Succinic acid, ethyl maltol, a discrepancy between a depicted chemical structure of a L-malic acid, L-tartaric acid, ethyl paraben, malonic acid, compound provided herein and a chemical name of a com urea, D-fructose, maltol, Vanillic acid, fumaric acid, D.L- pound provided herein, the chemical structure shall control. mandelic acid, Vanillin, gallic acid, methyl paraben, Zinc chloride, gentisic acid, or nicotinamide. In one embodiment, 5.2 Solid Forms Comprising Lenalidomide and a the coformer is benzoic acid, gallic acid, glycolic acid, hip Coformer puric acid, magnesium bromide, malonic acid, oxalic acid, 0081. In one embodiment, provided herein are solid forms propyl gallate, Sodium lauryl Sulfate, L-tartaric acid, Vanillic (e.g., crystal forms, amorphous forms, or mixtures thereof) acid, or Zinc chloride. comprising (a) lenalidomide, or a pharmaceutically accept I0085. In one embodiment, solid forms provided herein able salt, Solvate, hydrate, Stereoisomer, prodrug, or clathrate may be a crystal form or an amorphous form or mixtures thereof; and (b) a coformer. In one embodiment, provided thereof (e.g., mixtures of crystal forms, or mixtures of crystal herein are solid forms (e.g., crystal forms, amorphous forms, and amorphous forms), which comprises (a) lenalidomide or or mixtures thereof) comprising (a) a free base of lenalido a pharmaceutically acceptable salt, Solvate, hydrate, Stereoi mide, or a Solvate, hydrate, Stereoisomer, prodrug, or clath Somer, prodrug, or clathrate thereof and (b) a coformer. In one rate thereof; and (b) a coformer. Lenalidomide can be synthe embodiment, provided herein is a crystal form comprising (a) sized or obtained according to a method known in the lenalidomide or a pharmaceutically acceptable salt, Solvate, literature or based upon the teachings herein, including the hydrate, Stereoisomer, prodrug, or clathrate thereof and (b) a methods described in detail in the examples herein. coformer. In one embodiment, provided herein is a cocrystal 0082 In one embodiment, lenalidomide can be prepared comprising (a) lenalidomide or a pharmaceutically accept according to methods described in, for example, U.S. Pat. able salt, Solvate, hydrate, Stereoisomer, prodrug, or clathrate Nos. 6,281.230 and 5,635,517, the entireties of which are thereof and (b) a coformer. In one embodiment, provided incorporated herein by reference. For example, the com herein is an amorphous form comprising (a) lenalidomide or pound can be prepared through catalytic hydrogenation of a pharmaceutically acceptable salt, Solvate, hydrate, Stereoi 3-(4-nitro-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6- Somer, prodrug, or clathrate thereof and (b) a coformer. In one dione. 3-(4-Nitro-1-oxo-1.3 dihydro-isoindol-2-yl)-piperi embodiment, provided herein is a mixture comprising (i) a dine-2,6-dione can be obtained by allowing 2,6-dioxopiperi cocrystal comprising (a) lenalidomide or a pharmaceutically din-3-ammonium chloride to react with methyl acceptable salt, Solvate, hydrate, stereoisomer, prodrug, or 2-bromomethyl-3-nitrobenzoate in dimethylformamide in clathrate thereof and (b) a coformer; and (ii) a crystal form of the presence of triethylamine. The methyl 2-bromomethyl-3- lenalidomide or a pharmaceutically acceptable salt, Solvate, nitrobenzoate in turn is obtained from the corresponding hydrate, Stereoisomer, prodrug, or clathrate thereof. In one methyl ester of nitro-ortho-toluic acid by conventional bro embodiment, provided herein is a mixture comprising (i) a mination with N-bromosuccinimide under the influence of cocrystal comprising (a) lenalidomide or a pharmaceutically light. acceptable salt, Solvate, hydrate, stereoisomer, prodrug, or 0083 Polymorphs of lenalidomide can be obtained by clathrate thereof and (b) a coformer, and (ii) an amorphous techniques known in the art, including solvent recrystalliza form of lenalidomide or a pharmaceutically acceptable salt, tion, desolvation, vapor diffusion, rapid evaporation, slow Solvate, hydrate, Stereoisomer, prodrug, or clathrate thereof. evaporation, rapid cooling and slow cooling. Polymorphs can I0086. In one embodiment, provided herein is an unsol be made by dissolving a weighed quantity of 3-(4-amino-1- vated Solid form comprising (a) lenalidomide and (b) a oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione in vari coformer. In one embodiment, provided herein is an anhy ous solvents at elevated temperatures. The solutions of the drous Solid form comprising (a) lenalidomide and (b) a compound can then be filtered and allowed to evaporate either coformer. In one embodiment, provided herein is an unsol in an open vial (for fast hot evaporation) or in a vial covered vated crystal form comprising (a) lenalidomide and (b) a with aluminum foil containing pinholes (hot slow evapora coformer. In one embodiment, provided herein is an anhy tion). Polymorphs can also be obtained from slurries. Poly drous crystal form comprising (a) lenalidomide and (b) a morphs can be crystallized from Solutions or slurries using coformer. In one embodiment, provided herein is an unsol several methods. For example, a solution created at an vated amorphous form comprising (a) lenalidomide and (b) a elevated temperature (e.g., 60°C.) can be filtered quickly then coformer. In one embodiment, provided herein is an anhy allowed to cool to room temperature. Once at room tempera drous amorphous form comprising (a) lenalidomide and (b) a ture, the sample that does not crystallize can be moved to a coformer. In one embodiment, provided herein is a solvated refrigerator then filtered. Alternatively, the solutions can be Solid form comprising (a) lenalidomide and (b) a coformer. In crash cooled by dissolving the Solid in a solvent at an one embodiment, provided herein is a hydrated solid form increased temperature (e.g., 45-65 C.) followed by cooling comprising (a) lenalidomide and (b) a coformer (e.g., a in a dry ice/solvent bath. hydrate having a stoichiometric or non-stoichiometric 0084. The coformer can be any pharmaceutically accept amount of water). In one embodiment, provided herein is a able coformer known in the art. In one embodiment, the hydrated form of (a) lenalidomide and (b) a coformer, includ coformer is acetylsalicylic acid, D-glucose, nicotinic acid, ing, but not limited to, a hemihydrate, a monohydrate, a aconitic acid, L-glutamic acid, oxalic acid, adipic acid, glu dihydrate, a trihydrate, and the like. In one embodiment, the taric acid, L-proline, 4-aminosalicylic acid, glycine, propyl hydrated form is substantially crystalline. In one embodi gallate, L-ascorbic acid, glycolic acid, L-pyroglutamic acid, ment, the hydrated form is substantially amorphous. In one benzoic acid, hippuric acid, saccharin, (+)-camphoric acid, embodiment, the anhydrous form is Substantially crystalline. 1-hydroxy-2-naphthoic acid, salicylic acid, capric acid, keto In one embodiment, the anhydrous form is Substantially glutaric acid, sebacic acid, cinnamic acid, L-lysine, sodium amorphous. In one embodiment, provided herein is an unsol lauryl Sulfate, citric acid, magnesium bromide, Sorbic acid, vated cocrystal comprising (a) lenalidomide and (b) a US 2016/0045483 A1 Feb. 18, 2016

coformer. In one embodiment, provided herein is an anhy dromes (MDS) associated with a deletion 5q cytogenetic drous cocrystal comprising (a) lenalidomide and (b) a abnormality with or without additional cytogenetic abnor coformer. In one embodiment, provided herein is a hydrated malities. cocrystal comprising (a) lenalidomide and (b) a coformer. In I0089. In another embodiment, provided herein are meth one embodiment, provided herein is a solvated cocrystal ods of using these compositions in combination with a sec comprising (a) lenalidomide and (b) a coformer. ond, third, or fourth agent in the treatment, prevention, or management of conditions and disorders including, but not 0087 Solid forms provided herein can be prepared by the limited to: cancer, including hematologic cancer or Solid methods described herein, or by techniques, including, but tumor, for example, multiple myeloma; leukemia including not limited to, heating, cooling, freeze drying, spray drying, but not limited to acute lymphoblastic leukemia, acute lyophilization, quench cooling the melt, rapid solvent evapo myeloid leukemia, acute lymphoblastic leukemia, cchronic ration, slow solvent evaporation, Solvent recrystallization, lymphocytic leukemia, chronic myelogenous leukemia: lym antisolvent addition, slurry recrystallization, crystallization phoma including but not limbited to Hodgkins and Non from the melt, desolvation, recrystallization in confined Hodgkins lymphoma (B-cell and T-cell lymphomas, includ spaces, such as, e.g., in nanopores or capillaries, recrystalli ing follicular lymphoma, mantle cell lymphoma, Burkitt Zation on Surfaces or templates, such as, e.g., on polymers, lymphoma, indolent lymphomas and others), sarcoma, pros recrystallization in the presence of additives, such as, e.g., tate cancer, or Small cell lung cancer, glioma, neuroblastoma, co-crystal counter-molecules, desolvation, dehydration, Scleroderma; amyloidosis; pain; myelofibrosis; myeloprolif rapid cooling, slow cooling, exposure to solvent and/or water, erative disease, for example, myelofibrosis with myeloid drying, including, e.g., vacuum drying, vapor diffusion, Sub metaplasia (MMM); myelodysplastic syndromes; diffuse limation, grinding (including, e.g., cryo-grinding and Sol systemic sclerosis; macular degeneration; an immunodefi Vent-drop grinding), microwave-induced precipitation, Soni ciency disorder; a CNS disorder; a CNS injury; atherosclero cation-induced precipitation, laser-induced precipitation, and sis; hemoglobinopathy; anemia, for example, sickle cell ane precipitation from a supercritical fluid. The particle size of the mia; an inflammatory disease; an autoimmune disease; a viral resulting Solid forms, which can vary (e.g., from nanometer disease; a genetic disease; an allergic disease; a bacterial dimensions to millimeter dimensions), can be controlled, disease; an ocular neovascular disease; a choroidal neovas e.g., by varying crystallization conditions, such as, e.g., the cular disease; a retina neovascular disease; and rubeosis. In a rate of crystallization and/or the crystallization solvent sys specific embodiment, provided herein are methods of using tem, or by particle-size reduction techniques, e.g., grinding, these compositions in combination with dexamethasone for milling, micronizing, or Sonication. the treatment of patients with multiple myeloma who have 0088. In another embodiment, provided herein are com received at least one prior therapy. positions comprising one or more solid form(s) comprising 0090 While not intending to be bound by any particular (a) lenalidomide or a pharmaceutically acceptable salt, Sol theory, certain solid forms provided herein exhibit physical Vate, hydrate, Stereoisomer, prodrug, or clathrate thereof, and properties, e.g., stability, Solubility and/or dissolution rate, (b) a coformer. Also provided herein are compositions com appropriate for use in clinical and therapeutic dosage forms. prising: (i) one or more solid form(s) provided herein (e.g., Moreover, while not wishing to be bound by any particular one or more crystal forms, one or more amorphous forms, and theory, certain solid forms provided herein exhibit physical mixtures thereof), and (ii) other active ingredient(s). Also properties, e.g., crystal morphology, compressibility and/or provided herein are methods of using these compositions in hardness, Suitable for manufacture of a Solid dosage form. In the treatment, prevention, or management of conditions and Some embodiments, such properties can be determined using disorders including, but not limited to: cancer, including techniques such as X-ray diffraction, microscopy, IR spec hematologic cancer or Solid tumor, for example, multiple troscopy and thermal analysis, as described herein and known myeloma; leukemia including but not limited to acute lym in the art. phoblastic leukemia, acute myeloid leukemia, acute lympho 0091 Certain embodiments herein provide solid forms blastic leukemia, cchronic lymphocytic leukemia, chronic comprising (a) lenalidomide and (b) a coformer. In one myelogenous leukemia, lymphoma including but not lim embodiment, provided herein is a solid form comprising (a) bited to Hodgkins and Non-Hodgkins lymphoma (B-cell and lenalidomide and (b) a coformer that is substantially crystal T-cell lymphomas, including follicular lymphoma, mantle line. In one embodiment, provided herein is a cocrystal com cell lymphoma, Burkitt lymphoma, indolentlymphomas and prising (a) lenalidomide and (b) a coformer. In one embodi others), sarcoma, prostate cancer, or Small cell lung cancer, ment, provided herein is a Solid form comprising a cocrystal glioma, neuroblastoma, Scleroderma; amyloidosis; pain; comprising (a) lenalidomide and (b) a coformer. In one myelofibrosis; myeloproliferative disease, for example, embodiment, provided herein is a solid form comprising (i) a myelofibrosis with myeloid metaplasia (MMM); myelodys cocrystal comprising (a) lenalidomide and (b) a coformer and plastic syndromes; diffuse systemic Sclerosis; macular (ii) an amorphous form of lenalidomide. In one embodiment, degeneration; an immunodeficiency disorder; a CNS disor provided herein is a solid form comprising (i) a cocrystal der; a CNS injury; atherosclerosis; hemoglobinopathy; ane comprising (a) lenalidomide and (b) a coformer and (ii) one or mia, for example, sickle cell anemia; an inflammatory dis more additional crystal forms of lenalidomide. ease; an autoimmune disease; a viral disease; a genetic 0092. In some embodiments, the cocrystal comprising (a) disease; an allergic disease; a bacterial disease; an ocular lenalidomide and (b) a coformer can be obtained by crystal neovascular disease; a choroidal neovascular disease; a retina lization from certain solvent systems, for example, Solvent neovascular disease; and rubeosis. In a specific embodiment, systems comprising one or more of the following solvents: provided herein are methods of using these compositions for acetone, acetonitrile, methanol, and tetrahydrofuran. N.N- the treatment in patients with transfusion-dependent anemia dimethylformamide is another example of a solvent. Other due to Low- or Intermediate-1-risk myelodysplastic Syn examples of solvent systems are provided herein elsewhere. US 2016/0045483 A1 Feb. 18, 2016

In certain embodiments, a solid form provided herein (e.g., a robenzenesulfonic acid, 2-naphthalenesulfonic acid, p-tolu cocrystal comprising (a) lenalidomide and (b) a coformer) enesulfonic acid, camphorsulfonic acid, 4-methylbicyclo2. can be obtained by slurry crystallization, evaporation crystal 2.2 oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'- lization, cooling crystallization, and precipitation crystalliza methylenebis(3-hydroxy-2-ene-1-carboxylic acid), tion. 3-phenylpropionic acid, trimethylacetic acid, tertiary buty 0093. In some embodiments, the cocrystals is a crystalline lacetic acid, lauryl Sulfuric acid, gluconic acid, glutaric acid, material comprised of an API and one or more coformers. In hydroxynaphthoic acid, Salicylic acid, Stearic acid, and certain embodiments the API and the coformer interact muconic acid. Base addition salts include, but are not limited through non-covalent forces in a crystal lattice. to, inorganic bases such as Sodium, potassium, lithium, 0094. In certain embodiments, the non-covalent forces are ammonium, calcium and magnesium salts, and organic bases one or more hydrogen bonds (H-bonds). The coformer may Such as primary, secondary and tertiary amines (e.g., isopro be H-bonded directly to the API or may be H-bonded to an pylamine, trimethyl amine, diethyl amine, tri(iso-propyl) additional molecule which is bound to the API. The additional amine, tri(n-propyl)amine, ethanolamine, 2-dimethylamino molecule may be H-bonded to the API or bound ionically or ethanol, tromethamine, lysine, arginine, histidine, procaine, covalently to the API. The additional molecule could also be hydrabamine, choline, betaine, ethylenediamine, glu a different API. In certain embodiments, the co-crystals may cosamine, N-alkylglucamines, theobromine, purines, pipera include one or more Solvate molecules in the crystalline lat Zine, piperidine, morpholine, and N-ethylpiperidine). tice, i.e., Solvates of co-crystals, or a co-crystal further com (0099. The ratio of API to coformer may be stoichiometric prising a solvent or compound that is a liquid at room tem or non-stoichiometric. In one embodiment, the ratio of API to perature. In certain embodiments, the co-crystals may be a coformer is about 5:1, 4:1, 3:1, 2.5:1, 2:1, 1.5:1, 1:1, 1:1.5, co-crystal between a coformer and a salt of an API. In certain 1:2, 1:2.5, 1:3, 1:4, or 1:5. In one embodiment, the ratio of API embodiments, the non-covalent forces are pi-stacking, guest to coformer is about 1:1. In one embodiment, the co-crystal host complexation and/or van der Waals interactions. comprises more than one coformers. In one embodiment, the 0095. In certain embodiments, hydrogen bonding may co-crystal comprises two coformers. result in different intermolecular configurations. In certain 0100. In certain embodiments, cocrystals can be prepared embodiments the intermolecular configurations are dimmers, using Solid-state methods such as Solid-state grinding and linear chains, or cyclic structures that can additionally include Solvent-drop grinding. In certain embodiments, cocrystals extended hydrogen bond networks and isolated triads. can be prepared using high-throughput screening. In certain 0096. In certain embodiments, the coformer is a solid embodiments cocrystals can be prepared using solution under ambient temperature conditions when in its pure form. based crystallization. In certain embodiments, the solid form lenalidomide is solu 0101. In certain embodiments, cocrystals formation can bilized with acetone, acetonitrile, methanol, or tetrahydrofu lead to enchancment of physical properties of the resulting al solid forms, such as solubility, dissolution rate, bioavailablity, 0097. In certain embodiments, the coformer is selected physical stability, chemical stability, flowability, fractability, from acetylsalicytic acid, aconitic acid, adipic acid, 4-ami or compressibility. In certain embodiments, a given API may nosalicylic acid, L-ascorbic acid, benzoic acid, (+)-cam form different cocrystals with many different counter-mol phoric acid, capric acid, cinnamic acid, citric acid, cyclamic ecules, and some of these cocrystals may exhibit enhanced acid, ethyl maltol, ethyl paraben, D-fructose, fumaric acid, solubility or stability. In certain embodiments pharmaceutical gallic acid, gentisic acid, D-glucose, L-glutamic acid, glutaric cocrystals increase the bioavailability or stability profile of a acid, gycine, glycolic acid, hippuric acid, 1-hydroxy-2-naph compound without the need for chemical (covalent) modifi thoic acid, ketoglutaric acid, L-lysine, magnesium bromide, cation of the API. maleic acid, L-malic acid, malonic acid, maltol, D.L-man 0102. In certain embodiments, the compounds provide delic acid, methyl paraben, nicotinamide, nicotinic acid, herein may also contain an unnatural proportion of an atomic oxalic acid, L-proline, propyl gallate, L-pyroglutamic acid, isotope at one or more of the atoms that constitute such a saccharin, Salicylic acid, sebacic acid, Sodium lauryl Sulfate, compound. For example, the compound may be radiolabeled Sorbic acid. Succinic acid, L-tartaric acid, urea, Vanillic acid, with radioactive isotopes, such as for example tritium (3H), Vanillin, and Zinc chloride. In specific embodiments, the iodine-125 (125I) sulfur-35 (35S), or carbon-14 (14C). coformer is selected from benzoic acid, gallic acid, hippuric Radiolabeled compounds are useful as therapeutic agents, acid, magnesium bromide, malonic acid, maltol, Oxalic acid, e.g., cancer therapeutic agents, research reagents, e.g., bind proplylgallate, Sodium lauryl Sulfate, L-tartaric acid, Vanillic ing assay reagents, and diagnostic agents, e.g., in Vivo imag acid, and Zinc chloride. In certain embodiments, the coformer ing agents. All isotopic variations of the compounds provided is a second API. herein, whether radioactive or not, are intended to be encom 0098. In certain embodiments, the co-crystals include an passed herein. In certain embodiments, a compound provided acid addition salt or base addition salt of an API. Acid addi herein contains unnatural proportion(s) of one or more iso tion salts include, but are not limited to, inorganic acids Such topes, including, but not limited to, hydrogen (1H), deuterium as hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric (2H), tritium (3H), carbon-11 (11C), carbon-12 (12C), car acid, and phosphoric acid, and organic acids such as acetic bon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen acid, propionic acid, hexanoic acid, heptanoic acid, cyclopen 14 (14N), nitrogen-15 (15N), oxygen-14 (14O), oxygen-15 tanepropionic acid, glycolic acid, pyruvic acid, lactic acid, (15O), oxygen-16 (16O), oxygen-17 (17O), oxygen-18 malonic acid, Succinic acid, malic acid, maleic acid, fumaric (18O), fluorine-17 (17F), fluorine-18 (18F), phosphorus-31 acid, tartatic acid, citric acid, benzoic acid, o-(4-hydroxyben (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 Zoyl)benzoic acid, cinnamic acid, madelic acid, methane (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sul Sulfonic acid, ethanesulfonic acid, 1.2-ethanedisulfonic acid, fur-36 (36S), chlorine-35 (35Cl), chlorine-36 (36Cl), chlo 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlo rine-37 (37Cl), bromine-79 (79Br), bromine-81 (81 Br), US 2016/0045483 A1 Feb. 18, 2016

iodine-123 (123I), iodine-125 (125I), iodine-127 (127I), methods, such as filtration, centrifugation, or decantation, iodine-129 (129I), and iodine-131 (131I). In certain embodi and the crystals can be dried in air or under vacuum. ments, a compound provided herein contains unnatural pro 0107. In certain embodiments, cooling crystallization is portion(s) of one or more isotopes in a stable form, that is, effected by adding a solvent or solvent mixture to a solid non-radioactive, including, but not limited to, hydrogen (1H), Substrate at elevated temperature, and allowing the resultant deuterium (2H), carbon-12 (12C), carbon-13 (13C), nitro mixture to stand for a period of time at a reduced temperature. gen-14 (14N), nitrogen-15 (15N), oxygen-16 (16O), oxygen In certain embodiments, the elevated temperature is, for 17 (17O), oxygen-18 (18O), fluorine-17 (17F), phosphorus example, about 30° C., about 40°C., about 50° C., about 60° 31 (31P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), C., about 70° C., or about 80°C. In certain embodiments, the sulfur-36 (36S), chlorine-35 (35C1), chlorine-37 (37Cl), bro reduced temperature is, for example, about 15°C., about 10° mine-79 (79Br), bromine-81 (81 Br), and iodine-127 (127I). C., about 5° C., about 0°C., about -5°C., about -10° C., In certain embodiments, a compound provided herein con about -15°C., or about -20°C. The residual solvent can be tains unnatural proportion(s) of one or more isotopes in an removed by wicking, or other Suitable methods, such as fil unstable form, that is, radioactive, including, but not limited tration, centrifugation, or decantation, and the crystals can be to, tritium (3H), carbon-11 (11C), carbon-14 (14C), nitrogen dried in air or under vacuum. 13 (13N), oxygen-14 (14O), oxygen-15 (15O), fluorine-18 (18F), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-35 5.2.1 Cocrystal Compositions Comprising (35S), chlorine-36 (36Cl), iodine-123 (123I), iodine-125 Lenalidomide and Gallic Acid (125I), iodine-129 (129I), and iodine-131 (131I). In certain 0.108 Certain embodiments herein provide solid forms embodiments, in a compound as provided herein, any hydro comprisinglenalidomide and gallic acid. In one embodiment, gen can be 2H, for example, or any carbon can be 13C, for provided herein is a solid form comprising lenalidomide and example, or any nitrogen can be 15N, for example, or any gallic acid that is substantially crystalline. In one embodi oxygen can be 180, for example, where feasible according to ment, provided herein is a cocrystal comprisinglenalidomide the judgment of one of skill. In certain embodiments, a com and gallic acid. In one embodiment, provided herein is a solid pound provided herein contains unnatural proportions of deu form comprising a cocrystal comprising lenalidomide and terium (D). In exemplary embodiments, provided herein are gallic acid. In one embodiment, provided herein is a solid isotopologues of lenalidomide, as disclosed in U.S. Provi form comprising (i) a cocrystal comprisinglenalidomide and sional Application No. 61/500,053, filed Jun. 22, 2011, which gallic acid and (ii) anamorphous form of lenalidomide. In one is incorporated by reference herein in its entirety. In one embodiment, provided herein is a solid form comprising (i) a embodiment, provided herein are solid forms (e.g., crystal cocrystal comprisinglenalidomide and gallic acid and (ii) one forms, amorphous forms, or mixtures thereof) of isotopo or more additional crystal forms of lenalidomide. Provided logues of lenalidomide provided herein. herein are various embodiments, preparations, or modifica 0103) In certain embodiments, slurry crystallization is tions of a cocrystal comprising lenalidomide and gallic acid. effected by adding solvent or solvent mixtures to a solid 0109. In some embodiments, the cocrystal comprising Substrate, and the slurry is stirred, and optionally heated to lenalidomide and gallic acid is obtained by mixing lenalido various temperatures. In certain embodiments, the slurry is mide and gallic acid in a solvent system. In some embodi heated at about 25°C., about 50° C., about 80° C., or about ments, the cocrystal is obtained by mixing lenalidomide and 100° C. In certain embodiments, upon heating and cooling, gallic acid in a solvent system saturated with gallic acid. In the residual solvents of the slurry can be removed by wicking, Some embodiments, the cocrystal is obtained by mixing lena or other Suitable methods, such as filtration, centrifugation, or lidomide and gallic acid in a solvent system saturated with decantation, and the crystals can be dried in air or under gallic acid, and Subsequently stirring the mixture at room WaCUU. temperature for about 24 hours. In some embodiments, the 0104. In certain embodiments, stoichiometric wet milling cocrystal is obtained by mixing lenalidomide and gallic acid is effected by charging a PEEK grinding cup with a solvent or in a solvent system saturated with gallic acid, Subsequently Solvent mixture with a substrate and a steel grinding ball, stirring the mixture at room temperature for about 24 hours, which can then be sealed and shaken. In certain embodiments, and isolating the Solid by centrifugation. In some embodi upon heating and cooling, the residual solvents of the slurry ments, the cocrystal is obtained by mixing approximately can be removed by wicking, or other Suitable methods. Such equal molar amount of lenalidomide and gallic acid. In some as filtration, centrifugation, or decantation, and the crystals embodiments the solvent system is a mixed solvent of metha can be dried in air or under vacuum. nol and water. In some embodiments the solvent system is a 0105. In certain embodiments, evaporation crystallization mixed solvent of methanol and water with a volume ratio of is effected by adding a solvent or solvent mixture to a solid methanol to water of about 1:1. Substrate, and allowing the solvent or solvent mixture to 0110. In some embodiments, provided herein is a cocrys evaporate under ambient conditions. In certain embodiments, tal comprisinglenalidomide and gallic acid with a molar ratio the residual solvent can be removed by wicking, or other of lenalidomide to gallic acid of approximately 2:1 to 1:2. In Suitable methods, such as filtration, centrifugation, or decan Some embodiments, the molar ratio of lenalidomide to gallic tation, and the crystals can be dried in air or under vacuum. acid is approximately 1:1. 0106. In certain embodiments, precipitation crystalliza 0111. A representative XRPD pattern of a solid form com tion is effected by adding a solvent or solvent mixture to a prising lenalidomide and gallic acid is provided in FIG.1. In Solid Substrate, and Subsequently adding an anti-solvent. In Some embodiments, provided herein is a solid form compris certain embodiments, the resultant mixture stands for a period ing lenalidomide and gallic acid characterized by one or more of time, e.g., overnight, and under certain conditions, for XRPD peaks (e.g., 1,2,3,4,5,6,7,8,9, 10, 11, 12, 13, 14, 15, example at room temperature. In certain embodiments, the 16, or more peaks) selected from peaks located at the follow residual solvent can be removed by wicking, or other suitable ing or approximately the following positions: 5.36, 6.44. US 2016/0045483 A1 Feb. 18, 2016

10.03, 13.11, 13.92, 14.31, 15.92, 16.40, 16.56, 17.09, 19.03, provided herein is a cocrystal comprising lenalidomide and 19.37, 19.69, 20.46, 20.98, 21.32, 22.11, 23.49, 23.74, 24.23, vanillin. In one embodiment, provided herein is a solid form 24.40, 25.22, 25.28, 25.38, 25.86, 26.38, 26.47, 27.53, 27.81, comprising a cocrystal comprisinglenalidomide and Vanillin. 28.52, 28.89, 29.62, 30.00, 30.81, 31.46, 32.04, 32.21, 34.07, In one embodiment, provided herein is a Solid form compris 35.30, 35.96, 36.33, 36.61, 37.18, 38.24, 38.76, and 39.35 ing (i) a cocrystal comprising lenalidomide and Vanillin and degrees 20, plus or minus 0.10. In some embodiments, pro (ii) an amorphous form of lenalidomide. In one embodiment, vided herein is a Solid form comprising lenalidomide and provided herein is a solid form comprising (i) a cocrystal gallic acid characterized by one or more XRPD peaks (e.g., 1, comprising lenalidomide and Vanillin and (ii) one or more 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more peaks) additional crystal forms of lenalidomide. Provided herein are selected from peaks located at the following or approximately various embodiments, preparations, or modifications of a the following positions: 13.11, 14.31, 16.40, 16.56, 20.46, cocrystal comprising lenalidomide and Vanillin. 21.32, 23.49, 23.74, 24.23, 24.40, 25.22, 25.28, 25.38, 25.86, 0117. In some embodiments, the cocrystal comprising 26.47. 27.53, 27.81, 28.52, 28.89, 31.46, and 32.04 degrees lenalidomide and vanillin is obtained by removing solvent 20, plus or minus 0.10. In some embodiments, the solid form from a solution containing lenalidomide and Vanillin. In some is characterized by at least 3 of the peaks. In some embodi embodiments, the cocrystal is obtained by removing solvent ments, the solid form is characterized by at least 5 of the from a solution containing lenalidomide and Vanillin on a peaks. In some embodiments, the Solid form is characterized rotary evaporator at about 65°C. In some embodiments, the by at least 7 of the peaks. In some embodiments, the solid cocrystal is obtained by removing solvent from a solution form is characterized by at least 10 of the peaks. In some containing lenalidomide and Vanillin, and Subsequently stor embodiments, the solid form is characterized by at least 13 of ing the residue at about 75% relative humidity for 1 day. In the peaks. In some embodiments, the Solid form is character Some embodiments, the cocrystal is obtained by removing ized by all of the peaks. Solvent from a solution containing lenalidomide and Vanillin, 0112. In some embodiments, provided herein is a solid and subsequently storing the residue at about 60° C. over form comprising lenalidomide and gallic acid having an night. In some embodiments, the cocrystal is obtained by XRPD pattern comprising peaks at approximately 13.11, removing solvent from a solution containing approximately 25.22 (or 25.28), and 27.53 degrees 20. In certain embodi equal molar amount of lenalidomide and Vanillin. ments, the solid form further comprises peaks at approxi 0118. In some embodiments, provided herein is a cocrys mately 16.40 and 21.32 degrees 20. In one embodiment, the tal comprisinglenalidomide and Vanillin with a molar ratio of solid form further comprises peaks at approximately 23.49 lenalidomide to Vanillin of approximately 2:1 to 1:2. In some and 25.86 degrees 20. In one embodiment, the solid form embodiments, the molar ratio of lenalidomide to vanillin is comprises peaks at approximately 13.11, 14.31, 16.40, 16.56, approximately 1:1. 20.46, 21.32, 23.49, 23.74, 24.23, 24.40, 25.22, 25.28, 25.38, 25.86, 26.47, 27.53, 27.81, 28.52, 28.89, 31.46, and 32.04 0119) A representative XRPD pattern of a solid form com degrees 20. prising lenalidomide and vanillin is provided in FIG. 2. In 0113. In one embodiment, provided herein is a solid form Some embodiments, provided herein is a solid form compris comprising lenalidomide and gallic acid having an XRPD ing lenalidomide and Vanillin characterized by one or more pattern comprising peaks at approximately 13.11 and 21.32 XRPD peaks (e.g., 1, 2, 3, 4, 5, or more peaks) selected from degrees 20. In one embodiment, the solid form further com peaks located at the following or approximately the following prises a peak at approximately 25.86 degree 20. In one positions: 5.02, 10.30, 12.06, 15.77, 20.70, and 31.26 degrees embodiment, the Solid form further comprises a peak at 20, plus or minus 0.10. In some embodiments, the solid form approximately 23.49 degree 20. is characterized by at least 3 of the peaks. In some embodi 0114. In some embodiments, provided herein is a solid ments, the solid form is characterized by at least 4 of the form comprising lenalidomide and gallic acid having an peaks. In some embodiments, the Solid form is characterized XRPD pattern comprising peaks at approximately 23.74. by at least 5 of the peaks. In some embodiments, the solid 28.89, and 25.86 degrees 20. In certain embodiments, the form is characterized by 6 of the peaks. Solid form comprises peaks at approximately 24.23, 14.31, I0120 In some embodiments, provided herein is a solid and 32.04 degrees 20. In one embodiment, the solid form form comprising lenalidomide and vanillin having an XRPD comprises peaks at approximately 16.40, 23.49 and 21.32 pattern comprising peaks at approximately 12.06, 15.77, and degrees 20. In one embodiment, the solid form comprises 20.70 degrees 20. In certain embodiments, the solid form peaks at approximately 13.11, 25.22, 27.53, and 25.28 further comprises peaks at approximately 10.30 and 31.26 degrees 20. degrees 20. In one embodiment, the Solid form comprises 0115. In certain embodiments, the XRPD peaks above peaks at approximately 5.02, 10.30, 12.06, 15.77, 20.70, and (degrees 20 peaks) are obtained when analyzed using copper 31.26 degrees 20. KC. radiation. In some embodiments, provided herein is a I0121. In some embodiments, provided herein is a solid Solid form comprising lenalidomide and gallic acid, wherein form comprising lenalidomide and vanillin having an XRPD the solid form is characterized by an XRPD diffraction pat pattern comprising peaks at approximately 12.06 and 31.26 tern which matches the XRPD pattern presented in FIG. 1. degrees 20. In certain embodiments, the Solid form comprises peaks at approximately 15.77 and 5.02 degrees 20. In one 5.2.2 Cocrystal Comprising Lenalidomide and embodiment, the solid form comprises peaks at approxi Vanillic Acid mately 15.77, 5.02 and 20.70 degrees 20. 0116 Certain embodiments herein provide solid forms I0122. In certain embodiments, the XRPD peaks above comprising lenalidomide and Vanillin. In one embodiment, (degrees 20 peaks) are obtained when analyzed using copper provided herein is a solid form comprising lenalidomide and KC. radiation. In some embodiments, provided herein is a vanillin that is substantially crystalline. In one embodiment, Solid form comprisinglenalidomide and Vanillin, wherein the US 2016/0045483 A1 Feb. 18, 2016

solid form is characterized by an XRPD diffraction pattern the peaks. In some embodiments, the Solid form is character which matches the XRPD pattern presented in FIG. 2. ized by at least 13 of the peaks. In some embodiments, the solid form is characterized by all of the peaks. 5.2.3 Cocrystal Comprising Lenalidomide and I0127. In some embodiments, provided herein is a solid Oxalic Acid form comprising lenalidomide and oxalic acid having an 0123 Certain embodiments herein provide solid forms XRPD pattern comprising peaks at approximately 19.44, comprising lenalidomide and oxalic acid. In one embodi 22.13, and 26.82 degrees 20. In certain embodiments, the ment, provided herein is a solid form comprising lenalido solid form further comprises peaks at approximately 13.76. mide and oxalic acid that is substantially crystalline. In one 21.58, and 22.58 degrees 20. In one embodiment, the solid embodiment, provided herein is a cocrystal comprising lena form comprises peaks at approximately 5.57, 10.86, 12.06, lidomide and oxalic acid. In one embodiment, provided 13.06, 13.76, 15.74, 17.73, 19.08, 19.44, 20.28, 21.16, 21.58, herein is a Solid form comprising a cocrystal comprising 22.13, 22.58, 23.88, 24.39, 26.09, 26.39, 26.82, 27.29, 27.60, lenalidomide and oxalic acid. In one embodiment, provided 27.74, 29.27, 31.48, 32.44, 33.15, 34.50, and 37.09 degrees herein is a solid form comprising (i) a cocrystal comprising 20. lenalidomide and oxalic acid and (ii) an amorphous form of I0128. In one embodiment, provided herein is a solid form lenalidomide. In one embodiment, provided herein is a solid comprising lenalidomide and oxalic acid having an XRPD form comprising (i) a cocrystal comprisinglenalidomide and pattern comprising peaks at approximately 13.76, 19.44, and oxalic acid and (ii) one or more additional crystal forms of 26.09 degrees 20. In one embodiment, the solid form further lenalidomide. Provided herein are various embodiments, comprises peaks at approximately 17.73, 21.58, and 24.39 preparations, or modifications of a cocrystal comprisinglena degrees 20. lidomide and oxalic acid. I0129. In some embodiments, provided herein is a solid 0124. In some embodiments, the cocrystal comprising form comprising lenalidomide and oxalic acid having an lenalidomide and oxalic acid is obtained by grinding lenali XRPD pattern comprising peaks at approximately 5.57, domide and oxalic acid together in the presence of a minor 33.15, 34.50, 15.74, 20.28 and 10.86 degrees 20. In certain quantity of a solvent system. In some embodiments, the coc embodiments, the Solid form comprises peaks at approxi rystal comprisinglenalidomide and oxalic acid is obtained by mately 13.06, 23.88 and 37.09 degrees 20. In one embodi grinding approximately equal molar amount of lenalidomide ment, the Solid form comprises peaks at approximately 27.74. and oxalic acid together in the presence of a minor quantity of 32.44, 21.16, 31.48, 27.60 and 12.06 degrees 20. In one a solvent system. In some embodiments, the solvent system is embodiment, the solid form comprises peaks at approxi a mixed solvent of methanol and water. In some embodi mately 26.39, 24.39, 29.27, 26.09, 17.73, 19.08 and 27.29 ments, the solvent system is a mixed solvent of methanol and degrees 20. In one embodiment, the Solid form comprises water with a volume ratio of methanol to water of about 3:1. peaks at approximately 21.58, 13.76 and 22.58 degrees 20. In 0.125. In some embodiments, provided herein is a cocrys one embodiment, the Solid form comprises peaks at approxi tal comprising lenalidomide and oxalic acid with a molar mately 19.44, 26.82 and 22.13 degrees 20. ratio of lenalidomide to oxalic acid of approximately 2:1 to 0.130. In certain embodiments, the XRPD peaks above 1:2. In some embodiments, the molar ratio of lenalidomide to (degrees 20 peaks) are obtained when analyzed using copper oxalic acid is approximately 1:1. KC. radiation. In some embodiments, provided herein is a 0126. A representative XRPD pattern of a solid form com Solid form comprisinglenalidomide and oxalic acid, wherein prisinglenalidomide and oxalic acid is provided in FIG.3. In the solid form is characterized by an XRPD diffraction pat Some embodiments, provided herein is a solid form compris tern which matches the XRPD pattern presented in FIG. 3. ing lenalidomide and oxalic acid characterized by one or 5.2.4 Cocrystal Comprising Lenalidomide and more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, Propyl Gallate 14, 15, 16, or more peaks) selected from peaks located at the following or approximately the following positions: 5.57, I0131 Certain embodiments herein provide solid forms 6.59, 7.80, 10.86, 11.35, 12.06, 13.06, 13.21, 13.76, 14.12, comprising lenalidomide and propyl gallate. In one embodi 14.38, 14.78, 15.25, 15.74, 16.19, 16.51, 16.75, 17.19, 17.73, ment, provided herein is a Solid form comprising lenalido 18.10, 19.08, 19.44, 20.28, 20.69, 20.91, 21.16, 21.58, 22.13, mide and propyl gallate that is substantially crystalline. In one 22.58, 23.88, 24.39, 26.09, 26.39, 26.82, 27.29, 27.60, 27.74, embodiment, provided herein is a cocrystal comprisinglena 28.98, 29.27, 29.96, 31.48, 32.08, 32.44, 33.15, 34.50, 34.77, lidomide and propyl gallate. In one embodiment, provided 35.58, 36.03, 37.09, 37.41, 37.93, and 39.68 degrees 20, plus herein is a solid form comprising a cocrystal comprising or minus 0.10. In some embodiments, provided herein is a lenalidomide and propyl gallate. In one embodiment, pro Solid form comprising lenalidomide and oxalic acid charac vided herein is a solid form comprising (i) a cocrystal com terized by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, prisinglenalidomide and propyl gallate and (ii) anamorphous 9, 10, 11, 12, 13, 14, 15, 16, or more peaks) selected from form of lenalidomide. In one embodiment, provided herein is peaks located at the following or approximately the following a solid form comprising (i) a cocrystal comprising lenalido positions: 5.57, 10.86, 12.06, 13.06, 13.76, 15.74, 17.73, mide and propyl gallate and (ii) one or more additional crystal 19.08, 19.44, 20.28, 21.16, 21.58, 22.13, 22.58, 23.88, 24.39, forms of lenalidomide. Provided herein are various embodi 26.09, 26.39, 26.82, 27.29, 27.60, 27.74, 29.27, 31.48, 32.44, ments, preparations, or modifications of a cocrystal compris 33.15. 34.50, and 37.09 degrees 20, plus or minus 0.10. In ing lenalidomide and propyl gallate. some embodiments, the solid form is characterized by at least 0.132. In some embodiments, the cocrystal comprising 3 of the peaks. In some embodiments, the solid form is char lenalidomide and propyl gallate is obtained by mixing lena acterized by at least 5 of the peaks. In some embodiments, the lidomide and propyl gallate in a solvent system. In some solid form is characterized by at least 7 of the peaks. In some embodiments, the cocrystal is obtained by mixing lenalido embodiments, the solid form is characterized by at least 10 of mide and propyl gallate in a solvent system saturated with US 2016/0045483 A1 Feb. 18, 2016

propyl gallate. In some embodiments, the cocrystal is 0.136. In some embodiments, provided herein is a solid obtained by mixing lenalidomide and propyl gallate in a form comprising lenalidomide and propyl gallate having an Solvent system saturated with propyl gallate, and Subse XRPD pattern comprising peaks at approximately 3.72, quently stirring the mixture at room temperature for about 24 22.09, and 26.60 degrees 20. In certain embodiments, the hours. In some embodiments, the cocrystal is obtained by solid form further comprises peaks at approximately 11.96, mixing lenalidomide and propyl gallate in a solvent system 20.72, and 23.89 degrees 20. In one embodiment, the solid saturated with propyl gallate, Subsequently stirring the mix form comprises peaks at approximately 3.72, 9.89, 11.79, ture at room temperature for about 24 hours, and isolating the 11.96, 12.05, 13.04, 15.70, 19.14, 19.58, 20.72, 21.17, 21.52, Solid by centrifugation. In some embodiments, the cocrystal 22.09, 22.60, 23.89, 24.83, 26.23, 26.60, 27.05, 27.75, 29.22, is obtained by mixing approximately equal molar amount of 31.16, and 37.71 degrees 20. lenalidomide and propyl gallate in a solvent system saturated 0.137 In one embodiment, provided herein is a solid form with propyl gallate. In some embodiments, the solvent system comprisinglenalidomide and propyl gallate having an XRPD is a mixed solvent of water and methanol. In some embodi pattern comprising peaks at approximately 3.72, 23.89, and ments, the solvent system is a mixed solvent of water and 26.60 degrees 20. In one embodiment, the solid form further methanol with a volume ratio of water to methanol of about comprises peaks at approximately 11.96 and 20.72 degrees 1:1. 20. 0133. In some embodiments, the cocrystal comprising 0.138. In some embodiments, provided herein is a solid lenalidomide and propyl gallate is obtained by grinding lena form comprising lenalidomide and propyl gallate having an lidomide and propyl gallate together in the presence of a XRPD pattern comprising peaks at approximately 22.60. minor quantity of a solvent system. In some embodiments, the 27.05, 11.79, 19.14, 24.83, 15.70 and 13.04 degrees 20. In cocrystal comprising lenalidomide and propyl gallate is certain embodiments, the Solid form comprises peaks at obtained by grinding approximately equal molar amount of approximately 12.05, 27.75, 29.22, 26.23 and 11.96 degrees lenalidomide and propyl gallate together in the presence of a 20. In one embodiment, the solid form comprises peaks at minor quantity of a solvent system. In some embodiments, the approximately 20.72, 23.89, 22.09, 26.60 and 3.72 degrees Solvent system is a mixed solvent of methanol and water. In 20. Some embodiments, the solvent system is a mixed solvent of (0.139. In certain embodiments, the XRPD peaks above methanol and water with a volume ratio of methanol to water (degrees 20 peaks) are obtained when analyzed using copper of about 3:1. KC. radiation. In some embodiments, provided herein is a 0134. In some embodiments, provided herein is a cocrys solid form comprising lenalidomide and propyl gallate, tal comprising lenalidomide and propyl gallate with a molar wherein the solid form is characterized by an XRPD diffrac ratio of lenalidomide to propyl gallate of approximately 2:1 to tion pattern which matches the XRPD pattern presented in 1:2. In some embodiments, the molar ratio of lenalidomide to FIG. 4. propyl gallate is approximately 1:1. 0135 A representative XRPD patterns of a solid form 5.2.5 Cocrystal Comprising Lenalidomide and comprising lenalidomide and propyl gallate is provided in Glycolic Acid FIG. 4. In some embodiments, provided herein is a solid form 0140 Certain embodiments herein provide solid forms comprisinglenalidomide and propyl gallate characterized by comprising lenalidomide and glycolic acid. In one embodi one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6,7,8,9, 10, 11, ment, provided herein is a Solid form comprising lenalido 12, 13, 14, 15, 16, or more peaks) selected from peaks located mide and glycolic acid that is Substantially crystalline. In one at the following or approximately the following positions: embodiment, provided herein is a cocrystal comprisinglena 3.72, 7.73, 9.35, 9.89, 11.09, 11.79, 11.96, 12.05, 13.04, lidomide and glycolic acid. In one embodiment, provided 13.17, 13.84, 14.12, 14.42, 14.84, 15.24, 15.70, 16.48, 17.21, herein is a solid form comprising a cocrystal comprising 17.66, 18.06, 18.33, 18.47, 18.71, 19.14, 19.40, 19.58, 20.72, lenalidomide and glycolic acid. In one embodiment, provided 20.92, 21.17, 21.52, 22.09, 22.43, 22.60, 23.89, 24.15, 24.46, herein is a solid form comprising (i) a cocrystal comprising 24.83, 26.23, 26.60, 27.05, 27.55, 27.75, 28.24, 29.22, 29.98, lenalidomide and glycolic acid and (ii) anamorphous form of 30.22, 31.16, 31.66, 31.80, 32.09, 33.20, 33.74, 34.55, 34.88, lenalidomide. In one embodiment, provided herein is a solid 35.39,37.18,37.71, and 38.46 degrees 20, plus or minus 0.10. form comprising (i) a cocrystal comprisinglenalidomide and In some embodiments, provided herein is a solid form com glycolic acid and (ii) one or more additional crystal forms of prising lenalidomide and propyl gallate characterized by one lenalidomide. Provided herein are various embodiments, or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, preparations, or modifications of a cocrystal comprisinglena 13, 14, 15, 16, or more peaks) selected from peaks located at lidomide and glycolic acid. the following or approximately the following positions: 3.72, 0.141. In some embodiments, the cocrystal comprising 9.89, 11.79, 11.96, 12.05, 13.04, 15.70, 19.14, 19.58, 20.72, lenalidomide and glycolic acid is obtained by mixing lenali 21.17, 21.52, 22.09, 22.60, 23.89, 24.83, 26.23, 26.60, 27.05, domide and glycolic acid in a solvent system. In some 27.75,29.22, 31.16, and 37.71 degrees 20, plus or minus 0.10. embodiments, the cocrystal is obtained by mixing lenalido In some embodiments, the solid form is characterized by at mide and glycolic acid in a solvent system saturated with least 3 of the peaks. In some embodiments, the solid form is glycolic acid. In some embodiments, the cocrystal is obtained characterized by at least 5 of the peaks. In some embodi by mixing lenalidomide and glycolic acid in a solvent system ments, the solid form is characterized by at least 7 of the saturated with glycolic acid, and Subsequently stirring the peaks. In some embodiments, the Solid form is characterized mixture at room temperature for about 24 hours. In some by at least 10 of the peaks. In some embodiments, the solid embodiments, the cocrystal is obtained by mixing lenalido form is characterized by at least 13 of the peaks. In some mide and glycolic acid in a solvent system saturated with embodiments, the solid form is characterized by all of the glycolic acid, Subsequently stirring the mixture at room tem peaks. perature for about 24 hours, and isolating the solid by cen US 2016/0045483 A1 Feb. 18, 2016

trifugation. In some embodiments, the cocrystal is obtained 0.147. In certain embodiments, the XRPD peaks above by mixing approximately equal molar amount of lenalido (degrees 20 peaks) are obtained when analyzed using copper mide and glycolic acid in a solvent system saturated with KC. radiation. In some embodiments, provided herein is a glycolic acid. In some embodiments, the solvent system is Solid form comprising lenalidomide and glycolic acid, acetonitrile. wherein the solid form is characterized by an XRPD diffrac 0142. In some embodiments, provided herein is a cocrys tion pattern which matches the XRPD pattern presented in tal comprising lenalidomide and glycolic acid with a molar FIG.S. ratio of lenalidomide to glycolic acid of approximately 2:1 to 1:2. In some embodiments, the molar ratio of lenalidomide to 5.2.6 Cocrystal Comprising Lenalidomide and glycolic acid is approximately 1:1. Sodium Lauryl Sulfate 0143 A representative XRPD pattern of a solid form com 0148 Certain embodiments herein provide solid forms prising lenalidomide and glycolic acid is provided in FIG. 5. comprising lenalidomide and Sodium lauryl Sulfate. In one In some embodiments, provided herein is a solid form com embodiment, provided herein is a solid form comprisinglena prising lenalidomide and glycolic acid characterized by one lidomide and sodium lauryl sulfate that is substantially crys or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, talline. In one embodiment, provided herein is a cocrystal 13, 14, 15, 16, or more peaks) selected from peaks located at comprising lenalidomide and Sodium lauryl Sulfate. In one the following or approximately the following positions: 7.91. embodiment, provided herein is a Solid form comprising a 9.85, 9.88, 11.32, 11.99, 13.74, 14.36, 14.81, 15.13, 15.83, cocrystal comprisinglenalidomide and Sodium lauryl Sulfate. 16.26, 17.64, 17.78, 18.36, 18.43, 18.73, 19.75, 2004, 20.16, In one embodiment, provided herein is a Solid form compris 20.58, 20.90, 21.70, 21.88, 22.89, 23.80, 24.13, 24.85, 25.10, ing (i) a cocrystal comprisinglenalidomide and Sodium lauryl 25.39, 26.01, 26.14, 26.46, 27.14, 27.35, 28.32, 29.48, 29.80, Sulfate and (ii) an amorphous form of lenalidomide. In one 30.33, 30.54, 31.09, 31.35, 31.96, 32.59, 32.73, 33.09, 33.55, embodiment, provided herein is a solid form comprising (i) a 33.91, 34.22, 34.92, 35.33,35.83, 36.27, 38.17,38.50, 38.99, cocrystal comprisinglenalidomide and sodium lauryl Sulfate and 39.71 degrees 20, plus or minus 0.10. In some embodi and (ii) one or more additional crystal forms of lenalidomide. ments, provided herein is a Solid form comprising lenalido Provided herein are various embodiments, preparations, or mide and glycolic acid characterized by one or more XRPD modifications of a cocrystal comprising lenalidomide and peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, Sodium lauryl Sulfate. or more peaks) selected from peaks located at the following or 0149. In some embodiments, the cocrystal comprising approximately the following positions: 9.85, 14.36, 16.26. lenalidomide and sodium laurylsulfate is obtained by mixing 17.64, 17.78, 18.43, 18.73, 19.75, 20.58, 21.70, 22.89, 23.80, lenalidomide and sodium lauryl Sulfate in a solvent system. In 24.13, 25.10, 25.39, 26.01, 26.14, and 29.48 degrees 20, plus Some embodiments, the cocrystal is obtained by mixing lena or minus 0.10. In some embodiments, the solid form is char lidomide and Sodium lauryl Sulfate in a solvent system satu acterized by at least 3 of the peaks. In some embodiments, the rated with sodium lauryl sulfate. In some embodiments, the solid form is characterized by at least 5 of the peaks. In some cocrystal is obtained by mixing lenalidomide and sodium embodiments, the solid form is characterized by at least 7 of lauryl Sulfate in a solvent system Saturated with sodium lauryl the peaks. In some embodiments, the Solid form is character Sulfate, and Subsequently stirring the mixture at room tem ized by at least 10 of the peaks. In some embodiments, the perature for about 24 hours. In some embodiments, the coc solid form is characterized by at least 13 of the peaks. In some rystal is obtained by mixing lenalidomide and Sodium lauryl embodiments, the solid form is characterized by all of the Sulfate in a solvent system saturated with sodium lauryl Sul peaks. fate, Subsequently stirring the mixture at room temperature 0144. In some embodiments, provided herein is a solid for about 24 hours, and isolating the Solid by centrifugation. form comprising lenalidomide and glycolic acid having an In some embodiments, the cocrystal is obtained by mixing XRPD pattern comprising peaks at approximately 9.85, approximately equal molar amount of lenalidomide and 22.89, and 25.39 degrees 20. In certain embodiments, the Sodium lauryl Sulfate in a solvent system saturated with solid form further comprises peaks at approximately 20.58, Sodium lauryl Sulfate. In some embodiments, the solvent 24.13, and 29.48 degrees 20. In one embodiment, the solid system is methanol. form comprises peaks at approximately 9.85, 14.36, 16.26. 0150. In some embodiments, provided herein is a cocrys 17.64, 17.78, 18.43, 18.73, 19.75, 20.58, 21.70, 22.89, 23.80, tal comprisinglenalidomide and Sodium lauryl Sulfate with a 24.13, 25.10, 25.39, 26.01, 26.14, and 29.48 degrees 20. molar ratio of lenalidomide to sodium lauryl sulfate of 0145. In one embodiment, provided herein is a solid form approximately 2:1 to 1:2. In some embodiments, the molar comprising lenalidomide and glycolic acid having an XRPD ratio of lenalidomide to Sodium lauryl Sulfate is approxi pattern comprising peaks at approximately 9.85, 22.89, and mately 1:1. 29.48 degrees 20. In one embodiment, the solid form further 0151. A representative XRPD pattern of a solid form com comprises peaks at approximately 17.78 and 18.43 degrees prising lenalidomide and sodium lauryl Sulfate is provided in 20. FIG. 6. In some embodiments, provided herein is a solid form 0146 In some embodiments, provided herein is a solid comprising lenalidomide and sodium lauryl Sulfate charac form comprising lenalidomide and glycolic acid having an terized by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, XRPD pattern comprising peaks at approximately 21.70, 9, 10, 11, 12, 13, 14, 15, 16, or more peaks) selected from 26.14, 25.10, 23.80, 19.75 and 14.36 degrees 20. In certain peaks located at the following or approximately the following embodiments, the Solid form comprises peaks at approxi positions: 2.19, 2.69, 4.38, 5.34, 6.53, 8.00, 10.63, 11.36, mately 17.78, 18.73, 18.43, 16.26 and 26.01 degrees 20. In 13.30, 14.44, 14.86, 15.85, 16.28, 17.66, 18.06, 20.17, 20.62, one embodiment, the Solid form comprises peaks at approxi 21.03, 21.42, 22.80, 23.85, 24.16, 24.88, 25.29, 26.01, 27.98, mately 17.64, 29.48, 24.13, 20.58, 22.89, 25.39 and 9.85 28.36, 29.10, 31.43, 31.99, 32.71, 33.16, 33.59, 35.08, and degrees 20. 36.27 degrees 20, plus or minus 0.10. In some embodiments, US 2016/0045483 A1 Feb. 18, 2016 provided herein is a solid form comprising lenalidomide and lidomide and magnesium bromide in a solvent system satu sodium lauryl sulfate characterized by one or more XRPD rated with magnesium bromide. In some embodiments, the peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, cocrystal is obtained by mixing lenalidomide and magnesium or more peaks) selected from peaks located at the following or bromide in a solvent system saturated with magnesium bro approximately the following positions: 2.19, 2.69, 4.38, 5.34. mide, and Subsequently stirring the mixture at room tempera 6.53, 8.00, 10.63, 14.44, 14.86, 15.85, 16.28, 17.66, 20.17, ture for about 24 hours. In some embodiments, the cocrystal 20.62. 21.03, 21.42, 23.85, 24.16, 26.01, and 32.71 degrees is obtained by mixing lenalidomide and magnesium bromide 20, plus or minus 0.10. In some embodiments, the solid form in a solvent system saturated with magnesium bromide, Sub is characterized by at least 3 of the peaks. In some embodi sequently stirring the mixture at room temperature for about ments, the solid form is characterized by at least 5 of the 24 hours, and isolating the Solid by centrifugation. In some peaks. In some embodiments, the Solid form is characterized embodiments, the cocrystal is obtained by mixing approxi by at least 7 of the peaks. In some embodiments, the solid mately equal molar amount of lenalidomide and magnesium form is characterized by at least 10 of the peaks. In some bromide in a solvent system saturated with magnesium bro embodiments, the solid form is characterized by at least 13 of mide. In some embodiments, the solvent system is acetone. the peaks. In some embodiments, the Solid form is character 0157. In some embodiments, the cocrystal comprising ized by all of the peaks. lenalidomide and magnesium bromide is obtained by remov 0152. In some embodiments, provided herein is a solid ing solvent from a solution containing lenalidomide and mag form comprisinglenalidomide and sodium lauryl Sulfatehav nesium bromide. In some embodiments, the cocrystal is ing an XRPD pattern comprising peaks at approximately obtained by removing solvent from a solution containing 2.19, 2.69, and 5.34 degrees 20. In certain embodiments, the lenalidomide and magnesium bromide on a rotary evaporator solid form further comprises peaks at approximately 8.00, at about 65° C. In some embodiments, the cocrystal is 17.66, and 20.62 degrees 20. In one embodiment, the solid obtained by removing solvent from a solution containing form comprises peaks at approximately 2.19, 2.69, 4.38, 5.34. lenalidomide and magnesium bromide, and Subsequently 6.53, 8.00, 10.63, 14.44, 14.86, 15.85, 16.28, 17.66, 20.17, storing the residue at about 75% relative humidity for 1 day. 20.62. 21.03, 21.42, 23.85, 24.16, 26.01, and 32.71 degrees In some embodiments, the cocrystal is obtained by removing 20. Solvent from a solution containing lenalidomide and magne 0153. In some embodiments, provided herein is a solid sium bromide, and Subsequently storing the residue at about form comprisinglenalidomide and sodium lauryl Sulfatehav 60° C. overnight. In some embodiments, the cocrystal is ing an XRPD pattern comprising peaks at approximately 8.00 obtained by removing solvent from a solution containing and 5.34 degrees 20. In certain embodiments, the solid form approximately equal molaramount of lenalidomide and mag comprises peaks at approximately 5.34 and 2.19 degrees 20. nesium bromide. In some embodiments, the solvent system is In one embodiment, the Solid form comprises peaks at methanol. approximately 2.19 and 2.69 degrees 20. 0158. In some embodiments, provided herein is a cocrys 0154) In certain embodiments, the XRPD peaks above tal comprising lenalidomide and magnesium bromide with a (degrees 20 peaks) are obtained when analyzed using copper molar ratio of lenalidomide to magnesium bromide of KC. radiation. In some embodiments, provided herein is a approximately 2:1 to 1:2. In some embodiments, the molar Solid form comprising lenalidomide and sodium lauryl Sul ratio of lenalidomide to magnesium bromide is approxi fate, wherein the solid form is characterized by an XRPD mately 1:1. diffraction pattern which matches the XRPD pattern pre 0159. A representativeXRPD pattern of a solid form com sented in FIG. 6. prising lenalidomide and magnesium bromide is provided in 5.2.7 Cocrystal Comprising Lenalidomide and FIG. 7A. In some embodiments, provided herein is a solid Magnesium Bromide form comprisinglenalidomide and magnesium bromide char acterized by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 0155 Certain embodiments herein provide solid forms 8, 9, 10, 11, 12, 13, 14, 15, 16, or more peaks) selected from comprising lenalidomide and magnesium bromide. In one peaks located at the following or approximately the following embodiment, provided herein is a Solid form comprisinglena positions: 8.43, 8.94, 12.02, 12.78, 13.88, 14.29, 15.06, lidomide and magnesium bromide that is Substantially crys 15.75, 15.92, 16.22, 16.59, 16.98, 18.06, 18.63, 19.29, 19.68, talline. In one embodiment, provided herein is a cocrystal 20.39, 21.01, 21.82, 21.98, 22.72, 23.21, 23.95, 24.27, 25.44, comprising lenalidomide and magnesium bromide. In one 25.71, 25.92, 26.07, 26.58, 26.84, 27.59, 27.96, 28.26, 28.52, embodiment, provided herein is a Solid form comprising a 28.76, 29.18, 29.59, 29.92, 31.51, 32.07, 32.85, 33.00, 34.43, cocrystal comprisinglenalidomide and magnesium bromide. 36.45,37.03, 37.90, and 38.72 degrees 20, plus or minus 0.10. In one embodiment, provided herein is a solid form compris In some embodiments, provided herein is a solid form com ing (i) a cocrystal comprising lenalidomide and magnesium prising lenalidomide and magnesium bromide characterized bromide and (ii) an amorphous form of lenalidomide. In one by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, embodiment, provided herein is a solid form comprising (i) a 11, 12, 13, 14, 15, 16, or more peaks) selected from peaks cocrystal comprising lenalidomide and magnesium bromide located at the following or approximately the following posi and (ii) one or more additional crystal forms of lenalidomide. tions: 12.02, 14.29, 15.06, 15.75, 15.92, 16.22, 16.59, 16.98, Provided herein are various embodiments, preparations, or 18.63, 19.29, 21.01, 21.82, 21.98, 23.21, 23.95, 24.27, 25.44, modifications of a cocrystal comprising lenalidomide and 25.71, 26.07, 26.84, 28.52, 28.76, 29.59, 29.92, 31.51,32.07, magnesium bromide. 32.85,33.00, 37.90, and 38.72 degrees 20, plus or minus 0.10. 0156. In some embodiments, the cocrystal comprising In some embodiments, the solid form is characterized by at lenalidomide and magnesium bromide is obtained by mixing least 3 of the peaks. In some embodiments, the solid form is lenalidomide and magnesium bromide in a solvent system. In characterized by at least 5 of the peaks. In some embodi Some embodiments, the cocrystal is obtained by mixing lena ments, the solid form is characterized by at least 7 of the US 2016/0045483 A1 Feb. 18, 2016

peaks. In some embodiments, the Solid form is characterized with a temperature of about 180 to about 250° C. In some by at least 10 of the peaks. In some embodiments, the solid embodiments, provided herein is a solid form comprising form is characterized by at least 13 of the peaks. In some lenalidomide and magnesium bromide that exhibits thermal embodiments, the solid form is characterized by all of the events, as characterized by DSC, with a peak temperature of peaks. about 123°C., and with a temperature of about 180 to about 0160 A representative XRPD pattern of a solid form com 250° C. Without being limited by any particular theory, the prising lenalidomide and magnesium bromide is provided in event with a temperature of about 180 to about 250° C. cor FIG. 7B. In some embodiments, provided herein is a solid responds to melting and/or decomposition. In some embodi form comprisinglenalidomide and magnesium bromide char ments, provided herein is a solid form comprising lenalido acterized by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, mide and magnesium bromide, wherein the Solid form is 8, 9, 10, 11, 12, 13, 14, 15, 16, or more peaks) selected from characterized by a DSC thermogram which matches the DSC peaks located at the following or approximately the following thermogram presented in FIG.8. positions: 12.02, 14.29, 15.06, 15.75, 15.92, 16.22, 16.59, 0.165. In some embodiments, provided herein is a solid 16.98, 18.63, 19.29, 21.82, 21.98, 23.21, 23.95, 24.27, 25.44, form comprising lenalidomide and magnesium bromide, 25.71, 26.07, 26.84, 28.52, 28.76, 29.59, 29.92, 31.51, 32.07, which exhibits, as characterized by TGA, about 16% weight 37.90, and 38.72 degrees 20. In some embodiments, the solid loss upon heating from about 70 to about 200° C. In some form is characterized by at least 3 of the peaks. In some embodiments, provided herein is a solid form comprising embodiments, the solid form is characterized by at least 5 of lenalidomide and magnesium bromide, wherein the Solid the peaks. In some embodiments, the Solid form is character form is characterized by a TGA thermogram which matches ized by at least 7 of the peaks. In some embodiments, the solid the TGA thermogram presented in FIG. 8. form is characterized by at least 10 of the peaks. In some 0166 A representative DVS isotherm plot of a solid form embodiments, the solid form is characterized by at least 13 of comprising lenalidomide and magnesium bromide is pro the peaks. In some embodiments, the Solid form is character vided in FIG. 9. In some embodiments, provided herein is a ized by all of the peaks. Solid form comprising lenalidomide and magnesium bro 0161 In some embodiments, provided herein is a solid mide, wherein the solid form is characterized by a DVS form comprisinglenalidomide and magnesium bromide hav isotherm plot which matches the DVS isotherm plot pre ing an XRPD pattern comprising peaks at approximately sented in FIG. 9. In some embodiments, a mass gain of about 15.75, 21.98, and 28.76 degrees 20. In certain embodiments, 43% occurs when the relative humidity (RH) is increased the solid form further comprises peaks at approximately from about 5% to about 95%. In some embodiments, a mass 18.63, 24.27, and 25.71 degrees 20. In one embodiment, the loss of about 29% occurs when the relative humidity (RH) is Solid form comprises peaks at approximately 12.02, 14.29. decreased from about 95% to about 5%. In one embodiment, 15.06, 15.75, 15.92, 16.22, 16.59, 16.98, 18.63, 19.29, 21.82, the solid form remains unchanged, as characterized by XRPD 21.98, 23.21, 23.95, 24.27, 25.44, 25.71, 26.07, 26.84, 28.52, (data not shown), after it undergoes adsorption/desorption 28.76, 29.59, 29.92, 31.51, 32.07, 37.90, and 38.72 degrees cycles. 20. 0.167 A representative Raman spectrum of a solid form 0162. In some embodiments, provided herein is a solid comprising lenalidomide and magnesium bromide is pro form comprisinglenalidomide and magnesium bromide hav vided in FIG. 10. In some embodiments, provided herein is a ing an XRPD pattern comprising peaks at approximately Solid form comprising lenalidomide and magnesium bro 25.44, 16.98, 26.07, 38.72, 14.29 and 12.02 degrees 20. In mide, wherein the solid form is characterized by a Raman certain embodiments, the Solid form comprises peaks at spectrum which matches the Raman spectrum presented in approximately 29.59, 37.90, 15.92, 15.06, 16.59, 25.71 and FIG 10. 26.84 degrees 20. In one embodiment, the solid form com (0168 A representative H-NMR spectrum of a solid form prises peaks at approximately 24.27, 31.51, 23.95, 16.22 and comprising lenalidomide and magnesium bromide is pro 33.00 degrees 20. In one embodiment, the solid form com vided in FIG. 11. In some embodiments, provided herein is a prises peaks at approximately 23.21, 21.82 and 29.92 degrees Solid form comprising lenalidomide and magnesium bro 20. In one embodiment, the solid form comprises peaks at mide, wherein the solid form is characterized by a 'H-NMR approximately 32.07, 19.29, 15.75 and 18.63 degrees 20. In spectrum which matches the 'H-NMR spectrum presented in one embodiment, the Solid form comprises peaks at approxi FIG 11. mately 28.52 and 21.98 degrees 20. In one embodiment, the 0169. In some embodiments, provided herein is a solid solid form comprises peaks at approximately 32.85 and 21.01 form comprising lenalidomide and magnesium bromide, degrees 20. which has a chunk crystal habit. A representative crystal habit 0163. In certain embodiments, the XRPD peaks above is presented in FIG. 12. (degrees 20 peaks) are obtained when analyzed using copper KC. radiation. In some embodiments, provided herein is a 5.2.8 Cocrystal Comprising Lenalidomide and Solid form comprising lenalidomide and magnesium bro Malonic Acid mide, wherein the solid form is characterized by an XRPD 0170 Certain embodiments herein provide solid forms diffraction pattern which matches the XRPD pattern pre comprising lenalidomide and malonic acid. In one embodi sented in FIG. 7A or 7B. ment, provided herein is a Solid form comprising lenalido 0164 Representative thermal characteristics (DSC and mide and malonic acid that is Substantially crystalline. In one TGA) of a solid form comprising lenalidomide and magne embodiment, provided herein is a cocrystal comprisinglena sium bromide are provided in FIG.8. In some embodiments, lidomide and malonic acid. In one embodiment, provided provided herein is a solid form comprising lenalidomide and herein is a solid form comprising a cocrystal comprising magnesium bromide that exhibits a thermal event, as charac lenalidomide and malonic acid. In one embodiment, provided terized by DSC, with a peak temperature of about 123°C., or herein is a solid form comprising (i) a cocrystal comprising US 2016/0045483 A1 Feb. 18, 2016

lenalidomide and malonic acid and (ii) an amorphous form of 0.174. In some embodiments, provided herein is a solid lenalidomide. In one embodiment, provided herein is a solid form comprising lenalidomide and malonic acid having an form comprising (i) a cocrystal comprisinglenalidomide and XRPD pattern comprising peaks at approximately 18.83, malonic acid and (ii) one or more additional crystal forms of 20.71, and 22.97 degrees 20. In certain embodiments, the lenalidomide. Provided herein are various embodiments, solid form further comprises peaks at approximately 5.87 and preparations, or modifications of a cocrystal comprisinglena 15.81 degrees 20. In certain embodiments, the solid form lidomide and malonic acid. further comprises peaks at approximately 23.10, 26.69, and 27.44 degrees 20. In one embodiment, the solid form com 0171 In some embodiments, the cocrystal comprising prises peaks at approximately 5.87, 15.81, 18.83, 20.71, lenalidomide and malonic acid is obtained by mixing lenali domide and malonic acid in a solvent system. In some 21.69, 22.58, 22.97, 23.10, 23.52, 26.69, 27.44, 28.52, 30.10, embodiments, the cocrystal is obtained by mixing lenalido 30.85, and 31.89 degrees 20. mide and malonic acid in a solvent system saturated with 0.175. In some embodiments, provided herein is a solid malonic acid. In some embodiments, the cocrystal is obtained form comprising lenalidomide and malonic acid having an by mixing lenalidomide and malonic acid in a solvent system XRPD pattern comprising peaks at approximately 30.10, saturated with malonic acid, and Subsequently stirring the 21.69 and 23.52 degrees 20. In certain embodiments, the solid mixture at room temperature for about 24 hours. In some form comprises peaks at approximately 31.89, 30.85, 23.10, embodiments, the cocrystal is obtained by mixing lenalido 22.58 and 28.52 degrees 20. In one embodiment, the solid mide and malonic acid in a solvent system saturated with form comprises peaks at approximately 26.69, 5.87, 15.81 malonic acid, Subsequently stirring the mixture at room tem and 27.44 degrees 20. In one embodiment, the solid form perature for about 24 hours, and isolating the Solid by cen comprises peaks at approximately 18.83, 20.71 and 22.97 trifugation. In some embodiments, the cocrystal is obtained degrees 20. 0176). In certain embodiments, the XRPD peaks above by mixing approximately equal molar amount of lenalido (degrees 20 peaks) are obtained when analyzed using copper mide and malonic acid in a solvent system. In some embodi KC. radiation. In some embodiments, provided herein is a ments, the solvent is acetonitrile. Solid form comprising lenalidomide and malonic acid, 0172. In some embodiments, provided herein is a cocrys wherein the solid form is characterized by an XRPD diffrac tal comprising lenalidomide and malonic acid with a molar tion pattern which matches the XRPD pattern presented in ratio of lenalidomide to malonic acid of approximately 2:1 to FIG 13A or 13B. 1:2. In some embodiments, the molar ratio of lenalidomide to (0177 Representative thermal characteristics (DSC and malonic acid is approximately 1:1. In some embodiments, the TGA) of a solid form comprising lenalidomide and malonic molar ratio of lenalidomide to malonic acid is approximately acid are provided in FIG. 14. In some embodiments, provided 2:1. herein is a Solid form comprising lenalidomide and malonic 0173 A representative XRPD pattern of a solid form com acid that exhibits a thermal event, as characterized by DSC, prising lenalidomide and malonic acid is provided in FIG. with a peak temperature of about 102°C., with a peak tem 13A. A representative XRPD pattern of a solid form compris perature of about 111°C., or with a peak temperature of about ing lenalidomide and malonic acid is also provided in FIG. 159°C. In some embodiments, provided herein is a solid form 13B. In some embodiments, provided herein is a solid form comprisinglenalidomide and malonic acid that exhibits ther comprising lenalidomide and malonic acid characterized by mal events, as characterized by DSC, with a peak temperature one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6,7,8,9, 10, 11, of about 102°C., with a peak temperature of about 111°C., 12, 13, 14, or more peaks) selected from peaks located at the and with a peak temperature of about 159° C. In some following or approximately the following positions: 5.87, embodiments, provided herein is a solid form comprising 9.28, 9.68, 11.71, 12.03, 13.23, 13.80, 14.15, 15.81, 16.27, lenalidomide and malonic acid, wherein the solid form is 16.60, 17.24, 17.42, 17.58, 17.87, 18.10, 18.31, 18.83, 19.49, characterized by a DSC thermogram which matches the DSC 20.71, 21.41, 21.69, 22.14, 22.58, 22.97, 23.10, 23.52, 23.77, thermogram presented in FIG. 14. 24.49, 24.92, 25.83, 26.69, 27.44, 27.77, 28.26, 28.52, 29.27, 0178. In some embodiments, provided herein is a solid 29.49, 30.10, 30.42, 30.85, 31.51, 31.66, 31.89, 32.19, 32.57, form comprising lenalidomide and malonic acid, which 32.87, 33.46, 33.80, 34.28, 34.66, 35.22, 35.74, 36.76, 37.04, exhibits, as characterized by TGA, about 43% weight loss 37.37, 37.71, 38.14, 39.23, and 39.37 degrees 20, plus or upon heating from about 100 to about 180°C. In one embodi minus 0.10. In some embodiments, provided herein is a solid ment, without being limited by any particular theory, the form comprising lenalidomide and malonic acid character weight loss corresponds to decomposition. In one embodi ized by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9. ment, without being limited by any particular theory, the 10, 11, 12, 13, 14, or more peaks) selected from peaks located weight loss corresponds to loss of water. In some embodi at the following or approximately the following positions: ments, provided herein is a solid form comprising lenalido 5.87, 15.81, 18.83, 20.71, 21.69, 22.58, 22.97, 23.10, 23.52, mide and malonic acid, wherein the Solid form is character 26.69, 27.44, 28.52, 30.10, 30.85, and 31.89 degrees 20, plus ized by a TGA thermogram which matches the TGA or minus 0.10. In some embodiments, the solid form is char thermogram presented in FIG. 14. acterized by at least 3 of the peaks. In some embodiments, the (0179 A representative DVS isotherm plot of a solid form solid form is characterized by at least 5 of the peaks. In some comprising lenalidomide and malonic acid is provided in embodiments, the solid form is characterized by at least 7 of FIG. 15. In some embodiments, provided herein is a solid the peaks. In some embodiments, the Solid form is character form comprisinglenalidomide and malonic acid, wherein the ized by at least 10 of the peaks. In some embodiments, the solid form is characterized by a DVS isotherm plot which solid form is characterized by at least 13 of the peaks. In some matches the DVS isotherm plot presented in FIG. 15. In some embodiments, the solid form is characterized by all of the embodiments, a mass gain of about 42% occurs when the peaks. relative humidity (RH) is increased from about 5% to about US 2016/0045483 A1 Feb. 18, 2016

95%. In some embodiments, a mass loss of about 25% occurs cocrystal comprising lenalidomide and L-tartaric acid is when the relative humidity (RH) is decreased from about 95% obtained by grinding approximately equal molar amount of to about 5%. In one embodiment, the solid form remains lenalidomide and L-tartaric acid together in the presence of a unchanged, as characterized by XRPD (data not shown), after minor quantity of a solvent system. In some embodiments, the it undergoes adsorption/desorption cycles. Solvent system is a mixed solvent of methanol and water. In 0180 A representative Raman spectrum of a solid form Some embodiments, the solvent system is a mixed solvent of comprising lenalidomide and malonic acid is provided in methanol and water with a volume ratio of methanol to water FIG. 16. In some embodiments, provided herein is a solid of about 3:1. form comprisinglenalidomide and malonic acid, wherein the 0186. In some embodiments, the cocrystal comprising solid form is characterized by a Raman spectrum which lenalidomide and L-tartaric acid is obtained by removing matches the Raman spectrum presented in FIG. 16. Solvent from a solution containing lenalidomide and L-tar 0181. A representative 'H-NMR spectrum of a solid form taric acid. In some embodiments, the cocrystal is obtained by comprising lenalidomide and malonic acid is provided in removing solvent from a solution containing lenalidomide FIG.17A. A representative H-NMR spectrum of a solid form and L-tartaric acid on a rotary evaporator at about 65°C. In comprisinglenalidomide and malonic acid is also provided in Some embodiments, the cocrystal is obtained by removing FIG. 17B. In some embodiments, provided herein is a solid Solvent from a solution containing lenalidomide and L-tar form comprisinglenalidomide and malonic acid, wherein the taric acid, and subsequently storing the residue at about 75% solid form is characterized by a 'H-NMR spectrum which relative humidity for 1 day. In some embodiments, the coc matches the 'H-NMR spectrum presented in FIG. 17A or rystal is obtained by removing solvent from a solution con 17B. taining lenalidomide and L-tartaric acid, and Subsequently 0182. In some embodiments, provided herein is a solid storing the residue at about 60°C. overnight. In some embodi form comprisinglenalidomide and malonic acid, which has a ments, the cocrystal is obtained by removing solvent from a chunk crystal habit. A representative crystal habit is presented Solution containing approximately equal molar amount of in FIG. 18. lenalidomide and L-tartaric acid. In some embodiments, the Solvent system is methanol. 5.2.9 Cocrystal Comprising Lenalidomide and 0187. In some embodiments, provided herein is a cocrys L-Tartaric Acid tal comprising lenalidomide and L-tartaric acid with a molar 0183 Certain embodiments herein provide solid forms ratio of lenalidomide to L-tartaric acid of approximately 2:1 comprising lenalidomide and L-tartaric acid. In one embodi to 1:2. In some embodiments, the molar ratio of lenalidomide ment, provided herein is a solid form comprising lenalido to L-tartaric acid is approximately 1:1. mide and L-tartaric acid that is Substantially crystalline. In 0188 A representative XRPD pattern of a solid form com one embodiment, provided herein is a cocrystal comprising prising lenalidomide and L-tartaric acid is provided in FIG. lenalidomide and L-tartaric acid. In one embodiment, pro 19A. A representative XRPD pattern of a solid form compris vided herein is a Solid form comprising a cocrystal compris ing lenalidomide and L-tartaric acid is also provided in FIG. ing lenalidomide and L-tartaric acid. In one embodiment, 19B. In some embodiments, provided herein is a solid form provided herein is a solid form comprising (i) a cocrystal comprisinglenalidomide and L-tartaric acid characterized by comprisinglenalidomide and L-tartaric acid and (ii) an amor one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6,7,8,9, 10, 11, phous form of lenalidomide. In one embodiment, provided 12, 13, 14, 15, 16, or more peaks) selected from peaks located herein is a solid form comprising (i) a cocrystal comprising at the following or approximately the following positions: lenalidomide and L-tartaric acid and (ii) one or more addi 5.66, 9.32, 11.04, 11.32, 12.08, 12.52, 12.82, 13.19, 13.91, tional crystal forms of lenalidomide. Provided herein are 14.09, 14.64, 15.28, 15.78, 16.53, 17.03, 17.49, 18.09, 18.75, various embodiments, preparations, or modifications of a 19.18, 19.84, 20.32, 21.36, 22.16, 22.65, 23.86, 24.43, 24.77, cocrystal comprising lenalidomide and L-tartaric acid. 25.21, 25.78, 26.67, 27.32, 27.68, 28.47, 28.79, 29.27, 31.17, 0184 In some embodiments, the cocrystal comprising 31.95, 34.59, 34.90, 36.94, 37.40, and 37.95 degrees 20, plus lenalidomide and L-tartaric acid is obtained by mixing lena or minus 0.10. In some embodiments, provided herein is a lidomide and L-tartaric acid in a solvent system. In some Solid form comprising lenalidomide and L-tartaric acid char embodiments, the cocrystal is obtained by mixing lenalido acterized by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, mide and L-tartaric acid in a solvent system saturated with 8, 9, 10, 11, 12, 13, 14, 15, 16, or more peaks) selected from L-tartaric acid. In some embodiments, the cocrystal is peaks located at the following or approximately the following obtained by mixing lenalidomide and L-tartaric acid in a positions: 5.66, 11.04, 12.08, 13.19, 14.09, 14.64, 15.78, Solvent system saturated with L-tartaric acid, and Subse 16.53, 17.03, 17.49, 18.09, 18.75, 19.84, 20.32, 21.36, 22.16, quently stirring the mixture at room temperature for about 24 22.65, 23.86, 24.77, 25.78, 26.67, 27.32, 27.68, 28.47, 29.27, hours. In some embodiments, the cocrystal is obtained by 31.17, 31.95, 34.59, 36.94, and 37.40 degrees 20, plus or mixing lenalidomide and L-tartaric acid in a solvent system minus 0.10. In some embodiments, the solid form is charac saturated with L-tartaric acid, Subsequently stirring the mix terized by at least 3 of the peaks. In some embodiments, the ture at room temperature for about 24 hours, and isolating the solid form is characterized by at least 5 of the peaks. In some Solid by centrifugation. In some embodiments, the cocrystal embodiments, the solid form is characterized by at least 7 of is obtained by mixing approximately equal molar amount of the peaks. In some embodiments, the Solid form is character lenalidomide and L-tartaric acid in a solvent system. In some ized by at least 10 of the peaks. In some embodiments, the embodiments, the solvent is acetonitrile. solid form is characterized by at least 13 of the peaks. In some 0185. In some embodiments, the cocrystal comprising embodiments, the solid form is characterized by all of the lenalidomide and L-tartaric acid is obtained by grinding lena peaks. lidomide and L-tartaric acid together in the presence of a 0189 In some embodiments, provided herein is a solid minor quantity of a solvent system. In some embodiments, the form comprising lenalidomide and L-tartaric acid having an US 2016/0045483 A1 Feb. 18, 2016

XRPD pattern comprising peaks at approximately 5.66, relative humidity (RH) is increased from about 5% to about 18.09, and 24.77 degrees 20. In certain embodiments, the 95%. In some embodiments, a mass loss of about 18% occurs solid form further comprises peaks at approximately 19.84. when the relative humidity (RH) is decreased from about 95% 21.36, and 23.86 degrees 20. In certain embodiments, the to about 5%. In one embodiment, the solid form remains solid form further comprises peaks at approximately 13.19. unchanged, as characterized by XRPD (data not shown), after 16.53, and 25.78 degrees 20. In one embodiment, the solid it undergoes adsorption/desorption cycles. form comprises peaks at approximately 5.66, 11.04, 12.08, (0195 A representative H-NMR spectrum of a solid form 13.19, 14.09, 14.64, 15.78, 16.53, 17.03, 17.49, 18.09, 18.75, comprising lenalidomide and L-tartaric acid is provided in 19.84, 20.32, 21.36, 22.16, 22.65, 23.86, 24.77, 25.78, 26.67, FIG. 22. In some embodiments, provided herein is a solid 27.32, 27.68, 28.47, 29.27, 31.17, 31.95, 34.59, 36.94, and form comprising lenalidomide and L-tartaric acid, wherein 37.40 degrees 20. the solid form is characterized by a 'H-NMR spectrum which 0190. In some embodiments, provided herein is a solid matches the 'H-NMR spectrum presented in FIG. 22. form comprising lenalidomide and L-tartaric acid having an 0196. In some embodiments, provided herein is a solid XRPD pattern comprising peaks at approximately 36.94. form comprisinglenalidomide and L-tartaric acid, which has 37.40, 25.78, 15.78, 17.03, 14.09 and 34.59 degrees 20. In a chunk crystal habit. A representative crystal habit is pre certain embodiments, the Solid form comprises peaks at sented in FIG. 23. approximately 27.32, 31.17, 11.04, 1749, 14.64 and 29.27 degrees 20. In one embodiment, the solid form comprises 5.2.10 Cocrystal Comprising Lenalidomide and peaks at approximately 21.36, 28.47, 31.95, 16.53 and 22.16 Hippuric Acid degrees 20. In one embodiment, the solid form comprises 0.197 Certain embodiments herein provide solid forms peaks at approximately 12.08, 13.19, 23.86 and 20.32 degrees comprising lenalidomide and hippuric acid. In one embodi 20. In one embodiment, the solid form comprises peaks at ment, provided herein is a Solid form comprising lenalido approximately 27.68, 19.84, 18.75 and 24.77 degrees 20. In mide and hippuric acid that is Substantially crystalline. In one one embodiment, the Solid form comprises peaks at approxi embodiment, provided herein is a cocrystal comprisinglena mately 26.67, 18.09, 22.65 and 5.66 degrees 20. lidomide and hippuric acid. In one embodiment, provided 0191 In certain embodiments, the XRPD peaks above herein is a solid form comprising a cocrystal comprising (degrees 20 peaks) are obtained when analyzed using copper lenalidomide and hippuric acid. In one embodiment, pro KC. radiation. In some embodiments, provided herein is a vided herein is a solid form comprising (i) a cocrystal com solid form comprising lenalidomide and L-tartaric acid, prisinglenalidomide and hippuric acid and (ii) an amorphous wherein the solid form is characterized by an XRPD diffrac form of lenalidomide. In one embodiment, provided herein is tion pattern which matches the XRPD pattern presented in a solid form comprising (i) a cocrystal comprising lenalido FIG. 19A or 19B. mide and hippuric acid and (ii) one or more additional crystal 0.192 Representative thermal characteristics (DSC and forms of lenalidomide. Provided herein are various embodi TGA) of a solid form comprisinglenalidomide and L-tartaric ments, preparations, or modifications of a cocrystal compris acid are provided in FIG. 20. In some embodiments, provided ing lenalidomide and hippuric acid. herein is a solid form comprisinglenalidomide and L-tartaric 0.198. In some embodiments, the cocrystal comprising acid that exhibits a thermal event, as characterized by DSC, lenalidomide and hippuric acid is obtained by removing Sol with a peak temperature of about 148°C., or with a tempera vent from a solution containing lenalidomide and hippuric ture of about 180 to about 250° C. In some embodiments, acid. In some embodiments, the cocrystal is obtained by provided herein is a solid form comprising lenalidomide and removing solvent from a solution containing lenalidomide L-tartaric acid that exhibits thermal events, as characterized and hippuric acid on a rotary evaporator at about 65° C. In by DSC, with a peak temperature of about 148°C., and with Some embodiments, the cocrystal is obtained by removing a temperature of about 180 to about 250° C. Without being Solvent from a solution containing lenalidomide and hippuric limited by any particular theory, the event with a temperature acid, and subsequently storing the residue at about 75% rela of about 180 to about 250° C. corresponds to melting and/or tive humidity for 1 day. In some embodiments, the cocrystal decomposition. In some embodiments, provided herein is a is obtained by removing solvent from a solution containing Solid form comprising lenalidomide and L-tartaric acid, lenalidomide and hippuric acid, and Subsequently storing the wherein the solid form is characterized by a DSC thermogram residue at about 60° C. overnight. In some embodiments, the which matches the DSC thermogram presented in FIG. 20. cocrystal is obtained by removing solvent from a solution 0193 In some embodiments, provided herein is a solid containing approximately equal molar amount of lenalido form comprising lenalidomide and L-tartaric acid, which mide and hippuric acid. In some embodiments the solvent is exhibits, as characterized by TGA, about 12% weight loss methanol. upon heating from about 30 to about 200°C. In some embodi 0199. In some embodiments, provided herein is a cocrys ments, provided herein is a Solid form comprising lenalido tal comprising lenalidomide and hippuric acid with a molar mide and L-tartaric acid, wherein the Solid form is character ratio of lenalidomide to hippuric acid of approximately 2:1 to ized by a TGA thermogram which matches the TGA 1:2. In some embodiments, the molar ratio of lenalidomide to thermogram presented in FIG. 20. hippuric acid is approximately 1:1. 0.194. A representative DVS isotherm plot of a solid form 0200. A representative XRPD pattern of a solid form com comprising lenalidomide and L-tartaric acid is provided in prisinglenalidomide and hippuric acid is provided in FIG. 24. FIG. 21. In some embodiments, provided herein is a solid In some embodiments, provided herein is a solid form com form comprising lenalidomide and L-tartaric acid, wherein prising lenalidomide and hippuric acid characterized by one the solid form is characterized by a DVS isotherm plot which or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, matches the DVS isotherm plot presented in FIG. 21. In some or more peaks) selected from peaks located at the following or embodiments, a mass gain of about 22% occurs when the approximately the following positions: 11.71, 11.82, 12.05, US 2016/0045483 A1 Feb. 18, 2016

12.82, 13.12, 14.09, 15.21, 15.73, 16.55, 17.14, 19.32, 21.42, lenalidomide. Provided herein are various embodiments, 22.01, 22.10, 22.51, 23.04, 23.91, 26.27, 26.68, 27.56, 28.89, preparations, or modifications of a cocrystal comprisinglena 33.22, and 35.27 degrees 20, plus or minus 0.10. In some lidomide and zinc chloride. embodiments, provided herein is a solid form comprising 0206. In some embodiments, the cocrystal comprising lenalidomide and hippuric acid characterized by one or more lenalidomide and Zinc chloride is obtained by grinding lena XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more lidomide and Zinc chloride together in the presence of a minor peaks) selected from peaks located at the following or quantity of a solvent system. In some embodiments, the coc approximately the following positions: 12.05, 12.82, 13.12. rystal comprising lenalidomide and Zinc chloride is obtained 15.73, 19.32, 21.42, 22.10, 23.04, 23.91, 26.68, 27.56, 28.89, by grinding approximately equal molar amount of lenalido and 35.27 degrees 20, plus or minus 0.10. In some embodi mide and Zinc chloride acid together in the presence of a ments, the solid form is characterized by at least 3 of the minor quantity of a solvent system. In some embodiments, the peaks. In some embodiments, the Solid form is characterized Solvent system is a mixed solvent of methanol and water. In by at least 5 of the peaks. In some embodiments, the solid Some embodiments, the solvent system is a mixed solvent of form is characterized by at least 7 of the peaks. In some methanol and water with a volume ratio of methanol to water embodiments, the solid form is characterized by at least 10 of of about 3:1. the peaks. In some embodiments, the Solid form is character 0207. In some embodiments, provided herein is a cocrys ized by at least 13 of the peaks. In some embodiments, the tal comprising lenalidomide and Zinc chloride with a molar solid form is characterized by all of the peaks. ratio of lenalidomide to Zinc chloride of approximately 2:1 to 0201 In some embodiments, provided herein is a solid 1:2. In some embodiments, the molar ratio of lenalidomide to form comprising lenalidomide and hippuric acid having an Zinc chloride is approximately 1:1. XRPD pattern comprising peaks at approximately 13.12. 0208. A representative XRPD pattern of a solid form com 21.42, and 28.89 degrees 20. In certain embodiments, the prisinglenalidomide and Zinc chloride is provided in FIG.25. Solid form further comprises peaks at approximately 22.10, In some embodiments, provided herein is a solid form com 27.56, and 35.27 degrees 20. In one embodiment, the solid prising lenalidomide and Zinc chloride characterized by one form comprises peaks at approximately 12.05, 12.82, 13.12. or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15.73, 19.32, 21.42, 22.10, 23.04, 23.91, 26.68, 27.56, 28.89, 13, 14, 15, 16, or more peaks) selected from peaks located at and 35.27 degrees 20. the following or approximately the following positions: 7.50, 0202 In one embodiment, provided herein is a solid form 8.98, 14.01, 14.65, 15.02, 15.31, 15.80, 17.27, 18.00, 18.30, comprising lenalidomide and hippuric acid having an XRPD 18.68, 19.05, 19.30, 19.54, 20.60, 20.82, 21.07, 22.33, 24.46, pattern comprising peaks at approximately 21.42, 28.89, and 25.40, 26.48, 28.11, 28.86, 29.21, 29.78, 30.30, 30.51, 31.07, 35.27 degrees 20. In one embodiment, the solid form further 31.97, 33.38, 34.03, 36.19, 37.14, 38.10, and 39.52 degrees comprises a peak at approximately 12.05 degree 20. 20, plus or minus 0.10. In some embodiments, provided 0203. In some embodiments, provided herein is a solid herein is a solid form comprisinglenalidomide and Zinc chlo form comprising lenalidomide and hippuric acid having an ride characterized by one or more XRPD peaks (e.g., 1, 2, 3, XRPD pattern comprising peaks at approximately 23.04. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more peaks) 19.32, 15.73 and 12.05 degrees 20. In certain embodiments, selected from peaks located at the following or approximately the Solid form comprises peaks at approximately 23.91. the following positions: 14.01, 14.65, 15.02, 15.31, 15.80, 12.82. 26.68 and 22.10 degrees 20. In one embodiment, the 17.27, 18.00, 18.30, 18.68, 19.05, 19.30, 19.54, 20.60, 20.82, solid form comprises peaks at approximately 35.27 and 27.56 21.07, 22.33, 24.46, 26.48, 28.11, 28.86, 29.21, 29.78, 30.30, degrees 20. In one embodiment, the solid form comprises 30.51, 31.97, 34.03, 38.10, and 39.52 degrees 20, plus or peaks at approximately 21.42, 13.12 and 28.89 degrees 20. minus 0.10. In some embodiments, the solid form is charac 0204. In certain embodiments, the XRPD peaks above terized by at least 3 of the peaks. In some embodiments, the (degrees 20 peaks) are obtained when analyzed using copper solid form is characterized by at least 5 of the peaks. In some KC. radiation. In some embodiments, provided herein is a embodiments, the solid form is characterized by at least 7 of Solid form comprising lenalidomide and hippuric acid, the peaks. In some embodiments, the Solid form is character wherein the solid form is characterized by an XRPD diffrac ized by at least 10 of the peaks. In some embodiments, the tion pattern which matches the XRPD pattern presented in solid form is characterized by at least 13 of the peaks. In some FIG. 24. embodiments, the solid form is characterized by all of the peaks. 5.2.11 Cocrystal Comprising Lenalidomide and Zinc 0209. In some embodiments, provided herein is a solid Chloride form comprising lenalidomide and Zinc chloride having an 0205 Certain embodiments herein provide solid forms XRPD pattern comprising peaks at approximately 17.27, comprising lenalidomide and Zinc chloride. In one embodi 18.00, and 24.46 degrees 20. In certain embodiments, the ment, provided herein is a solid form comprising lenalido solid form further comprises peaks at approximately 15.80. mide and Zinc chloride that is Substantially crystalline. In one 20.82, and 22.33 degrees 20. In certain embodiments, the embodiment, provided herein is a cocrystal comprising lena solid form further comprises peaks at approximately 15.02, lidomide and zinc chloride. In one embodiment, provided 19.54, and 29.78 degrees 20. In one embodiment, the solid herein is a Solid form comprising a cocrystal comprising form comprises peaks at approximately 14.01, 14.65, 15.02, lenalidomide and zinc chloride. In one embodiment, provided 15.31, 15.80, 17.27, 18.00, 18.30, 18.68, 1905, 19.30, 19.54, herein is a solid form comprising (i) a cocrystal comprising 20.60, 20.82, 21.07, 22.33, 24.46, 26.48, 28.11, 28.86, 29.21, lenalidomide and Zinc chloride and (ii) anamorphous form of 29.78, 30.30, 30.51, 31.97, 34.03, 38.10, and 39.52 degrees lenalidomide. In one embodiment, provided herein is a solid 20. form comprising (i) a cocrystal comprisinglenalidomide and 0210. In some embodiments, provided herein is a solid Zinc chloride and (ii) one or more additional crystal forms of form comprising lenalidomide and Zinc chloride having an US 2016/0045483 A1 Feb. 18, 2016 20

XRPD pattern comprising peaks at approximately 8.98. 0215. A representative XRPD pattern of a solid form com 31.07 and 33.38 degrees 20. In certain embodiments, the solid prisinglenalidomide and benzoic acid is provided in FIG. 26. form comprises peaks at approximately 7.50, 38.10, 31.97 In some embodiments, provided herein is a solid form com and 20.60 degrees 20. In one embodiment, the solid form prising lenalidomide and benzoic acid characterized by one comprises peaks at approximately 15.31, 30.30, 28.11 and or more XRPD peaks (e.g., 1,2,3,4,5,6,7,8, or more peaks) 19.05 degrees 20. In certain embodiments, the solid form selected from peaks located at the following or approximately further comprises peaks at approximately 39.52. 21.07, 14.65 the following positions: 5.14, 15.07, 16.18, 17.12, 23.83, and 19.30 degrees 20. In one embodiment, the solid form 24.42, 27.66, 29.21, and 32.80 degrees 20, plus or minus 0.10. comprises peaks at approximately 34.03, 14.01, 28.86 and In some embodiments, the solid form is characterized by at 18.30 degrees 20. In certain embodiments, the solid form least 3 of the peaks. In some embodiments, the solid form is further comprises peaks at approximately 30.51, 26.48, 29.21 characterized by at least 5 of the peaks. In some embodi and 18.68 degrees 20. In one embodiment, the solid form ments, the solid form is characterized by at least 7 of the comprises peaks at approximately 19.54, 29.78, 15.02 and peaks. In some embodiments, the Solid form is characterized 15.80 degrees 20. In one embodiment, the solid form com by all of the peaks. prises peaks at approximately 20.82, 22.33, 18.00, 17.27 and 0216. In some embodiments, provided herein is a solid 24.46 degrees 20. form comprising lenalidomide and benzoic acid having an 0211. In certain embodiments, the XRPD peaks above XRPD pattern comprising peaks at approximately 16.18 and (degrees 20 peaks) are obtained when analyzed using copper 32.80 degrees 20. In certain embodiments, the solid form KC. radiation. In some embodiments, provided herein is a further comprises peaks at approximately 15.07 and 24.42 Solid form comprising lenalidomide and Zinc chloride, degrees 20. In certain embodiments, the solid form further wherein the solid form is characterized by an XRPD diffrac comprises a peak at approximately 5.14 degree 20. In one tion pattern which matches the XRPD pattern presented in embodiment, the solid form comprises peaks at approxi FIG. 25. mately 5.14, 15.07, 16.18, 17.12, 23.83, 24.42, 27.66, 29.21, and 32.80 degrees 20. 5.2.12 Cocrystal Comprising Lenalidomide and 0217. In one embodiment, provided herein is a solid form Benzoic Acid comprising lenalidomide and benzoic acid having an XRPD 0212. Certain embodiments herein provide solid forms pattern comprising peaks at approximately 15.07, 23.83, and comprising lenalidomide and benzoic acid. In one embodi 29.21 degrees 20. In one embodiment, the solid form further ment, provided herein is a solid form comprising lenalido comprises peaks at approximately 24.42 and 32.80 degrees mide and benzoic acid that is substantially crystalline. In one 20. embodiment, provided herein is a cocrystal comprising lena 0218. In one embodiment, provided herein is a solid form lidomide and benzoic acid. In one embodiment, provided comprising lenalidomide and benzoic acid having an XRPD herein is a Solid form comprising a cocrystal comprising pattern comprising peaks at approximately 15.07 and 29.21 lenalidomide and benzoic acid. In one embodiment, provided degrees 20. In one embodiment, the solid form further com herein is a solid form comprising (i) a cocrystal comprising prises a peak at approximately 32.80 degree 20. lenalidomide and benzoic acid and (ii) an amorphous form of 0219. In certain embodiments, the XRPD peaks above lenalidomide. In one embodiment, provided herein is a solid (degrees 20 peaks) are obtained when analyzed using copper form comprising (i) a cocrystal comprisinglenalidomide and KC. radiation. In some embodiments, provided herein is a benzoic acid and (ii) one or more additional crystal forms of Solid form comprising lenalidomide and benzoic acid, lenalidomide. Provided herein are various embodiments, wherein the solid form is characterized by an XRPD diffrac preparations, or modifications of a cocrystal comprisinglena tion pattern which matches the XRPD pattern presented in lidomide and benzoic acid. FIG. 26. 0213. In some embodiments, the cocrystal comprising lenalidomide and benzoic acid is obtained by removing Sol 5.3 Second Agents vent from a solution containing lenalidomide and benzoic acid. In some embodiments, the cocrystal is obtained by 0220. A solid form of the invention can be used with or removing solvent from a solution containing lenalidomide combined with other pharmacologically active compounds and benzoic acid on a rotary evaporator at about 65° C. In ("second active agents') in methods and compositions of the Some embodiments, the cocrystal is obtained by removing invention. It is believed that certain combinations work syn Solvent from a solution containing lenalidomide and benzoic ergistically in the treatment of particular types of cancers, and acid, and subsequently storing the residue at about 75% rela certain diseases and conditions associated with, or character tive humidity for 1 day. In some embodiments, the cocrystal ized by, undesired angiogenesis. Immunomodulatory com is obtained by removing solvent from a solution containing pounds of the invention can also work to alleviate adverse lenalidomide and benzoic acid, and Subsequently storing the effects associated with certain second active agents, and some residue at about 60° C. overnight. In some embodiments, the second active agents can be used to alleviate adverse effects cocrystal is obtained by removing solvent from a solution associated with immunomodulatory compounds of the inven containing approximately equal molar amount of lenalido tion. mide and benzoic acid. In some embodiments the solvent is 0221 One or more second active ingredients or agents can methanol. be used in the methods and compositions of the invention 0214. In some embodiments, provided herein is a cocrys together with a solid form of the invention. Second active tal comprising lenalidomide and benzoic acid with a molar agents can be large molecules (e.g., proteins, or monoclonal ratio of lenalidomide to benzoic acid of approximately 2:1 to antibodies (e.g., Rituximab or Elotuzmab)) or small mol 1:2. In some embodiments, the molar ratio of lenalidomide to ecules (e.g., synthetic inorganic, organometallic, or organic benzoic acid is approximately 1:1. molecules). US 2016/0045483 A1 Feb. 18, 2016

0222 One or more second active ingredients or agents can are not limited to, anti-cancer agents, antibiotics, immuno be used in the methods and compositions of the invention Suppressive agents, and steroids. together with a solid form of the invention. Second active 0229. Examples of anti-cancer agents include, but are not agents can be large molecules (e.g., proteins) or Small mol limited to: acivicin; aclarubicin; acodazole hydrochloride: ecules (e.g., synthetic inorganic, organometallic, or organic acronine; adoZelesin; aldesleukin; altretamine; ambomycin; molecules). ametantrone acetate; amsacrine; anastrozole; anthramycin; 0223 Examples of large molecule active agents include, asparaginase; asperlin; azacitidine; azetepa; azotomycin; but are not limited to, hematopoietic growth factors, cytok batimastat; benzodepa; bicalutamide; bisantrene hydrochlo ines, and monoclonal and polyclonal antibodies. Typical ride; bisnafide dimesylate: bizelesin; bleomycin sulfate; bre large molecule active agents are biological molecules, such as quinar Sodium; bropirimine; buSulfan; cactinomycin; calus naturally occurring or artificially made proteins. Proteins that terone; caracemide; carbetimer; carboplatin: carmustine; are particularly useful in this invention include proteins that carubicin hydrochloride; carzelesin, cedefingol; celecoxib stimulate the survival and/or proliferation of hematopoietic (COX-2 inhibitor); chlorambucil; cirolemycin; cisplatin: precursor cells and immunologically active poietic cells in cladribine; crisinatol mesylate; cyclophosphamide; cytara vitro or in vivo. Others stimulate the division and differentia bine; dacarbazine; dactinomycin; daunorubicin hydrochlo tion of committed erythroid progenitors in cells in vitro or in ride; decitabine; dexormaplatin; deZaguanine; deZaguanine vivo. Particular proteins include, but are not limited to: inter mesylate; diaziquone; docetaxel, doxorubicin; doxorubicin leukins, such as IL-2 (including recombinant IL-II (rIL2) hydrochloride; droloxifene; droloxifene citrate; dromo and canarypox IL-2), IL-10, IL-12, and IL-18; interferons, stanolone propionate; duaZomycin; ediatrexate; eflomithine such as interferon alfa-2a, interferon alfa-2b, interferon alfa hydrochloride; elsamitrucin; enloplatin; enpromate; epipro n1, interferon alfa-n3, interferon beta-I a, and interferon pidine; epirubicin hydrochloride; erbulozole; esorubicin gamma-Ib: GM-CF and GM-CSF; and EPO. hydrochloride; estramustine; estramustine phosphate 0224 Particular proteins that can be used in the methods Sodium; etanidazole; etoposide; etoposide phosphate: eto and compositions of the invention include, but are not limited prine; fadrozole hydrochloride; fazarabine; fenretinide; to: filgrastim, which is sold in the United States under the floxuridine; fludarabine phosphate; fluorouracil; flurocitab trade name Neupogen R (Amgen, Thousand Oaks, Calif); ine; fosquidone; fostriecin Sodium; gemcitabine; gemcitab sargramostim, which is sold in the United States under the ine hydrochloride; hydroxyurea; idarubicin hydrochloride: trade name Leukine(R) (Immunex, Seattle, Wash.); and recom ifosfamide; ilmofosine, iproplatin; irinotecan; irinotecan binant EPO, which is sold in the United States under the trade hydrochloride; lanreotide acetate; letrozole; leuprolide name Epogen R (Amgen, Thousand Oaks, Calif.). acetate; liaroZole hydrochloride; lometrexol Sodium, lomus tine; losoxantrone hydrochloride; masoprocol; maytansine; 0225 Recombinant and mutated forms of GM-CSF can be mechlorethamine hydrochloride; megestrol acetate; prepared as described in U.S. Pat. Nos. 5.391.485; 5,393,870; melengestrol acetate; melphalan; menogaril; mercaptopu and 5.229,496; all of which are incorporated herein by refer rine; methotrexate; methotrexate Sodium; metoprine; meture ence. Recombinant and mutated forms of G-CSF can be depa; mitindomide; mitocarcin, mitocromin, mitogillin; prepared as described in U.S. Pat. Nos. 4,810,643: 4,999.291; mitomalcin, mitomycin; mitosper, mitotane; mitoxantrone 5,528,823; and 5,580,755; all of which are incorporated hydrochloride; mycophenolic acid; nocodazole; nogalamy herein by reference. cin; Ormaplatin, OXisuran; taxane, paclitaxel, pegaspargase: 0226 Large molecule active agents may be administered peliomycin; pentamustine; peplomycin Sulfate; perfosfa in the form of anti-cancer vaccines. For example, vaccines mide; pipobroman; piposulfan; piroXantrone hydrochloride; that secrete, or cause the secretion of cytokines Such as IL-2, plicamycin; plomestane; porfimer Sodium; porfiromycin; G-CSF, and GM-CSF can be used in the methods, pharma prednimustine; procarbazine hydrochloride; puromycin; ceutical compositions, and kits of the invention. See, e.g., puromycin hydrochloride; pyrazofurin, riboprine; Safingol; Emens, L. A., et al., Curr. Opinion Mol. Ther. 3(1):77-84 Safingol hydrochloride; Semustine; simtraZene; sparfosate (2001). Sodium; sparsomycin; Spirogermanium hydrochloride; spiro 0227. In one embodiment of the invention, the large mol mustine; spiroplatin; Streptonigrin, streptozocin, Sulofenur; ecule active agent reduces, eliminates, or prevents an adverse talisomycin; tecogalan Sodium; taxotere; tegafur, telox effect associated with the administration of a solid form of the antrone hydrochloride; temoporfin, teniposide; teroxirone; invention. Depending on the particular immunomodulatory testolactone; thiamiprine; thioguanine; thiotepa, tiazofurin; compound of the invention and the disease or disorder begin tirapazamine; toremifene citrate; trestolone acetate; tricirib treated, adverse effects can include, but are not limited to, ine phosphate; trimetrexate; trimetrexate glucuronate; trip drowsiness and somnolence, dizziness and orthostatic torelin; tubulozole hydrochloride: uracil mustard; uredepa; hypotension, neutropenia, infections that result from neutro vapreotide; verteporfin; vinblastine sulfate; Vincristine sul penia, increased HIV-viral load, bradycardia, Stevens fate; Vindesine; Vindesine Sulfate; Vinepidine Sulfate; Vingly Johnson Syndrome and toxic epidermal necrolysis, and sei cinate sulfate; Vinleurosine sulfate; Vinorelbine tartrate; Vin Zures (e.g., grand mal convulsions). A specific adverse effect rosidine sulfate; Vinzolidine sulfate; Vorozole; Zeniplatin: is neutropenia. Zinostatin: Zorubicin hydrochloride, and proteasome inhibi 0228 Second active agents that are small molecules can tors such as bortezomib, carfilzomib, ixazomib, decitibine, also be used to alleviate adverse effects associated with the and romedepsin. In one embodiment, the anti-cancer agent is administration of a solid form of the invention. However, like taxane, paclitaxel, bortezomib, carfilzomib, ixazomib, Some large molecules, many are believed to be capable of decitibine, or romedepsin. providing a synergistic effect when administered with (e.g., 0230. Other anti-cancer drugs include, but are not limited before, after or simultaneously) a solid form of the invention. to: 20-epi-1.25 dihydroxyvitamin D3; 5-ethynyluracil; abi Examples of small molecule second active agents include, but raterone; aclarubicin; acylfulvene; adecypenol; adoZelesin; US 2016/0045483 A1 Feb. 18, 2016 22 aldesleukin; ALL-TK antagonists; altretamine; ambamus mitoxantrone; mofarotene; molgramoStim; Erbitux, human tine; amidox; amifostine; aminolevulinic acid; amrubicin; chorionic gonadotrophin, monophosphoryl lipid A+myobac amsacrine; anagrelide; anastrozole; andrographolide; angio terium cell wall sk; mopidamol, mustard anticancer agent; genesis inhibitors; antagonist D; antagonist G, antarelix; anti my caperoxide B; mycobacterial cell wall extract; myriapor dorsalizing morphogenetic protein-1, antiandrogen, prostatic one; N-acetyldinaline; N-substituted benzamides; nafarelin; carcinoma; antiestrogen; antineoplaston; antisense oligo nagrestip; naloxone-pentazocine; napavin; naphterpin, nar nucleotides; aphidicolin glycinate; apoptosis gene modula tograstim; nedaplatin; memorubicin; neridronic acid; niluta tors; apoptosis regulators; apurinic acid; ara-CDP-DL mide; nisamycin; nitric oxide modulators; nitroxide antioxi dant; nitrullyn; oblimersen (Genasense(R); O. Sup.6- PTBA, arginine deaminase; asulacrine; atamestane; benzylguanine; octreotide; okicenone; oligonucleotides; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; aza onapristone; ondansetron; ondansetron; oracin; oral cytokine setron; azatoxin; azatyrosine; baccatin III derivatives; bal inducer, ormaplatin: osaterone; oxaliplatin, oxaunomycin; anol; batimastat; BCR/ABL antagonists; benzochlorins; ben paclitaxel, paclitaxel analogues; paclitaxel derivatives; Zoylstaurosporine; beta lactam derivatives; beta-alethine; palauamine; palmitoylrhizoxin; pamidronic acid; panax betaclamycin B; betulinic acid; bFGF inhibitor; bicaluta ytriol; panomifene; parabactin; paZelliptine; pegaspargase; mide; bisantrene; bisaziridinylspermine; bisnafide; bistratene peldesine; pentosan polysulfate sodium; pentostatin: pentro A: bizelesin; breflate; bropirimine; budotitane; buthionine Zole; perflubron; perfosfamide; perillyl alcohol; phenazino Sulfoximine; calcipotriol; calphostin C; camptothecin deriva mycin; phenylacetate; phosphatase inhibitors; picibanil; pilo tives; capecitabine; carboxamide-amino-triazole; carboxya carpine hydrochloride; pirarubicin; piritrexim; placetin A; midotriazole; CaRest M3; CARN 700; cartilage derived placetin B; plasminogen activator inhibitor; platinum com inhibitor; carzelesin: casein kinase inhibitors (ICOS); plex; platinum compounds; platinum-triamine complex; por castanospermine; cecropin B; cetrorelix; chlorins; chloroqui fimer Sodium; porfiromycin; prednisone; propyl bis-acri noxaline Sulfonamide, cicaprost, cis-porphyrin, cladribine; done; prostaglandin J2, proteasome inhibitors; protein clomifene analogues; clotrimazole; collismycin A; collismy A-based immune modulator, protein kinase C inhibitor, pro cin B; combretastatin A4, combretastatin analogue; conage tein kinase C inhibitors, microalgal; protein tyrosine phos nin; crambescidin 816; crisinatol; cryptophycin 8: cryptophy phatase inhibitors; purine nucleoside phosphorylase inhibi cin A derivatives; curacin A; cyclopentanthraquinones; tors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin cycloplatam, cypemycin; cytarabine ocfosfate; cytolytic fac polyoxyethylene conjugate; raf antagonists; raltitrexed: tor; cytostatin: dacliximab; decitabine; dehydrodidemnin B; ramosetron; ras farnesyl protein transferase inhibitors; ras deslorelin; dexamethasone; dexifosfamide; dexrazoxane: inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhe deXVerapamil: diaziquone; didemnin B; didox; diethylnor nium Re 186 etidronate; rhizoxin: ribozymes: RII retinamide: spermine; dihydro-5-azacytidine; dihydrotaxol. 9-; dioxamy rohitukine; romurtide; roquinimex: rubiginone B1; ruboxyl, cin; diphenyl spiromustine; docetaxel, docosanol; dolas Safingol; Saintopin; SarCNU; sarcophytol A. SargramoStim; etron: doxifluridine: doxorubicin; droloxifene; dronabinol; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; duocarmycin SA; ebSelen; ecomustine, edelfosine; edrecolo sense oligonucleotides; signal transduction inhibitors; sizofi mab; eflornithine; elemene; emitefur; epirubicin; epristeride; ran; Sobuzoxane: Sodium borocaptate; sodium phenylacetate; estramustine analogue; estrogen agonists; estrogen antago Solverol; somatomedin binding protein; Sonermin; Sparfosic nists; etanidazole; etoposide phosphate; exemestane; fadro acid; spicamycin D; spiromustine; splenopentin; spongistatin Zole; fazarabine; fenretinide; filgrastim; finasteride; fla Vopiridol; flezelastine; fluasterone; fludarabine; 1; squalamine; stipiamide; stromelysin inhibitors; sulfi fluorodaunorunicin hydrochloride; forfenimex; formestane: nosine; Superactive vasoactive intestinal peptide antagonist; fostriecin, fotemustine; gadolinium texaphyrin; gallium Suradista; Suramin; Swainsonine; tallimustine; tamoxifen nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcit methiodide; tauromustine; tazarotene; tecogalan Sodium; abine; glutathione inhibitors; hepsulfam; heregulin; hexam tegafur, tellurapyrylium; telomerase inhibitors; temoporfin; ethylene bisacetamide; hypericin; ibandronic acid; idarubi teniposide; tetrachlorodecaoxide; tetraZomine; thaliblastine; cin; idoxifene; idramantone; ilmofosine; illomastat; imatinib thiocoraline; thrombopoietin; thrombopoietin mimetic; thy (e.g., GleeveccR); imiquimod, immunostimulant peptides; malfasin; thymopoietin receptor agonist; thymotrinan; thy insulin-like growth factor-1 receptor inhibitor; interferon roid stimulating hormone; tin ethyl etiopurpurin; tira agonists; interferons; interleukins; iobenguane; iododoxoru paZamine; titanocene bichloride; top sentin; toremifene; bicin; ipomeanol, 4-, iroplact; irsogladine; isobengaZole; iso translation inhibitors; tretinoin; triacetyluridine; triciribine; homohalicondrin B; itasetron; jasplakinolide; kahalalide F: trimetrexate; triptorelin; tropisetron; turosteride; tyrosine lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; kinase inhibitors; tyrphostins; UBC inhibitors: ubenimex: lentinan Sulfate; leptolstatin; letrozole; leukemia inhibiting urogenital sinus-derived growth inhibitory factor, urokinase factor, leukocyte alpha interferon; leuprolide+estrogen receptor antagonists; vapreotide; variolin B; Velaresol; progesterone; leuprorelin; levamisole; liarozole; linear Veramine; verdins; verteporfin; vinorelbine; vinxaltine; polyamine analogue; lipophilic disaccharide peptide; lipo vitaxin; Vorozole; Zanoterone; Zeniplatin: Zilascorb; and philic platinum compounds; lissoclinamide 7: lobaplatin: Zinostatin stimalamer. lombricine; lometrexol; lonidamine; losoxantrone; loxorib 0231 Specific second active agents include, but are not ine; lurtotecan; lutetium texaphyrin; lysofylline; lytic pep limited to, rituximab, oblimersen (Genasense(R), remicade, tides; maitansine; mannostatin A; marimastat; masoprocol; docetaxel, celecoxib, melphalan, dexamethasone (Decad maspin; matrilysin inhibitors; matrix metalloproteinase ronR), Steroids, gemcitabine, cisplatinum, temozolomide, inhibitors; menogaril; merbarone; meterelin; methioninase; etoposide, cyclophosphamide, temodar, carboplatin, procar metoclopramide; MIF inhibitor; mifepristone; miltefosine; bazine, gliadel, tamoxifen, topotecan, methotrexate, Arisa R, mirimoStim, mitoguaZone; mitolactol; mitomycin analogues; taxol, taxotere, fluorouracil, leucovorin, irinotecan, Xeloda, mitonafide; mitotoxin fibroblast growth factor-saporin; CPT-11, interferon alpha, pegylated interferon alpha (e.g., US 2016/0045483 A1 Feb. 18, 2016

PEG INTRON-A), capecitabine, cisplatin, thiotepa, fludara administered in combination with dexamethasone for the bine, carboplatin, liposomal daunorubicin, cytarabine, dox treatment of multiple myeloma in patients who have received etaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, at least one prior therapy. Vinorelbine, Zoledronic acid, palmitronate, biaxin, buSul 0237. In one embodiment the disease is transfusion-de phan, prednisone, bisphosphonate, arsenic trioxide, Vincris pendent anemia due to Low- or Intermediate-1-risk myelod tine, doxorubicin (DOXil(R), paclitaxel, ganciclovir, adriamy yspastic syndromes associated with a deletion 5q cytogenetic cin, estramustine sodium phosphate (EmcytR), Sulindac, and abnormality with or without additional cytogenetic abnor etoposide. malities. 0238. In one embodiment is provided a method of treating, 5.4 Methods of Treatments and Prevention preventing and/or managing a disease provided herein, com prising administering to a patient in need of Such treatment, 0232 Provided herein are methods of treating, preventing, prevention and/or management a therapeutically or prophy and/or managing various diseases or disorders using a solid lactically effective amount of a solid form comprising lena form provided herein. In certain embodiments, provided are lidomide and a coformer as described herein and a therapeu methods of treating, managing, and preventing various dis tically or prophylactically effective amount of a second active eases and disorders, which comprise administering to a agent. patient in need of Such treatment, prevention or management 0239 Certain examples of cancer include, but are not lim a therapeutically or prophylactically effective amount of a ited to, cancers of the skin, such as melanoma: lymph node: solid form provided herein. Examples of diseases and disor breast; cervix; uterus; gastrointestinal tract, lung; ovary; pros ders are described herein. tate; colon; rectum; mouth; brain; head and neck; throat; 0233 Examples of diseases or disorders include, but are testes; kidney; pancreas; bone; spleen; liver, bladder; larynx; not limited to: cancer including hematologic cancer or Solid nasal passages; and AIDS-related cancers. The Solid forms tumor, for example, multiple myeloma, leukemia, lym are also useful for treating cancers of the blood and bone phoma, Sarcoma, prostate cancer, or lung cancer (e.g., Small marrow, such as multiple myeloma and acute and chronic cell lung cancer); Scleroderma; amyloidosis; pain, for leukemias, for example, lymphoblastic, myelogenous, lym example, complex regional pain syndrome (CRPS); myelofi phocytic, and myelocytic leukemias. The solid forms pro brosis; myeloproliferative disease, for example, MMM; vided hereincan be used for treating, preventing, or managing myelodysplastic syndromes (MDS); diffuse systemic sclero either primary or metastatic tumors. sis; macular degeneration; a skin disease; a pulmonary disor 0240. Other cancers include, but are not limited to, der; an asbestos-related disorder; a parasitic disease; an advanced malignancy, amyloidosis, neuroblastoma, menin immunodeficiency disorder; a CNS disorder; a CNS injury: gioma, hemangiopericytoma, multiple brain metastases, glio atherosclerosis; hemoglobinopathy; anemia, for example, blastoma multiforms, glioblastoma, brain stem glioma, poor sickle cell anemia; an inflammatory disease; an autoimmune prognosis malignant brain tumor, malignant glioma, recur disease; a viral disease; a genetic disease; an allergic disease; rent malignant glioma, anaplastic astrocytoma, anaplastic oli a bacterial disease; an ocular neovascular disease; a choroidal godendroglioma, neuroendocrine tumor, rectal adenocarci neovascular disease; a retina neovascular disease; rubeosis; a noma, Dukes C & D colorectal cancer, unresectable sleep disorder, disorders associated with angiogenesis; and colorectal carcinoma, metastatic hepatocellular carcinoma, TNFO related disorders. Kaposi's sarcoma, karotype acute myeloblastic leukemia, 0234 Examples of cancer and precancerous conditions chronic lymphocytic leukemia (CLL), Hodgkin’s lymphoma, include, but are not limited to, those described in U.S. Pat. non-Hodgkin’s lymphoma, cutaneous T-Cell lymphoma, Nos. 8,207,200, 6,281.230 and 5,635,517 and in various U.S. cutaneous B-Cell lymphoma, diffuse large B-Cell lym patent including publication nos. 2004/022014.4A1, pub phoma, low grade follicular lymphoma, metastatic mela lished Nov. 4, 2004 (Treatment of Myelodysplastic Syn noma, localized melanoma (including, but not limited to, drome); 2004/0029832A1, published Feb. 12, 2004 (Treat ocular melanoma), malignant mesothelioma, malignant pleu ment of Various Types of Cancer); and 2004/0087546, ral effusion mesothelioma syndrome, peritoneal carcinoma, published May 6, 2004 (Treatment of Myeloproliferative Dis papillary serous carcinoma, gynecologic sarcoma, Soft tissue eases). Examples also include those described in WO 2004/ sarcoma, cutaneous vasculitis, Langerhans cell histiocytosis, 103274, published Dec. 2, 2004. All of these references are leiomyosarcoma, fibrodysplasia ossificans progressive, hor incorporated herein in their entireties by reference. mone refractory prostate cancer, resected high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, Walden 0235. Other examples of diseases or disorders include, but strom's macroglobulinemia, Smoldering myeloma, indolent are not limited to, those described in U.S. Pat. Nos. 5,712.291, myeloma, fallopian tube cancer, androgen independent pros 7,393,863, and 7,863,297; and U.S. Patent Application Pub tate cancer, androgen dependent stage IV non-metastatic lication Nos. 2005/0143420, 2006/0166932, 2006/0188475, prostate cancer, hormone-insensitive prostate cancer, chemo 2007/0048327, 2007/0066512, 2007/0155791, 2008/ therapy-insensitive prostate cancer, papillary thyroid carci 0051431, 2008/0317708, 2009/00874.07, 2009/0088410, noma, follicular thyroid carcinoma, medullary thyroid carci 2009/0148853, 2009/0232776, 2009/0232796, 2009/ noma, and leiomyoma. In a specific embodiment, the cancer 0317385, 2010/0098657, 2010/0099711, and 2011/0184025; is metastatic. In another embodiment, the cancer is refractory all of which are incorporated herein by reference in their or resistance to chemotherapy or radiation. entireties. 0241. In one embodiment is provided a method of treating, 0236. In one embodiment the disease is multiple preventing, or managing myeloproliferative disease (MPD), myeloma. In certain embodiments the Solid form is used to comprising administering to a patient in need of Such treat treat multiple myeloma in patients who have received at least ment, prevention, or management a therapeutically or pro one prior therapy. In certain embodiments the Solid form is phylactically effective amount of a solid form comprising US 2016/0045483 A1 Feb. 18, 2016 24 lenalidomide and a coformer as described herein. The sold in the United States under the trade name Leukine(R) embodiment encompasses the treatment, prevention or man (Immunex, Seattle, Wash.); recombinant Epo, which is sold agement of specific sub-types of MPD such as, but not limited in the United States under the trade name Epogen R (Amgen, to, polycythemia rubra Vera (PRV), primary thromob Thousand Oaks, Calif.); and methionyl stem cell factor ocythemia (PT), myelofibrosis with myeloid metaplasia (SCF), which is sold in the United States under the trade name (MMM) and agnogenic myeloid metaplasia (AMM). In one AncestimTM. Recombinant and mutated forms of GM-CSF embodiment, MPD includes: polycythemia rubravera (PRV), can be prepared as described in U.S. Pat. Nos. 5.391.485; primary thromobocythemia (PT), and agnogenic myeloid 5,393,870; and 5.229,496; all of which are incorporated metaplasia (AMM). In a specific embodiment, MPD excludes herein by reference. Recombinant and mutated forms of leukemia. In one embodiment, particular types of MPD are G-CSF can be prepared as described in U.S. Pat. Nos. 4,810, MMM, PRV, PT, and AMM. 643; 4,999,291; 5,528,823; and 5,580,755; all of which are 0242. In one embodiment, a Solid form comprising lena incorporated herein by reference. lidomide and a coformer is administered to patients who are 0249 Other cytokines may be used which encourage the refractory to conventional treatments for myeloproliferative survival and/or proliferation of hematopoietic precursor cells diseases as well as treatments using thalidomide. As used and immunologically active poietic cells in vitro or in Vivo, or herein, the term “refractory' means the patient’s response to which stimulate the division and differentiation of committed a MPDtreatment is not satisfactory by clinical standards, e.g., erythroid progenitors in cells in vitro or in vivo. Such cytok showing no or little improvement of symptoms or laboratory ines include, but are not limited to: interleukins, such as IL-2 findings. (including recombinant IL-II (rIL2) and canarypox IL-2), 0243 In one embodiment is provided a method of revers IL-10, IL-12, and IL-18; interferons, such as interferon alfa ing, reducing, or avoiding an adverse effect associated with 2a, interferon alfa-2b, interferon alfa-n1, interferon alfa-n3, the administration of an active agent used to treat MPD in a patient Suffering from MPD, comprising administering to a interferon beta-Ia, and interferon gamma-Ib; and G-CSF. patient in need thereof a therapeutically or prophylactically 0250 When administered to a person having a hemoglo effective amount of a Solid form comprisinglenalidomide and binopathy, a solid form comprising lenalidomide and a a coformer as described herein. Examples of active agents coformer as described herein, particularly in the presence of include, but are not limited to, the second active agents Epo, particularly in the presence of the combination of TNFC. described herein. SCF, Flt-3L and GM-CSF, or more particularly in the pres 0244 Examples of adverse effects associated with active ence of Epo and SCF, induces the production of erythrocytes, agents used to treat MPD include, but are not limited to: and the production offetal hemoglobin as well as the produc conversion to acute leukemia; severe myelosuppression; gas tion of AHSP. As noted above, cytokines used may include trointestinal toxicity Such as, but not limited to, early and purified or recombinant forms, or analogs or derivatives of late-forming diarrhea and flatulence; gastrointestinal bleed specific cytokines. ing; nausea; Vomiting; anorexia; leukopenia; anemia; neutro 0251 A solid form comprising lenalidomide and a penia; asthenia; abdominal cramping; fever, pain; loss of coformer as described herein may also be administered in body weight; dehydration; alopecia; dyspnea; insomnia; diz conjunction with one or more second compounds known to Ziness; mucositis, Xerostomia; mucocutaneous lesions; and have, or Suspected of having, a beneficial effect on a hemo kidney failure. globinopathy. In this context, “beneficial effect” means any 0245. In one embodiment, provided herein is a method of reduction of any symptom of a hemoglobinopathy or anemia. treating, preventing, or managing MPD, comprising admin 0252 For example, with specific reference to the hemo istering to a patient (e.g., a human) a solid form comprising globinopathy sickle cell anemia, the second compound can be lenalidomide and a coformer as described herein, before, a compound, other thana lenalidomide or a derivative thereof, during, or after transplantation therapy. that is known or suspected to induce the production of fetal 0246. In one embodiment, provided herein are pharma hemoglobin. Such compounds include hydroxyurea, and ceutical compositions, single unit dosage forms, and kits, butyrates or butyrate derivatives. The second compound may comprising a solid form comprising lenalidomide and a also be a compound that relaxes blood vessels, such as nitrous coformer as described herein, a second active ingredient, oxide, e.g., exogenously-applied or administered nitrous and/or blood or cells for transplantation therapy. For example, oxide. The second compound may also be a compound that a kit may comprise a solid form comprisinglenalidomide and binds directly to hemoglobin S. preventing it from assuming a coformer as described herein, stem cells for transplantation, the sickle-inducing conformation. For example, the plant an immunosuppressive agent, and an antibiotic or other drug. extract known as HEMOXINTM (NIPRISANTM; see U.S. Pat. 0247 The cytokines used in the methods provided herein No. 5,800.819), which is an extract of a mixture of about 12 may be naturally-occurring cytokines, or may be an artificial to about 17 parts by weight of Piper guineense seeds, from derivative or analog of the cytokines. For example, analogs or about 15 to about 19 parts by weight of Pterocarpus Osun derivatives of erythropoietin that may be used in combination stem, from about 12 to about 18 parts by weight of Eugenia with a solid form or compound provided herein include, but caryophyllata fruit, and from about 25 to about 32 parts by are not limited to, AranespTM and DarbopoietinTM. weight of Sorghum bicolor leaves, and optionally 15-22 parts 0248 Cytokines used may be purified from natural by weight potash, wherein the mixture is extracted with cold Sources or recombinantly produced. Examples of recombi water, has antisickling activity. The second compound may nant cytokines that may be used in the methods provided also be a Gardos channel antagonist. Examples of Gardos herein include filgrastim, or recombinant granulocyte-colony channel antagonists include clotrimazole and triaryl methane stimulating factor (G-CSF), which is sold in the United States derivatives. The second compound may also be one that under the trade name Neupogen R (Amgen, Thousand Oaks, reduces red blood cell adhesion, thereby reducing the amount Calif.); sargramostim, or recombinant GM-CSF, which is of clotting pervasive in sickle cell anemia. US 2016/0045483 A1 Feb. 18, 2016

0253 Other hemoglobinopathies may be treated with a or accidental introduction of a poison, toxin, or drug. For second compound known or Suspected to be efficacious for example, anemias resulting from cancer chemotherapies may the specific condition. For example, 13 thalassemia may addi be treated using the methods and solid forms provided herein. tionally be treated with the second compound Deferoxamine, As such, the methods described herein may be employed an iron chelator that helps prevent the buildup of iron in the when anemia or a hemoglobinopathy is the primary condition blood, or folate (vitamin B9). Thalassemia or sickle cell ane to be treated, or is a secondary condition caused by an under mia may also be treated with protein C as the second com lying disease or treatment regimen. pound (U.S. Pat. No. 6,372.213). There is some evidence that 0259. In one embodiment, the diseases or disorders are herbal remedies can ameliorate symptoms of hemoglobino various forms of leukemias Such as chronic lymphocytic leu pathies, e.g., thalassemia; Such remedies, and any of the spe kemia, chronic myelocytic leukemia, acute lymphoblastic cific active compounds contained therein, may also be used as leukemia, acute myelogenous leukemia, and acute myelo a second compound in the method provided herein. See, e.g., blastic leukemia, including leukemias that are relapsed, Wu Zhikui et al. “The Effect of Bushen Shengxue Fang on refractory, or resistant, as disclosed in U.S. publication no. B-thalassemia at the Gene Level.” Journal of Traditional Chi 2006/0030594, published Feb. 9, 2006, which is incorporated nese Medicine 18(4): 300-303 (1998): U.S. Pat. No. 6,538, in its entirety by reference. 023 “Therapeutic Uses of Green Tea Polyphenols for Sickle 0260 The term “leukemia' refers malignant neoplasms of Cell Disease'. Treatment of autoimmune hemolytic anemia the blood-forming tissues. The leukemia includes, but is not can include corticosteroids as the second compound. limited to, chronic lymphocytic leukemia, chronic myelo 0254 Second compounds that are proteins may also be cytic leukemia, acute lymphoblastic leukemia, acute myelog derivatives or analogs of other proteins. Such derivatives may enous leukemia, and acute myeloblastic leukemia. The leu include, but are not limited to, proteins that lack carbohydrate kemia can be relapsed, refractory or resistant to conventional moieties normally present in their naturally occurring forms therapy. The term “relapsed” refers to a situation where (e.g., nonglycosylated forms), pegylated derivatives, and patients who have had a remission of leukemia after therapy fusion proteins, such as proteins formed by fusing IgG1 or have a return of leukemia cells in the marrow and a decrease IgG3 to the protein or active portion of the protein of interest. in normal blood cells. The term “refractory or resistant” refers See, e.g., Penichet, M. L. and Morrison, S. L., J. Immunol. to a circumstance where patients, even after intensive treat Methods 248:91-101 (2001). ment, have residual leukemia cells in their marrow. 0255 Cytokines and/or other compounds potentially use 0261. In another embodiment, the diseases or disorders ful in the treatment of anemia or a hemoglobinopathy may be are various types of lymphomas, including Non-Hodgkin’s administered at the same time as lenalidomide or a derivative lymphoma (NHL). The term “lymphoma’ refers a heterog thereof. In this regard, the cytokines or other compounds may enous group of neoplasms arising in the reticuloendothelial be administered as formulations separate from a solid form and lymphatic systems. “NHL refers to malignant mono comprising lenalidomide and a coformer, or, where possible, clonal proliferation of lymphoid cells in sites of the immune may be compounded with a solid form comprising lenalido system, including lymph nodes, bone marrow, spleen, liver, mide and a coformer for administration as a single pharma and gastrointestinal tract. Examples of NHL include, but are ceutical composition. Alternatively, the cytokines, the other not limited to, mantle cell lymphoma (MCL), lymphocytic compounds, or both, may be administered separately from a lymphoma of intermediate differentiation, intermediate lym Solid form comprising lenalidomide and a coformer used in phocytic lymphoma (ILL), diffuse poorly differentiated lym the methods provided herein, and may follow the same or phocytic lymphoma (PDL), centrocytic lymphoma, diffuse different dosing schedules. In one embodiment, a Solid form small-cleaved cell lymphoma (DSCCL), follicular lym comprising lenalidomide and a coformer, cytokines, and/or phoma, and any type of the mantle cell lymphomas that can be any other compound useful to treat anemia or a hemoglobin seen under the microscope (nodular, diffuse, blastic and opathy, are administered at the same time, but in separate mentle Zone lymphoma). pharmaceutical formulations for flexibility in administration. 0262 Examples of diseases and disorders associated with, 0256 In addition to the treatment combinations outlined or characterized by, undesired angiogenesis include, but are herein, the treated individual may be given transfusions. Such not limited to, inflammatory diseases, autoimmune diseases, transfusions may be of blood, for example matched blood, or viral diseases, genetic diseases, allergic diseases, bacterial ofa blood substitute such as HemospanTM or HemospanTM PS diseases, ocular neovascular diseases, choroidal neovascular (Sangart). diseases, retina neovascular diseases, and rubeosis (neovas 0257. In any of the treatment combinations described cularization of the angle). Specific examples of the diseases herein, the treated individual is eukaryotic. In one embodi and disorders associated with, or characterized by, undesired ment, the treated individual is a mammal, for example a angiogenesis include, but are not limited to, arthritis, human. endometriosis, Crohn's disease, heart failure, advanced heart 0258. The methods described herein may be used to treat failure, renal impairment, endotoxemia, toxic shock Syn any anemia, including anemia resulting from a hemoglobin drome, osteoarthritis, retrovirus replication, wasting, menin opathy. Hemoglobinopathies and anemias treatable by the gitis, silica-induced fibrosis, asbestos-induced fibrosis, Vet methods provided herein may be genetic in origin, such as erinary disorder, malignancy-associated hypercalcemia, sickle-cell anemia or thalassemias. The hemoglobinopathy stroke, circulatory shock, periodontitis, gingivitis, macro may be due to a disease, such as cancer, including, but not cytic anemia, refractory anemia, and 5q-deletion syndrome. limited to, cancers of the hematopoietic or lymphatic sys 0263. Other disease or disorders treated, prevented, or tems. Other conditions treatable using the methods provided managed include, but not limited to, viral, genetic, allergic, herein include hypersplenism, splenectomy, bowel resection, and autoimmune diseases. Specific examples include, but are and bone marrow infiltration. The methods described herein not limited to, HIV, hepatitis, adult respiratory distress syn may also be used to treat anemia resulting from the deliberate drome, bone resorption diseases, chronic pulmonary inflam US 2016/0045483 A1 Feb. 18, 2016 26 matory diseases, dermatitis, cystic fibrosis, septic shock, sep 5.5 Combination Therapy with a Second Active sis, endotoxic shock, hemodynamic shock, sepsis syndrome, Agent post ischemic reperfusion injury, meningitis, psoriasis, 0268 Specific methods of the invention comprise admin fibrotic disease, cachexia, graft versus host disease, graft istering a solid form of the invention in combination with one rejection, auto-immune disease, rheumatoid spondylitis, or more second active agents, and/or in combination with Crohn's disease, ulcerative colitis, inflammatory-bowel dis radiation therapy, blood transfusions, or Surgery. Examples of ease, multiple Sclerosis, systemic lupus erythrematosus, ENL second active agents are also disclosed herein (see, e.g., sec in leprosy, radiation damage, cancer, asthma, or hyperoxic tion 5.3). alveolar injury. 0269 Administration of a solid form of this invention and 0264. In certain embodiments, a solid form provided the second active agents to a patient can occur simultaneously herein, or a composition comprising a solid form provided or sequentially by the same or different routes of administra herein, is administered orally, parenterally, topically, or tion. The suitability of a particular route of administration mucosally. Examples of Such dosage forms can be found in employed for a particular active agent will depend on the section 5.8, infra. active agent itself (e.g., whether it can be administered orally 0265. In certain embodiments, a solid form provided without decomposing prior to entering the blood stream) and herein, or a composition comprising a solid form provided the disease being treated. A preferred route of administration herein, is administered at a dosing frequency of once, twice, for a solid form of the invention is orally. Preferred routes of thrice, or four times daily. In certain embodiments, solid form administration for the second active agents or ingredients of provided herein, or a composition comprising a solid form the invention are known to those of ordinary skill in the art. provided herein, comprises lenalidomide in an amount of See, e.g., Physicians’ Desk Reference, 1755-1760 (56.sup.th from about 0.1 to about 100 mg, from about 0.5 to about 50 ed., 2002). mg, from, about 0.5 to about 25 mg, from about 1 mg to about 0270. In one embodiment of the invention, the second 10 mg, from about 0.5 to about 5 mg. or from about 1 mg to active agent is administered intravenously or Subcutaneously about 5 mg. In certain embodiments, provided herein is a and once or twice daily in an amount of from about 1 to about single unit dosage form suitable for oral administration to a 1,000 mg, from about 5 to about 500 mg, from about 10 to human comprising: an amount equal to or greater than about about 375 mg. or from about 50 to about 200 mg. The specific 1, 2, 3, 4, or 5 mg of a solid form comprisinglenalidomide and amount of the second active agent will depend on the specific a coformer provided herein; and a pharmaceutically accept agent used, the type of disease being treated or managed, the able excipient. In one embodiment, the amount of the active severity and stage of disease, and the amount(s) of immuno ingredient is about 0.5 mg. In another embodiment, the modulatory compounds of the invention and any optional amount of the active ingredient is about 1 mg. In another additional active agents concurrently administered to the embodiment, the amount of the active ingredient is about 2 patient. In a particular embodiment, the second active agent is mg. In another embodiment, the amount of the active ingre rituximab, oblimersen (Genasense(R), GM-CSF, G-CSF, EPO, taxotere, irinotecan, dacarbazine, transretinoic acid, dient is about 4 mg. topotecan, pentoxifylline, ciprofloxacin, dexamethasone, 0266. In one embodiment, the second active agent is Vincristine, doxorubicin, COX-2 inhibitor, IL2, IL8, IL18, administered intravenously or subcutaneously and once or IFN, Ara-C, vinorelbine, or a combination thereof. twice daily, once every other day, once every week, once 0271 In a specific embodiment, a solid form of the inven every two weeks, or once every three weeks, in an amount of tion is administered in combination with rituximab to patients from about 1 to about 1000 mg, from about 5 to about 500 mg. with leukemias. In a specific embodiment, the solid form is from about 10 to about 350 mg. or from about 50 to about 200 administered in an amount of from about 5 to about 25 mg per mg. In one embodiment, the second active agent is adminis day to patients with chronic lymphocytic leukemia in combi tered orally and once or twice daily, once every other day, nation with rituximab in an amount of 375 mg/m. Sup.2. once every week, once every two weeks, or once every three 0272. In another embodiment, a solid form of the inven weeks, in an amount of from about 1 to about 1000 mg, from tion is administered in combination with fludarabine, carbo about 5 to about 500 mg, from about 10 to about 350 mg, from platin, and/or topotecanto patients with refractory or relapsed about 10 to about 200 mg, from about 10 to about 100 mg. or or high-risk acute myelogenous leukemia. from about 20 to about 50 mg. In specific embodiments, the 0273. In another embodiment, a solid form of the inven second active agent is administered once every week in an tion is administered in combination with liposomal daunoru amount of about 40 mg. The specific amount of the second bicin, topotecan and/or cytarabine to patients with unfavor active agent will depend on the specific agent used, the type of able karotype acute myeloblastic leukemia. disease being treated or managed, the severity and stage of 0274. In another embodiment, a solid form of the inven disease, and the amount(s) of compounds provided herein and tion is administered alone or in combination with a second any optional additional active agents concurrently adminis active ingredient Such as vinblastine or fludarabine to patients tered to the patient. with various types of lymphoma, including, but not limited to, 0267 As discussed elsewhere herein, also encompassed is Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, cutaneous a method of reducing, treating and/or preventing adverse or T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large undesired effects associated with conventional therapy B-Cell lymphoma or relapsed or refractory low grade folli including, but not limited to, Surgery, chemotherapy, radia cular lymphoma. tion therapy, hormonal therapy, biological therapy and immu 0275. In another embodiment, GM-CSF, G-CSF or EPO is notherapy. Compounds provided herein and other active administered Subcutaneously during about five days in a four ingredients can be administered to a patient prior to, during, or six week cycle in an amount of from about 1 to about 750 or after the occurrence of the adverse effect associated with mg/m. Sup.2/day, preferably in an amount of from about 25 to conventional therapy. about 500 mg/m. Sup.2/day, more preferably in an amount of US 2016/0045483 A1 Feb. 18, 2016 27 from about 50 to about 250 mg/m. Sup.2/day, and most pref preferably from about 5 to about 25 mg orally and daily alone, erably in an amount of from about 50 to about 200 mg/m.sup. or in combination with a second active agent disclosed herein 2/day. In a certain embodiment, GM-CSF may be adminis (see, e.g., section 5.2), prior to, during, or after the use of tered in an amount of from about 60 to about 500 mcg/m. conventional therapy sup.2 intravenously over 2 hours, or from about 5 to about 12 0281 5.6 Use with Transplantation Therapy mcg/m. Sup.2/day Subcutaneously. In a specific embodiment, 0282 Compounds of the invention can be used to reduce G-CSF may be administered subcutaneously in an amount of the risk of Graft Versus Host Disease (GVHD). Therefore, the about 1 mcg/kg/day initially and can be adjusted depending invention encompasses a method of treating, preventing and/ on rise of total granulocyte counts. The maintenance dose of or managing cancer, which comprises administering the Solid G-CSF may be administered in an amount of about 300 (in form of the invention in conjunction with transplantation Smaller patients) or 480 mcg Subcutaneously. In a certain therapy. embodiment, EPO may be administered subcutaneously in an 0283 As those of ordinary skill in the art are aware, the amount of 10,000 Unit 3 times per week. treatment of cancer is often based on the stages and mecha 0276. This invention also encompasses a method of nism of the disease. For example, as inevitable leukemic increasing the dosage of an anti-cancer drug or agent that can transformation develops in certain stages of cancer, trans be safely and effectively administered to a patient, which plantation of peripheral blood stem cells, hematopoietic stem comprises administering to a patient (e.g., a human) a Solid cell preparation or bone marrow may be necessary. The com form of the invention, or a pharmaceutically acceptable bined use of the solid form of the invention and transplanta derivative, salt, Solvate, clathrate, hydrate, or prodrug thereof. tion therapy provides a unique and unexpected Synergism. In Patients that can benefit by this method are those likely to particular, an Solid form of the invention exhibits immuno suffer from an adverse effect associated with anti-cancer modulatory activity that may provide additive or synergistic drugs for treating a specific cancer of the blood, skin, Subcu effects when given concurrently with transplantation therapy taneous tissue, lymph nodes, brain, lung, liver, bone, intes in patients with cancer. tine, colon, heart, pancreas, adrenal, kidney, prostate, breast, 0284 Ansolid of the invention can work in combination colorectal, or combinations thereof. The administration of a with transplantation therapy reducing complications associ solid form of the invention alleviates or reduces adverse ated with the invasive procedure of transplantation and risk of effects which are of such severity that it would otherwise limit GVHD. This invention encompasses a method of treating, the amount of anti-cancer drug. preventing and/or managing cancer which comprises admin (0277. In one embodiment, a solid form of the invention istering to a patient (e.g., a human) a Solid form the invention can be administered orally and daily in an amount of from before, during, or after the transplantation of umbilical cord about 0.10 to about 150 mg, and preferably from about 1 to blood, placental blood, peripheral blood stem cell, hemato about 50 mg, more preferably from about 5 to about 25 mg poietic stem cell preparation or bone marrow. Examples of prior to, during, or after the occurrence of the adverse effect stem cells suitable for use in the methods of the invention are associated with the administration of an anti-cancer drug to a disclosed in U.S. patent publication nos. 2002/0123141, patient. In a particular embodiment, a Solid form of the inven 2003/0235909 and 2003/0032179, by R. Hariri et al., the tion in combination with specific agents such as heparin, entireties of which are incorporated herein by reference. aspirin, coumadin, or G-CSF to avoid adverse effects that are 0285. In one embodiment of this method, a solid form of associated with anti-cancer drugs such as but not limited to the invention is administered to patients with leukemias neutropenia or thrombocytopenia. before, during, or after the transplantation of autologous 0278. In another embodiment, this invention encompasses peripheral blood progenitor cell. a method of treating, preventing and/or managing cancer, 0286. In another embodiment, a solid form of the inven which comprises administering a solid form of the invention tion is administered to patients with relapsed leukemia after in conjunction with (e.g., before, during, or after) conven the stem cell transplantation. tional therapy including, but not limited to, Surgery, immu notherapy, biological therapy, radiation therapy, or other non 5.7 Cycling Therapy drug based therapy presently used to treat, prevent or manage 0287. In certain embodiments, the prophylactic or thera cancer. The combined use of the solid forms of the invention peutic agents provided herein are cyclically administered to a and conventional therapy may provide a unique treatment patient. Cycling therapy involves the administration of an regimen that is unexpectedly effective in certain patients. active agent for a period of time, followed by a rest (i.e., Without being limited by theory, it is believed that solid forms discontinuation of the administration) for a period of time, of the invention may provide additive or synergistic effects and repeating this sequential administration. Cycling therapy when given concurrently with conventional therapy. can reduce the development of resistance to one or more of the 0279. As discussed elsewhere herein, the invention therapies, avoid or reduce the side effects of one of the thera encompasses a method of reducing, treating and/or prevent pies, and/or improve the efficacy of the treatment. ing adverse or undesired effects associated with conventional 0288 Consequently, in one embodiment, a compound therapy including, but not limited to, Surgery, chemotherapy, provided herein is administered daily in a single or divided radiation therapy, hormonal therapy, biological therapy and doses in a four to six week cycle with a rest period of about a immunotherapy. A solid form of the invention and other week or two weeks. Cycling therapy further allows the fre active ingredient can be administered to a patient prior to, quency, number, and length of dosing cycles to be increased. during, or after the occurrence of the adverse effect associated Thus, another embodiment encompasses the administration with conventional therapy. of a compound provided herein for more cycles than are 0280. In one embodiment, a solid form of the invention typical when it is administered alone. In yet another embodi can be administered in an amount of from about 0.10 to about ment, a compound provided herein is administered for a 150 mg, and preferably from about 1 to about 50 mg, more greater number of cycles than would typically cause dose US 2016/0045483 A1 Feb. 18, 2016 28 limiting toxicity in a patient to whom a second active ingre Examples of dosage forms include, but are not limited to: dient is not also being administered. tablets; caplets; capsules. Such as Soft elastic gelatin capsules 0289. In one embodiment, a compound provided herein is or hard gelatin capsules; cachets; troches; lozenges; disper administered daily and continuously for three or four weeks sions; Suppositories; powders; aerosols (e.g., nasal sprays or at a dose of from about 0.1 mg to about 5 mg per day, followed inhalers); gels; liquid dosage forms suitable for oral or by a rest of one or two weeks. In other embodiments, the dose mucosal administration to a patient, including Suspensions can be from about 1 mg to about 5 mg per day (e.g., 1, 2, 3, or (e.g., aqueous or non-aqueous liquid Suspensions, oil-in-wa 4 mg/day), given on Days 1-21 of each 28-day cycle until ter emulsions, or water-in-oil liquid emulsions), Solutions, disease progression, followed by a rest of 7 days on Days and elixirs, liquid dosage forms suitable for parenteral admin 22-28 of each 28-day cycle, for example, in patients with istration to a patient; eye drops or other ophthalmic prepara relapsed and refractory multiple myeloma who are refractory tions Suitable for topical administration; and sterile Solids to their last myelomatherapy and have received at least 2 prior (e.g., crystalline or amorphous Solids) that can be reconsti therapies that included lenalidomide and bortezomib. tuted to provide liquid dosage forms suitable for parenteral 0290. In a preferred embodiment, the solid form is admin administration to a patient. In one embodiment, the single istered to patients with leukemia in an amount of from about dosage forms provided herein are tablets, caplets, or capsules 0.10 to about 150 mg per day for 21 days followed by seven comprising one or more solid forms provided herein. In one days rest in a 28 day cycle. In the most preferred embodiment, embodiment, the single dosage forms provided herein are the solid form is administered to patients with refractory or tablets or capsules comprising one or more Solid forms pro relapsed chronic lymphocytic leukemia in an amount of about vided herein. 25 mg per day for 21 days followed by seven days rest in a 28 0296. The composition, shape, and type of dosage forms day cycle. will typically vary depending on their use. For example, a 0291. In one embodiment, a compound provided herein dosage form used in the acute treatment of a disease may and a second active ingredient are administered orally, with contain larger amounts of one or more of the active ingredi administration of the compound provided herein occurring 30 ents it comprises than a dosage form used in the chronic to 60 minutes prior to the second active ingredient, during a treatment of the same disease. Similarly, a parenteral dosage cycle of four to six weeks. In another embodiment, the com form may contain Smaller amounts of one or more of the bination of a compound provided herein and a second active active ingredients it comprises than an oral dosage form used ingredient is administered by intravenous infusion over about to treat the same disease. These and other ways in which 90 minutes every cycle. specific dosage forms are used will vary from one another will 0292. In a specific embodiment, one cycle comprises the be readily apparent to those skilled in the art. See, e.g., Rem administration of from about 5 to about 25 mg/day of the solid ington's Pharmaceutical Sciences, 18th ed., Mack Publish form and from about 50 to about 750 mg/m/day of a second ing, Easton Pa. (1990). active ingredient daily for three to four weeks and then one or 0297. In one embodiment, pharmaceutical compositions two weeks of rest. In a preferred embodiment, rituximab can and dosage forms comprise one or more excipients or carri be administered in an amount of 375 mg/m as an additional ers. Suitable excipients are known to those skilled in the art of active agent to patients with refractory or relapsed chronic pharmacy, and non-limiting examples of Suitable excipients lymphocytic leukemia. Typically, the number of cycles dur are provided herein. Whether a particular excipient is suitable ing which the combinatorial treatment is administered to a for incorporation into a pharmaceutical composition or dos patient will be from about one to about 24 cycles, more age form depends on a variety of factors known in the art typically from about two to about 16 cycles, and even more including, but not limited to, the way in which the dosage typically from about four to about three cycles. form will be administered to a patient. For example, oral dosage forms such as tablets may contain excipients not 5.8 Pharmaceutical Compositions and Dosage Forms suited for use in parenteral dosage forms. The suitability of a 0293 Pharmaceutical compositions can be used in the particular excipient may also depend on the specific active preparation of single unit dosage forms comprising one or ingredients in the dosage form. For example, the decomposi more solid forms provided herein. In one embodiment, pro tion of Some active ingredients may be accelerated by some vided herein are pharmaceutical compositions and dosage excipients such as lactose, or when exposed to water. Active forms comprising one or more solid forms comprising a com ingredients that comprise primary or secondary amines are pound provided herein, or a pharmaceutically acceptable salt, particularly susceptible to Such accelerated decomposition. Solvate (e.g., hydrate), Stereoisomer, co-crystal, clathrate, or Consequently, in one embodiment, provided are pharmaceu prodrug thereof. Pharmaceutical compositions and dosage tical compositions and dosage forms that contain little, if any, forms provided herein can further comprise one or more lactose or other mono- or di-saccharides. As used herein, the pharmaceutically acceptable excipients or carriers. term “lactose-free” means that the amount of lactose present, 0294. In some embodiments, pharmaceutical composi if any, is insufficient to Substantially increase the degradation tions and dosage forms provided hereincan also comprise one rate of an active ingredient. Lactose-free compositions pro or more additional active ingredients. Examples of optional vided herein can comprise excipients which are known in the second, or additional, active ingredients are disclosed herein art and are listed in the U.S. Pharmacopeia (USP) 25-NF20 elsewhere. (2002), which is incorporated herein in its entirety. 0295. In one embodiment, single unit dosage forms pro 0298 Also provided are anhydrous pharmaceutical com vided herein are Suitable for oral, parenteral (e.g., Subcutane positions and dosage forms comprising active ingredient(s), ous, intravenous, bolus injection, intramuscular, or intraarte since water may facilitate the degradation of Some com rial), topical (e.g., eye drops or other ophthalmic pounds. Anhydrous pharmaceutical compositions and dosage preparations), mucosal (e.g., nasal, Sublingual, Vaginal, buc forms can be prepared using anhydrous or low moisture con cal, or rectal), or transdermal administration to a patient. taining ingredients and low moisture or low humidity condi US 2016/0045483 A1 Feb. 18, 2016 29 tions. An anhydrous pharmaceutical composition should be syrups. In one embodiment, such dosage forms contain pre prepared and stored Such that its anhydrous nature is main determined amounts of active ingredients, and may be pre tained. Accordingly, in one embodiment, anhydrous compo pared by methods of pharmacy known to those skilled in the sitions are packaged using materials known to prevent expo art. See generally, Remington's Pharmaceutical Sciences, sure to water such that they can be included in suitable 18th ed., Mack Publishing, EastonPa. (1990). As used herein, formulary kits. Examples of Suitable packaging include, but oral administration also includes buccal, lingual, and Sublin are not limited to, hermetically sealed foils, plastics, unit dose gual administration. containers (e.g., vials), blister packs, and strip packs. 0304. In one embodiment, the oral dosage form provided 0299. Also provided are pharmaceutical compositions and herein is a tablet. In one embodiment, the oral dosage form dosage forms that comprise one or more compounds that provided herein is a capsule. In one embodiment, the oral reduce the rate by which an active ingredient will decompose. dosage form provided herein is a caplet. In particular embodi Such compounds, which are referred to herein as “stabiliz ments, ers, include, but are not limited to, antioxidants such as 0305. In one embodiment, oral dosage forms provided ascorbic acid, pH buffers, or salt buffers. herein are prepared by combining the active ingredients in an 0300 Like the amounts and types of excipients, the intimate admixture with one or more pharmaceutically amounts and specific types of active ingredients in a dosage acceptable carrier or excipient, including, but not limited to, form may differ depending on factors such as, but not limited binders, fillers, diluents, disintegrants, wetting agents, lubri to, the route by which it is to be administered to patients. In cants, glidants, coloring agents, dye-migration inhibitors, one embodiment, dosage forms comprise the active ingredi Sweetening agents, flavoring agents, emulsifying agents, Sus ent or Solid form comprising lenalidomide and a coformer pending and dispersing agents, preservatives, solvents, non provided herein in an amount of from about 0.10 to about 50 aqueous liquids, organic acids, and sources of carbon dioxide, mg, or from about 0.50 to about 30 mg. In other embodiments, according to conventional pharmaceutical compounding dosage forms comprise a compound provided herein in an techniques. Excipients can take a wide variety of forms amount of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, depending on the form of preparation desired for administra 10, 12.5, 15, 20, or 25 mg. In one embodiment, dosage forms tion. For example, excipients suitable for use in oral liquid or comprise a compound provided herein in an amount of about aerosol dosage forms include, but are not limited to, water, 1, 2.5, 5, 10, 15, 20, or 25 mg. glycols, oils, alcohols, flavoring agents, preservatives, and 0301 In other embodiments, dosage forms comprise a coloring agents. Examples of excipients Suitable for use in second active ingredient in an amount from about 1 mg to Solid oral dosage forms (e.g., powders, tablets, capsules, and about 1000 mg, from about 5 mg to about 500 mg, from about caplets) include, but are not limited to, starches, Sugars, 10 mg to about 350 mg, from about 5 mg to about 250 mg. micro-crystalline cellulose, diluents, granulating agents, from about 5 mg to about 100 mg, from about 10 mg to about lubricants, binders, and disintegrating agents. 100 mg, from about 10 mg to about 50 mg. or from about 50 0306 In one embodiment, oral dosage forms are tablets or mg to about 200 mg. In one embodiment, the specific amount capsules, in which case Solid excipients are employed. In of the second active agent will depend on the specific agent specific embodiments, capsules comprising one or more solid used, the diseases or disorders being treated or managed, and forms comprising lenalidomide and a coformer provided the amount(s) of a compound provided herein, and any herein can be used for oral administration. In one embodi optional additional active agents concurrently administered ment, the total amount of lenalidomide in the capsule is about to the patient. 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, 0302) In particular embodiments, provided herein is a about 4, about 4.5, about 5, about 6, about 7, about 8, about 9, pharmaceutical composition comprising a solid form com about 10, about 12.5, about 15, about 20, or about 25 mg. In prising lenalidomide and a coformer provided herein and a one embodiment, the total amount of lenalidomide in the pharmaceutically acceptable excipient or carrier. In particular capsule is about 1, about 2.5, about 5, about 10, about 15, embodiments, provided herein is a pharmaceutical composi about 20, or about 25 mg. Each capsule can contain lenalido tion comprising a cocrystal comprising lenalidomide and a mide as the active ingredient and one or more of the following coformer provided herein and a pharmaceutically acceptable inactive ingredients: lactose anhydrous, microcrystalline cel excipient or carrier. In particular embodiments, provided lulose, croScarmellose Sodium, and magnesium Stearate. In herein is a pharmaceutical composition comprising an amor specific embodiments, the 5 mg and 25 mg capsule shell can phous lenalidomide provided herein and a pharmaceutically contain gelatin, titanium dioxide and black ink. In specific acceptable excipient or carrier. Exemplary embodiments of embodiments, the 2.5 mg and 10 mg capsule shell can contain formulations of lenalidomide are described in, for example, gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide U.S. Pat. Nos. 5,635,517, 6,335,349, 6,316,471, 6,476,052, and black ink. In specific embodiments, the 15 mg capsule 7,041,680, and 7,709,502; and U.S. Patent Application Pub shell can contain gelatin, FD&C blue #2, titanium dioxide lication No. 2011/0045064; the entireties of which are incor and black ink. In another embodiment, tablets can be coated porated herein by reference. by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In 5.8.1 Oral Dosage Forms general, pharmaceutical compositions and dosage forms are 0303 Pharmaceutical compositions that are suitable for prepared by uniformly and intimately admixing the active oral administration can be provided as discrete dosage forms, ingredients with liquid carriers, finely divided solid carriers, such as, but not limited to, tablets, fastmelts, chewable tablets, or both, and then shaping the product into the desired presen capsules, pills, strips, troches, lozenges, pastilles, cachets, tation if necessary. pellets, medicated chewing gum, bulk powders, effervescent 0307. In certain embodiments, the dosage form is a tablet, or non-effervescent powders or granules, oral mists, Solu wherein the tablet is manufactured using standard, art-recog tions, emulsions, Suspensions, wafers, sprinkles, elixirs, and nized tablet processing procedures and equipment. In certain US 2016/0045483 A1 Feb. 18, 2016 30 embodiments, the method for forming the tablets is direct DON, PLASDONE), microcrystalline cellulose, among oth compression of a powdered, crystalline and/or granular com ers. Binding agents also include, e.g., acacia, agar, alginic position comprising a solid form provided herein, alone or in acid, cabomers, carrageenan, cellulose acetate phthalate, combination with one or more excipients, such as, for ceratonia, chitosan, confectioner's Sugar, copovidone, dex example, carriers, additives, polymers, or the like. In certain trates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl embodiments, as an alternative to direct compression, the behenate, guar gum, hydroxyethyl cellulose, hydroxyethyl tablets may be prepared using wet granulation or dry granu methyl cellulose, hydroxypropyl cellulose, hydroxypropyl lation processes. In certain embodiments, the tablets are starch, hypromellose, inulin, lactose, magnesium aluminum molded rather than compressed, starting with a moist or oth silicate, maltodextrin, maltose, methylcellulose, poloxamer, erwise tractable material. In certain embodiments, compres polycarbophil, polydextrose, polyethylene oxide, polym sion and granulation techniques are used. ethylacrylates, povidone, Sodium alginate, sodium car 0308. In certain embodiments, the dosage form is a cap boxymethylcellulose, starch, pregelatinized starch, Stearic Sule, wherein the capsules may be manufactured using stan acid, Sucrose, and Zein. In one embodiment, the binding agent dard, art-recognized capsule processing procedures and can be, relative to the weight of the dosage form, in an amount equipments. In certain embodiments, soft gelatin capsules of from about 50% to about 99% w/w. In certain embodi may be prepared in which the capsules contain a mixture ments, a Suitable amount of a particular binder is determined comprising a solid form provided herein and vegetable oil or by one of ordinary skill in the art. non-aqueous, water miscible materials, such as, for example, 0311 Suitable forms of microcrystalline cellulose polyethylene glycol and the like. In certain embodiments, include, but are not limited to, the materials sold as AVICEL hard gelatin capsules may be prepared containing granules of PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH solid forms provided herein in combination with a solid pull 105 (FMC Corporation, Marcus Hook, Pa.), and mixtures Verulent carrier, Such as, for example, lactose, Saccharose, thereof. In one embodiment, a specific binder is a mixture of Sorbitol, mannitol, potato starch, corn starch, amylopectin, microcrystalline cellulose and sodium carboxymethyl cellu cellulose derivatives, or gelatin. In certain embodiments, a lose sold as AVICEL RC-581. Suitable anhydrous or low hard gelatin capsule shell may be prepared from a capsule moisture excipients or additives include AVICEL-PH-103TM composition comprising gelatin and a Small amount of plas and Starch 1500 LM. ticizer Such as glycerol. In certain embodiments, as an alter 0312 Examples of fillers suitable for use in the pharma native to gelatin, the capsule shell may be made of a carbo ceutical compositions and dosage forms provided herein hydrate material. In certain embodiments, the capsule include, but are not limited to, talc, calcium carbonate (e.g., composition may additionally include polymers, colorings, granules or powder), microcrystalline cellulose, powdered flavorings and opacifiers as required. In certain embodiments, cellulose, dextrates, kaolin, mannitol, silicic acid, Sorbitol, the capsule comprises HPMC. starch, pre-gelatinized starch, and mixtures thereof. The 0309 Examples of excipients or carriers that can be used binder or filler in a pharmaceutical composition is, in one in oral dosage forms provided herein include, but are not embodiment, present in from about 50 to about 99 weight limited to, diluents (bulking agents), lubricants, disintegrants, percent of the pharmaceutical composition or dosage form. fillers, stabilizers, Surfactants, preservatives, coloring agents, 0313. In certain embodiments, dosage forms provided flavoring agents, binding agents (binders), excipient Sup herein comprise one or more diluents. Diluents may be used, ports, glidants, permeation enhancement excipients, plasti e.g., to increase bulk so that a practical size tablet or capsule cizers and the like, e.g., as known in the art. It will be under is ultimately provided. Suitable diluents include dicalcium stood by those in the art that some substances serve more than phosphate, calcium Sulfate, lactose, cellulose, kaolin, manni one purpose in a pharmaceutical composition. For instance, tol, Sodium chloride, dry starch, microcrystalline cellulose some substances are binders that help hold a tablet together (e.g., AVICEL), microfine cellulose, pregelitinized starch, after compression, yet are also disintegrants that help break calcium carbonate, calcium Sulfate, Sugar, dextrates, dextrin, the tablet apart once it reaches the target delivery site. Selec dextrose, dibasic calcium phosphate dihydrate, tribasic cal tion of excipients and amounts to use may be readily deter cium phosphate, kaolin, magnesium carbonate, magnesium mined by the formulation scientist based upon experience and oxide, maltodextrin, mannitol, polymethacrylates (e.g., consideration of Standard procedures and reference works EUDRAGIT), potassium chloride, sodium chloride, sorbitol available in the art. and talc, among others. Diluents also include, e.g., ammo 0310. In certain embodiments, dosage forms provided nium alginate, calcium carbonate, calcium phosphate, cal herein comprise one or more binders. Binders may be used, cium sulfate, cellulose acetate, compressible Sugar, confec e.g., to impart cohesive qualities to a tablet or a capsule, and tioner's Sugar, dextrates, dextrin, dextrose, erythritol, thus ensure that the formulation remains intact after compres ethylcellulose, fructose, fumaric acid, glyceryl palmitostear sion. Suitable binders include, but are not limited to, starch ate, isomalt, kaolin, lacitol, lactose, mannitol, magnesium (including potato starch, corn Starch, and pregelatinized carbonate, magnesium oxide, maltodextrin, maltose, starch), gelatin, Sugars (including Sucrose, glucose, dextrose medium-chain triglycerides, microcrystalline cellulose, and lactose), polyethylene glycol, propylene glycol, waxes, microcrystalline silicified cellulose, powered cellulose, poly and natural and Synthetic gums, e.g., acacia Sodium alginate, dextrose, polymethylacrylates, simethicone, sodium algi polyvinylpyrrolidone (PVP), cellulosic polymers (including nate, sodium chloride, Sorbitol, starch, pregelatinized starch, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellu Sucrose, Sulfobutylether-B-cyclodextrin, talc, tragacanth, tre lose(HPMC), methylcellulose, ethylcellulose, hydroxyethyl halose, and Xylitol. Diluents may be used in amounts calcu cellulose (HEC), carboxymethyl cellulose and the like), vee lated to obtain a desired volume for a tablet or capsule. The gum, carbomer (e.g., carbopol), Sodium, dextrin, guar gum, amount of a diluent in the pharmaceutical compositions pro hydrogenated vegetable oil, magnesium aluminum silicate, vided herein varies upon the type of formulation, and is maltodextrin, polymethacrylates, povidone (e.g., KOLLI readily discernible to those of ordinary skill in the art. US 2016/0045483 A1 Feb. 18, 2016

0314 Disintegrants may be used in the compositions to tants, such as polyoxyethylene Sorbitan monooleate provide tablets or capsules that disintegrate when exposed to (TWEENR 20), polyoxyethylene sorbitan monooleate 80 an aqueous environment. Dosage forms that contain too much (TWEENR 80), and triethanolamine oleate. Suitable sus disintegrant may disintegrate in storage, while those that con pending and dispersing agents include, but are not limited to, tain too little may not disintegrate at a desired rate or under the Sodium carboxymethylcellulose, pectin, tragacanth, Veegum, desired conditions. Thus, a Sufficient amount of disintegrant acacia, Sodium carbomethylcellulose, hydroxypropyl meth that is neither too much nor too little to detrimentally alter the ylcellulose, and polyvinylpyrrolidone. Suitable preservatives release of the active ingredient(s) may be used to form solid include, but are not limited to, glycerin, methyl and propy oral dosage forms. The amount of disintegrant used varies lparaben, benzoic add, sodium benzoate and alcohol. Suitable based upon the type of formulation, and is readily discernible wetting agents include, but are not limited to, propylene gly to those of ordinary skill in the art. In one embodiment, col monostearate, Sorbitan monooleate, diethylene glycol pharmaceutical compositions comprise from about 0.5 to monolaurate, and polyoxyethylene lauryl ether. Suitable sol about 15 weight percent of disintegrant, or from about 1 to vents include, but are not limited to, glycerin, Sorbitol, ethyl about 5 weight percent of disintegrant. alcohol, and syrup. Suitable non-aqueous liquids utilized in 0315 Suitable disintegrants include, but are not limited to, emulsions include, but are not limited to, mineral oil and agar, bentonite; celluloses. Such as methylcellulose and car cottonseed oil. Suitable organic acids include, but are not boxymethylcellulose; wood products; natural sponge; cation limited to, citric and tartaric acid. Suitable sources of carbon exchange resins; alginic acid: gums, such as guar gum and dioxide include, but are not limited to, sodium bicarbonate Veegum HV. citrus pulp, cross-linked celluloses, such as and sodium carbonate. croScarmellose; cross-linked polymers, such as crospovi 0318. In one embodiment, a solid oral dosage form com done; cross-linked Starches; calcium carbonate; microcrys prises a compound provided herein, and one or more excipi talline cellulose, Such as sodium starch glycolate; polacrilin ents selector from anhydrous lactose, microcrystalline cellu potassium; Starches, such as corn starch, potato starch, tapi lose, polyvinylpyrrolidone, Stearic acid, colloidal anhydrous oca starch, and pre-gelatinized starch; clays; aligns; and mix silica, and gelatin. In one embodiment, capsules comprise one tures thereof. The amount of a disintegrant in the pharmaceu or more Solid forms comprisinglenalidomide and a coformer tical compositions provided herein varies upon the type of provided herein, and one or more of the following inactive formulation, and is readily discernible to those of ordinary ingredients: mannitol, pregelatinized starch, sodium Stearyl skill in the art. The amount of a disintegrant in the pharma fumarate, gelatin, titanium dioxide, FD&C blue 2, yellow ceutical compositions provided herein varies upon the type of iron oxide, white ink, black ink, FD&C red 3, and a combi formulation, and is readily discernible to those of ordinary nation thereof. skill in the art. 0319. The pharmaceutical compositions provided herein 0316 Lubricants that can be used in pharmaceutical com for oral administration can be provided as compressed tablets, positions and dosage forms include, but are not limited to, tablet triturates, chewable lozenges, rapidly dissolving tab calcium Stearate, magnesium Stearate, mineral oil, light min lets, multiple compressed tablets, or enteric-coating tablets, eral oil, glycerin, Sorbitol, mannitol, polyethylene glycol, Sugar-coated, or film-coated tablets. Enteric-coated tablets other glycols, Stearic acid, sodium lauryl Sulfate, talc, hydro are compressed tablets coated with substances that resist the genated vegetable oil (e.g., peanut oil, cottonseed oil, Sun action of stomach acid but dissolve or disintegrate in the flower oil, Sesame oil, olive oil, corn oil, and soybean oil), intestine, thus protecting the active ingredients from the Zinc Stearate, ethyl oleate, ethyl laureate, agar, and mixtures acidic environment of the stomach. Enteric-coatings include, thereof. Additional lubricants include, for example, a syloid but are not limited to, fatty acids, fats, phenyl salicylate, silica gel (AEROSIL200, manufactured by W.R. Grace Co. of waxes, shellac, ammoniated shellac, and cellulose acetate Baltimore, Md.), a coagulated aerosol of synthetic silica phthalates. Sugar-coated tablets are compressed tablets Sur (marketed by Degussa Co. of Plano, Tex.), CAB-O-SIL (a rounded by a Sugar coating, which may be beneficial in cov pyrogenic silicon dioxide product sold by Cabot Co. of Bos ering up objectionable tastes or odors and in protecting the ton, Mass.), and mixtures thereof. The pharmaceutical com tablets from oxidation. Film-coated tablets are compressed positions provided herein may contain about 0.1 to about 5% tablets that are covered with a thin layer or film of a water by weight of a lubricant. soluble material. Film coatings include, but are not limited to, 0317 Suitable glidants include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, colloidal silicon dioxide, CAB-O-SILR) (Cabot Co. of Bos polyethylene glycol 4000, and cellulose acetate phthalate. ton, Mass.), and asbestos-free talc. Suitable coloring agents Film coating imparts the same general characteristics as Sugar include, but are not limited to, any of the approved, certified, coating. Multiple compressed tablets are compressed tablets water soluble FD&C dyes, and water insoluble FD&C dyes made by more than one compression cycle, including layered Suspended on alumina hydrate, and color lakes and mixtures tablets, and press-coated or dry-coated tablets. thereof. A color lake is the combination by adsorption of a 0320. The tablet dosage forms can be prepared from the water-soluble dye to a hydrous oxide of a heavy metal, result active ingredient in powdered, crystalline, or granular forms, ing in an insoluble form of the dye. Suitable flavoring agents alone or in combination with one or more carriers or excipi include, but are not limited to, natural flavors extracted from ents described herein, including binders, disintegrants, con plants, such as fruits, and synthetic blends of compounds trolled-release polymers, lubricants, diluents, and/or colo which produce a pleasant taste sensation, such as peppermint rants. Flavoring and Sweetening agents are especially useful and methyl salicylate. Suitable Sweetening agents include, in the formation of chewable tablets and lozenges. but are not limited to. Sucrose, lactose, mannitol, Syrups, 0321. The pharmaceutical compositions provided herein glycerin, and artificial Sweeteners, such as saccharin and for oral administration can be provided as Soft or hard cap aspartame. Suitable emulsifying agents include, but are not Sules, which can be made from gelatin, methylcellulose, limited to, gelatin, acacia, tragacanth, bentonite, and Surfac starch, or calcium alginate. The hard gelatin capsule, also US 2016/0045483 A1 Feb. 18, 2016 32 known as the dry-filled capsule (DFC), consists of two sec excipients used in the non-effervescent granules or powders tions, one slipping over the other, thus completely enclosing may include diluents, Sweeteners, and wetting agents. the active ingredient. The soft elastic capsule (SEC) is a soft, globular shell. Such as a gelatin shell, which is plasticized by 0326 Pharmaceutically acceptable carriers and excipients the addition of glycerin, sorbitol, or a similar polyol. The soft used in the effervescent granules or powders may include gelatin shells may contain a preservative to prevent the organic acids and a source of carbon dioxide. growth of microorganisms. Suitable preservatives are those 0327 Coloring and flavoring agents can be used in all of as described herein, including methyl- and propyl-parabens, the above dosage forms. and Sorbic acid. The liquid, semisolid, and Solid dosage forms provided herein may be encapsulated in a capsule. Suitable 0328. The pharmaceutical compositions provided herein liquid and semisolid dosage forms include solutions and Sus for oral administration can be formulated as immediate or pensions in propylene carbonate, vegetable oils, or triglycer modified release dosage forms, including delayed-, Sus ides. Capsules containing Such solutions can be prepared as tained, pulsed-, controlled, targeted-, and programmed-re described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410, lease forms. 545. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the 6. EXAMPLES active ingredient. 0322 The pharmaceutical compositions provided herein 0329. Certain embodiments provided herein are illus for oral administration can be provided in liquid and semi trated by the following non-limiting examples. Solid dosage forms, including emulsions, Solutions, Suspen sions, elixirs, and syrups. An emulsion is a two-phase system, 6.1 Preparation of Cocrystal Comprising in which one liquid is dispersed in the form of small globules Lenalidomide and a Coformer throughout another liquid, which can be oil-in-water or water-in-oil. Emulsions may include a pharmaceutically Example 1 acceptable non-aqueous liquid or solvent, emulsifying agent, and preservative. Suspensions may include a pharmaceuti cally acceptable Suspending agent and preservative. Aqueous Solubilities of Lenalidomide alcoholic Solutions may include a pharmaceutically accept able acetal, such as a di(lower alkyl)acetal of a lower alkyl 0330 Solubility of lenalidomide in various solvents at aldehyde, e.g., acetaldehyde diethyl acetal; and a water-mis ambient temperature was determined and is shown in Table 1. cible solvent having one or more hydroxyl groups, such as Solubility was estimated by treating a weighed sample of propylene glycol and ethanol. Elixirs are clear, Sweetened, lenalidomide with measured aliquots of the test solvent at and hydroalcoholic Solutions. Syrups are concentrated aque ambient temperature, with shaking and/or Sonication ous solutions of a Sugar, for example, Sucrose, and may also between aliquots. Dissolution was determined by visual contain a preservative. For a liquid dosage form, for example, inspection. Solubility numbers were calculated by dividing a solution in a polyethylene glycol may be diluted with a the total amount of solvent used to dissolve the sample by the Sufficient quantity of a pharmaceutically acceptable liquid weight of the sample. The actual solubilities may be greater carrier, e.g., water, to be measured conveniently for adminis than the numbers calculated because of the use of solvent tration. aliquots that were too large or because of slow dissolution rates. The solubility number is expressed as “less than’ if 0323. Other useful liquid and semisolid dosage forms dissolution did not occur during the experiment. The solubil include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or ity number is expressed as “greater than’ if dissolution poly-alkylene glycol, including, 1,2-dimethoxymethane, dig occurred on addition of the first solvent aliquot. lyme, triglyme, tetraglyme, polyethylene glycol-350-dim ethyl ether, polyethylene glycol-550-dimethyl ether, polyeth TABLE 1 ylene glycol-750-dimethyl ether, wherein 350, 550, and 750 Estimated Solubility of Lenalidonide refer to the approximate average molecular weight of the polyethylene glycol. These formulations can further com Solvent Solubility (mg/mL) prise one or more antioxidants, such as butylated hydroxy acetOne 2.2 toluene (BHT), butylated hydroxyanisole (BHA), propyl gal acetonitrile 3.4 late, vitamin E, hydroquinone, hydroxycoumarins, methanol 2.6 ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, tetrahydrofuran 3.0 sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates. 0324. The pharmaceutical compositions provided herein Example 2 for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems. Micellar Conformers Used in the Cocrystal Screen of dosage forms can be prepared as described in U.S. Pat. No. Lenalidomide 6,350,458. 0325 The pharmaceutical compositions provided herein 0331. A set of 50 coformers was selected from an internal for oral administration can be provided as non-effervescent or database based on toxicity profiles (pharmaceutical accept effervescent, granules and powders, to be reconstituted into a ability) and anticipated non-covalent and ionic interactions liquid dosage form. Pharmaceutically acceptable carriers and with lenalidomide. US 2016/0045483 A1 Feb. 18, 2016

TABLE 2 samples made using twelve (12) different coformers were found that exhibit XRPD patterns suggestive of cocrystal Coformers Used in the Cocrystal Screen of Lenalidomide formation: benzoic acid, gallic acid, glycolic acid, hippuric acetylsalicylic acid D-glucose nicotinic acid acid, magnesium bromide (2 Samples), malonic acid, oxalic aconitic acid L-glutamic acid oxalic acid acid, propyl gallate (2 Samples), Sodium lauryl Sulfate, L-tar adipic acid glutaric acid L-proline taric acid (3 samples), Vanillic acid, and Zinc chloride. Those 4-aminosalicylic acid glycine propyl gallate L-ascorbic acid glycolic acid L-pyroglutamic acid patterns contain peaks that do not appear to arise from any benzoic acid hippuric acid Saccharin polymorph of lenalidomide or the relevant coformer. (+)-camphoric acid -hydroxy-2-naphtholic salicylic acid acid Example 7 capric acid ketoglutaric acid Sebacic acid cinnamic acid L-lysine Sodium lauryl Sulfate citric acid magnesium bromide Sorbic acid Solid Forms Comprising Lenalidomide and Gallic cyclamic acid maleic acid Succinic acid Acid ethyl maltol L-malic acid L-tartaric acid ethyl paraben malonic acid 8 0336 Acocrystal comprisinglenalidomide and gallic acid D-fructose maltol vanillic acid was prepared using the stoichiometric slurry method fumaric acid D.L-mandelic acid vanillin described in Example 3. A 1:1 mixture of methanol: water was gallic acid methyl paraben Zinc chloride used as the solvent. The XRPD pattern of the solid form is gentisic acid nicotinamide provided in FIG. 1. The overlay plot of the XRPD pattern of the solid form with a pattern from gallic acid is provided in FIG. 27. Example 3 Example 8 Preparation of Cocrystal Comprising Lenalidomide and a Coformer Using Stoichiometric Slurry Solid Forms Comprising Lenalidomide and Vanillic Experiments Acid 0332 Stoichiometric slurry experiments were carried out 0337. A cocrystal comprising lenalidomide and vanillic in glass vials. Each of the vials was charged with about 20 mg acid was prepared using the Stoichiometric flash evaporation of lenalidomide, an approximately equimolar amount of method described in Example 5. Methanol was used as the coformer, and 500 uL of a saturated solution of the same solvent. The XRPD pattern of the solid form is provided in coformer in the solvent used for that experiment. A magnetic FIG 2. stir bar was placed in each vial and the rack of vials was placed on a stir plate at room temperature for 24 hours. The Example 9 Solids were isolated by centrifugation. Solid Forms Comprising Lenalidomide and Oxalic Example 4 Acid Preparation of Cocrystal Comprising Lenalidomide 0338 A cocrystal comprising lenalidomide and oxalic and a Coformer Using Stoichiometric Wet Milling acid was prepared using the Stoichiometric wet milling Experiments method described in Example 4. The XRPD pattern of the 0333 For each experiment, A PEEK grinding cup was solid form is provided in FIG. 3. The overlay plot of the charged with about 20 mg of lenalidomide, an approximately XRPD pattern of the solid form with a pattern from lenalido equimolar amount of coformer, about 100 uL of a mixture of mide form D is provided in FIG. 28. methanol and water (3:1), and one steel grinding ball. The cup was sealed and shaken on a Retsch mill for 20 min. The solid Example 10 was collected. Solid Forms Comprising Lenalidomide and Propyl Example 5 Gallate Preparation of Cocrystal Comprising Lenalidomide 0339. A cocrystal comprising lenalidomide and propyl and a Coformer Using Stoichiometric Flash gallate was prepared using the Stoichiometric slurry method Evaporation Experiments described in Example 3. A 1:1 mixture of methanol: water was used as the solvent. A cocrystal comprisinglenalidomide and 0334 For each experiment, he solvent was removed from propyl gallate was also prepared using the Stoichiometric wet Solutions containing about 20 mg of lenalidomide and milling method described in Example 4. The XRPD pattern of approximately equimolar amount of coformer on a rotary the solid form is provided in FIG. 4. The overlay plot of the evaporator using a bath set at 65°C. If the residue was solid it XRPD patterns of the solid form with a pattern from lenali was stored at 75% relative humidity for 1 day. If the residue domide form D is provided in FIG. 29. was oil it was stored at 60° C. overnight. The resulting solids were collected. Example 11 Example 6 Solid Forms Comprising Lenalidomide and Glycolic Potential New Solid Phases from Screening Acid Experiments 0340. A cocrystal comprising lenalidomide and glycolic 0335. One hundred and thirty-nine (139) experiments acid was prepared using the Stoichiometric slurry method using fifty (50) coformers were carried out. Sixteen (16) described in Example 3. Acetonitrile was used as the solvent. US 2016/0045483 A1 Feb. 18, 2016 34

The XRPD pattern of the solid form is provided in FIG.5. The 0349. In a scale up experiment, to 1.5 mL of acetonitrile overlay plot of the XRPD pattern of the solid form with a was added malonic acid until solid persisted. The slurry was pattern from lenalidomide form A and glycolic acid is pro stirred at ambient temperature overnight and centrifuged. The vided in FIG. 30. liquid was decanted and treated with 82.6 mg (0.319 mmol) of lenalidomide and 33.2 mg (0.286 mmol) of malonic acid. The Example 12 slurry was stirred at ambient temperature for 4 days and Solid Forms Comprising Lenalidomide and Sodium centrifuged. The liquid was decanted and the remaining Solid Lauryl Sulfate was dried in an oven at 60° C. oven to give a lenalidomide/ 0341. A cocrystal comprising lenalidomide and sodium malonic acid cocrystal. lauryl Sulfate was prepared using the Stoichiometric slurry 0350. The cocrystal was characterized by XRPD (FIG. method described in Example 3. Methanol was used as the 13A and FIG.13B), DSC and TGA (FIG. 14), DVS (FIG. 15), solvent. The XRPD pattern of the solid form is provided in Raman (FIG. 16), 'H-NMR (FIGS. 17A & 17B), and optical FIG. 6. The overlay plot of the XRPD pattern of the solid form microscope (FIG. 18). with a pattern from lenalidomide form A is provided in FIG. 0351 DSC analysis revealed relatively sharp endothermic 31. events at about 102 and 111° C., followed by a broad endot hermic event at about 159°C. TGA analysis showed a weight Example 13 loss of 43% between 100 and 180°C. That large weight loss Suggested a decomposition reaction(s) was occurring, but Solid Forms Comprising Lenalidomide and may included water loss as well. Magnesium Bromide 0352. The "H-NMR spectrum in DMSO-d showed peaks 0342. A cocrystal comprising lenalidomide and magne from both lenalidomide and malonic acid. 'H-NMR spectra sium bromide was prepared using the Stoichiometric slurry were acquired of lenalidomide and the cocrystal in CH-OH method described in Example 3. Acetone was used as the da Peaks from the CH group of malonic acid were integrated Solvent. A cocrystal comprising lenalidomide and magne and the integral obtained was one proton, which indicated that sium bromide was also prepared using the Stoichiometric the cocrystal Stoichiometry is 2:1 lenalidomide:malonic acid. flash evaporation method described in Example 5. Methanol 0353 Dynamic vapor sorption (DVS) analysis showed was used as the solvent. that the cocrystal is hygroscopic, increasing in weight by 42% 0343. In a scale up experiment, a solution of 66.1 mg from 5-95% RH. Most of that gain was lost in the desorption (0.255 mmol) of lenalidomide and 75.0 mg (0.257 mmol) of cycle and the crystalline form of the resulting solid was the magnesium bromide hexahydrate in 75 mL of methanol was same as that of the starting material, Suggesting that the concentrated on a rotary evaporator at 60°C. The flask con cocrystal was still present after the DVS experiment. taining the resulting Solid was placed in an oven at 60° C. overnight. A few milliliters of diethyl ether were added to the Example 15 flask, the Solid was scraped from the walls with a spatula, and the mixture was transferred to a vial. The ether was evapo Solid Forms Comprising Lenalidomide and rated in a stream of dry air to give 105.8 mg (94% yield) of the L-Tartaric Acid lenalidomide/magnesium bromide cocrystal. (0344) The cocrystal was characterized by XRPD (FIG.7A 0354 Acocrystal comprising lenalidomide and L-tartaric and FIG.7B), DSC and TGA (FIG. 8), DVS (FIG.9), Raman acid was prepared using the Stoichiometric wet milling (FIG. 10), 'H-NMR (FIG. 11), and optical microscope (FIG. method described in Example 4. 12). The overlay plot of the XRPD patterns of the solid form 0355. In a scale up experiment, a mixture of 59.8 mg with a pattern from magnesium bromide is provided in FIG. (0.332 mmol) of lenalidomide, 68.8 mg (0.335 mmol) of 32. L-tartaric acid, 40 uL of a 1:3 (v:v) mixture of water and (0345. The TGA showed about 16% weight loss from 70 to methanol, and one stainless steel grinding ball was placed in 200° C. However, there were no clear events observed by a polyether ether ketone (PEEK) grinding cup. The cup was DSC. A ragged endothermic event was present at about 123° closed and agitated on a Retsch mill at 100% power for about C. A noisy appearance of the DSC thermogram around 180 20 minutes. The grinding ball was removed and the contents 250° C. Suggested decomposition may be occurring. of the cup were recovered to give the lenalidomide/L-tartaric (0346. The H-NMR spectrum was consistent with the acid cocrystal. structure of lenalidomide (magnesium bromide is inactive in 0356. The cocrystal was characterized by XRPD (FIG. H-NMR spectroscopy). 19A and FIG. 19B), DSC and TGA (FIG. 20), DVS (FIG. 21), 0347 Dynamic vapor sorption (DVS) analysis showed 'H-NMR (FIG. 22), and optical microscope (FIG. 23). that the cocrystal is hygroscopic, increasing in weight by 43% 0357 The TGA showed continuous weight loss from the from 5-95% RH. Most of that gain was lost in the desorption start of the experiment, totaling about 12% by 200° C. An cycle and the crystalline form of the resulting solid was the endothermic event at about 148°C. was observed by DSC. same as that of the starting material, Suggesting that the The noisy appearance of the DSC thermogram around 180 cocrystal was still present after the DVS experiment. 250° C. Suggested decomposition may be occurring. Example 14 0358. The H-NMR spectrum showed peaks from both lenalidomide and L-tartaric acid; integrations indicated that Solid Forms Comprising Lenalidomide and Malonic the cocrystal contains a 1:1 molar ratio of those components. Acid 0359 Dynamic vapor sorption (DVS) analysis showed 0348. A cocrystal comprising lenalidomide and malonic that the cocrystal is hygroscopic, increasing in weight by 22% acid was prepared using the Stoichiometric slurry method from 5-95% RH. Most of that gain was lost in the desorption described in Example 3. Acetonitrile was used as the solvent. cycle and the crystalline form of the resulting solid was the US 2016/0045483 A1 Feb. 18, 2016 same as that of the starting material, Suggesting that the sample was analyzed from 2 to 40°20 using a continuous scan cocrystal was still present after the DVS experiment. of 620 per minute with an effective step size of 0.02°20. Example 16 Differential Scanning Calorimetry (DSC) Solid Forms Comprising Lenalidomide and Hippuric 0365 DSC analyses were carried out using a TA Instru Acid ments Q2000 instrument. The instrument temperature cali 0360. A cocrystal comprising lenalidomide and hippuric bration was performed using indium. The DSC cell was kept acid was prepared using the Stoichiometric flash evaporation under a nitrogen purge of about 50 mL perminute during each method described in Example 5. Methanol was used as the analysis. The sample was placed in a standard, crimped, alu solvent. The XRPD pattern of the solid form is provided in minum pan and was heated from 20°C. to 350° C. at a rate of FIG. 24. The overlay plot of the XRPD pattern of the solid 10° C. per minute. form with a pattern from lenalidomide form D is provided in FIG. 33. Thermogravimetric (TG) Analysis Example 17 0366. The TG analysis was carried out using a TA Instru ments Q50 instrument. The instrument balance was cali Solid Forms Comprising Lenalidomide and Zinc brated using class M weights and the temperature calibration Chloride was performed using alumel. The nitrogen purge was about 40 mL per minute at the balance and about 60 mL per minute 0361 Acocrystal comprisinglenalidomide and zinc chlo at the furnace. Each sample was placed into a pre-tared plati ride was prepared using the Stoichiometric wet milling num pan and heated from 20° C. to 350° C. at a rate of 10° C. method described in Example 4. The XRPD pattern of the per minute. solid form is provided in FIG. 25. Example 18 Dynamic Vapor Sorption 0367 DVS analyses were carried out TA Instruments Solid Forms Comprising Lenalidomide and Benzoic Q5000 Dynamic Vapor Sorption analyzer. The instrument Acid was calibrated with standard weights and a sodium bromide 0362. A cocrystal comprising lenalidomide and benzoic standard for humidity. Samples were analyzed at 25°C. with acid was prepared using the Stoichiometric flash evaporation a maximum equilibration time of 60 minutes in 10% relative method described in Example 5. Methanol was used as the humidity (RH) steps from 5 to 95% RH (adsorption cycle) solvent. The XRPD pattern of the solid form is provided in and from 95 to 5% RH (desorption cycle). FIG. 26. The overlay plot of the XRPD patterns of the solid form with a pattern from benzoic acid is provided in FIG. 34. Raman Spectroscopy 6.2 Characterization of Cocrystal Comprising 0368 Fourier transform (FT) Raman spectra were Lenalidomide and a Coformer X-Ray Powder acquired on a Nicolet model 6700 spectrometer interfaced to Diffraction (XRPD) a Nexus Raman accessory module. This instrument is config 0363 The Rigaku Smart-Lab X-ray diffraction system ured with a Nd:YAG laser operating at 1024 nm, a CaF2 was configured for reflection Bragg-Brentano geometry beamsplitter, and a indium gallium arsenide detector. using a line Source X-ray beam. The X-ray source is a Cu Long OMNIC 8.1 software was used for control of data acquisition Fine Focus tube that was operated at 40 kV and 44 ma. That and processing of the spectra. Samples were packed into a Source provides an incident beam profile at the sample that 3-inch glass NMR tube for analysis. changes from a narrow line at high angles to a broad rectangle at low angles. Beam conditioning slits are used on the line Nuclear Magnetic Resonance (NMR) Spectroscopy X-ray Source to ensure that the maximum beam size is less than 10 mm both along the line and normal to the line. The 0369. The 1H NMR spectra were acquired on a Bruker Bragg-Brentano geometry is a para-focusing geometry con DRX-500 spectrometer located at the Chemistry Department trolled by passive divergence and receiving slits with the of Purdue University. Samples were prepared by dissolving sample itself acting as the focusing component for the optics. material in DMSO-d6. The solutions were filtered and placed The inherent resolution of Bragg-Brentano geometry is gov into individual 5-mm NMR tubes for subsequent spectral erned in part by the diffractometer radius and the width of the acquisition. The temperature controlled (298K) 1H NMR receiving slit used. Typically, the Rigaku Smart-Lab is oper spectra acquired on the DRX-500 utilized a 5-mm cryoprobe ated to give peak widths of 0.1°20 or less. The axial diver operating at an observing frequency. Processing of NMR data gence of the X-ray beam is controlled by 5.0-degree Soller at Triclinic was done using the program NUTS. slits in both the incident and diffracted beam paths. 0364 Powder samples were prepared in a low background Optical Microscopy Si holder using light manual pressure to keep the sample surfaces flat and level with the reference surface of the sample 0370 Optical microscopy experiments were carried out holder. The single-crystal, Si, low-background holder has a on a Leica DM 2500 P compound microscope. Images were Small circular recess (7 mm diameter and about 1 mm depth) captured using a QImaging MicroPublisher 3.3 RTV camera. that holds between 5 and 10 mg of powdered material. Each Images were collected at 10x magnification. US 2016/0045483 A1 Feb. 18, 2016 36

6.3 Assays regression, sigmoidal dose-response, constraining the top to 100% and bottom to 0%, allowing variable slope (GraphPad 6.3.1 TNFC. Inhibition Assay in PBMC Prism v3.02). 0371 Peripheral blood mononuclear cells (PBMC) from 6.3.3 Cell Proliferation Assay normal donors are obtained by Ficoll Hypaque (Pharmacia, 0375 Cell lines Namalwa, MUTZ-5, and UT-7 are Piscataway, N.J., USA) density centrifugation. Cells are cul obtained from the Deutsche Sammlung von Mikroorganis tured in RPMI 1640 (Life Technologies, Grand Island, N.Y., men and Zellkulturen GmbH (Braunschweig, Germany). The USA) supplemented with 10% AB+human serum (Gemini cell line KG-1 is obtained from the American Type Culture Bio-products, Woodland, Calif., USA), 2 mM L-glutamine, Collection (Manassas, Va., USA). Cell proliferation as indi 100U/ml penicillin, and 100 ug/ml streptomycin (Life Tech cated by H-thymidine incorporation is measured in all cell nologies). lines as follows. 0372 PBMC (2x10 cells) are plated in 96-well flat-bot 0376 Cells are plated in 96-well plates at 6000 cells per tom Costar tissue culture plates (Corning, N.Y., USA) in well in media. The cells are pre-treated with compounds at triplicate. Cells are stimulated with LPS (from Salmonella about 100, 10, 1, 0.1, 0.01, 0.001, 0.0001 and 0 uM in a final abortus equi, Sigma cat. no. L-1887, St. Louis, Mo., USA) at concentration of about 0.25% DMSO in triplicate at 37° C. in 1 ng/mL final in the absence or presence of compounds. a humidified incubator at 5% CO for 72 hours. One micro Compounds provided herein are dissolved in DMSO (Sigma) curie of H-thymidine (Amersham) is then added to each and further dilutions are done in culture medium immediately well, and cells are incubated again at 37°C. in a humidified before use. The final DMSO concentration in all assays can be incubator at 5% CO, for 6 hours. The cells are harvested onto about 0.25%. Compounds are added to cells 1 hour before UniFilter GF/C filter plates (Perkin Elmer) using a cell har LPS stimulation. Cells are then incubated for 18-20 hours at vester (Tomtec), and the plates are allowed to dry overnight. 37°C. in 5% CO, and supernatants are then collected, diluted Microscint 20 (Packard) (25ul/well) is added, and plates are with culture medium and assayed for TNFC. levels by ELISA analyzed in TopCount NXT (Packard). Each well is counted (Endogen, Boston, Mass., USA). ICsos are calculated using for one minute. Percent inhibition of cell proliferation is non-linear regression, sigmoidal dose-response, constraining calculated by averaging all triplicates and normalizing to the the top to 100% and bottom to 0%, allowing variable slope DMSO control (0% inhibition). Each compound is tested in (GraphPad Prism v3.02). each cell line in three separate experiments. Final ICsos are calculated using non-linear regression, Sigmoidal dose-re sponse, constraining the top to 100% and bottom to 0%. 6.3.2. IL-2 and MIP-3C. Production by T Cells allowing variable slope. (GraphPad Prism v3.02). 0373 PBMC are depleted of adherent monocytes by plac ing 1x10 PBMC in 10 ml complete medium (RPMI 1640 6.3.4. Immunoprecipitation and Immunoblot supplemented with 10% heat-inactivated fetal bovine serum, 0377 Namalwa cells are treated with DMSO oran amount 2 mM L-glutamine, 100U/ml penicillin, and 100 g/ml strep of a compound provided herein for 1 hour, then stimulated tomycin) per 10 cm tissue culture dish, in 37° C., 5% CO, with 10 U/ml of Epo (R&D Systems) for 30 minutes. Cell incubator for 30-60 minutes. The dish is rinsed with medium lysates are prepared and either immunoprecipitated with Epo to remove all non-adherent PBMC. T cells are purified by receptor Ab or separated immediately by SDS-PAGE. Immu negative selection using the following antibody (Pharmin noblots are probed with Akt, phospo-Akt (Ser473 or Thr308), gen) and Dynabead (Dynal) mixture for every 1x10' non phospho-Gabl (Y627), Gab1, IRS2, actin and IRF-1 Abs and adherent PBMC: 0.3 ml Sheep anti-mouse IgG beads, 15 ul analyzed on a Storm 860 Imager using ImageOuant Software anti-CD16, 15ul anti-CD33, 15ul anti-CD56, 0.23 ml anti (Molecular Dynamics). CD19 beads, 0.23 ml anti-HLA class II beads, and 56 ul anti-CD14 beads. The cells and bead/antibody mixture is 6.3.5 Cell Cycle Analysis rotated end-over-end for 30-60 minutes at 4° C. Purified T 0378 Cells are treated with DMSO or an amount of a cells are removed from beads using a Dynal magnet. Typical compound provided herein overnight. Propidium iodide yield is about 50% T cells, 87-95% CD3" by flow cytometry. staining for cell cycle is performed using CycleTEST PLUS 0374 Tissue culture 96-well flat-bottom plates are coated (Becton Dickinson) according to manufacturer's protocol. with anti-CD3 antibody OKT3 at 5ug/ml in PBS, 100 ul per Following staining, cells are analyzed by a FACSCalibur flow well, incubated at 37° C. for 3-6 hours, then washed four cytometer using ModFit LT software (Becton Dickinson). times with complete medium 100 ul/well just before T cells are added. Compounds are diluted to 20 times of final in a 6.3.6 Apoptosis Analysis round bottom tissue culture 96-well plate. Final concentra 0379 Cells are treated with DMSO or an amount of a tions are about 10 LM to about 0.00064 uM. A 10 mM stock compound provided herein at various time points, then of compounds provided herein is diluted 1:50 in complete for washed with annexin-V wash buffer (BD Biosciences). Cells the first 20x dilution of 200 uM in 2% DMSO and serially are incubated with annexin-Vbinding protein and propidium diluted 1:5 into 2% DMSO. Compound is added at 10 ul per iodide (BD Biosciences) for 10 minutes. Samples are ana 200 ul culture, to give a final DMSO concentration of 0.1%. lyzed using flow cytometry. Cultures are incubated at 37° C., 5% CO, for 2-3 days, and supernatants analyzed for IL-2 and MIP-3C. by ELISA (R&D 6.3.7 Luciferase Assay Systems). IL-2 and MIP-3C levels are normalized to the amount produced in the presence of an amount of a compound 0380 Namalwa cells are transfected with 4 ug of AP1 provided herein, and ECsos calculated using non-linear luciferase (Stratagene) per 1x10 cells and 3 ul Lipo US 2016/0045483 A1 Feb. 18, 2016 37 fectamine 2000 (Invitrogen) reagent according to manufac 17. The solid form of claim 1, which is substantially crys turers instructions. Six hours post-transfection, cells are talline. treated with DMSO or an amount of a compound provided 18. The solid form of claim 1, which is substantially a herein. Luciferase activity is assayed using luciferase lysis cocrystal. buffer and Substrate (Promega) and measured using a lumi 19. The solid form of claim 1, which is greater than 80% by nometer (Turner Designs). weight, greater than 90% by weight, greater than 95% by 0381. The embodiments described above are intended to weight, greater than 97% by weight, or greater than 99% by be merely exemplary, and those skilled in the art will recog weight a cocrystal. nize, or will be able to ascertain using no more than routine 20. The solid form claim 1, which is substantially physi experimentation, numerous equivalents of specific com cally pure. pounds, materials, and procedures. All Such equivalents are 21. The solid form of claim 20, which is substantially free considered to be within the scope of the disclosure and are of other solid forms of 3-(4-amino-1-oxo-1.3 dihydro-isoin encompassed by the appended claims. dol-2-yl)-piperidine-2,6-dione. 0382 All of the patents, patent applications and publica 22. The solid form of claim 1, which is substantially chemi tions referred to herein are incorporated herein in their entire cally pure. ties. Citation or identification of any reference in this appli 23. The solid form of claim 1, which is substantially free of cation is not an admission that Such reference is available as solvent. prior art. The full scope of the disclosure is better understood 24. The solid form of claim 1, which is substantially free of with reference to the appended claims. Water. 1. A Solid form comprising (a) 3-(4-amino-1-oxo-1.3 dihy 25. The solid form claim 1, further comprising amorphous dro-isoindol-2-yl)-piperidine-2,6-dione, or a pharmaceuti 3-(4-amino-1-oxo-1.3 dihydro-isoindol-2-yl)-piperidine-2, cally acceptable salt, Solvate, hydrate, Stereoisomer, prodrug, 6-dione. or clathrate thereof; and (b) a coformer. 2. The solid form of claim 1, wherein the coformer is 26. The solid form of claim 1, which is stable. benzoic acid, gallic acid, glycolic acid, hippuric acid, mag 27. The solid form of claim 1, which is substantially crys nesium bromide, malonic acid, maltol, oxalic acid, propyl talline and thermally stable. gallate, sodium lauryl Sulfate, L-tartaric acid, Vanillic acid, or 28. A pharmaceutical composition comprising the Solid Zinc chloride. form of claim 1. 3. The solid form of claim 2, wherein the coformer is 29. The pharmaceutical composition of claim 28, further benzoic acid. comprising a pharmaceutically acceptable excipient or car 4. The solid form of claim 2, wherein the coformer is gallic 1. acid. 30. The pharmaceutical composition of claim 28, which is 5. The solid form of claim 2, wherein the coformer is a single unit dosage form. glycolic acid. 31. The pharmaceutical composition of claim 28, which is 6. The solid form of claim 2, wherein the coformer is a tablet. hippuric acid. 32. The pharmaceutical composition of claim 28, which is 7. The solid form of claim 2, wherein the coformer is a capsule. magnesium bromide. 33. The pharmaceutical composition of claim 28, wherein 8. The solid form of claim 2, wherein the coformer is the lenalidomide is in an amount of from about 0.1 to about 5 malonic acid. ng. 9. The solid form of claim 2, wherein the coformer is 34. A method of treating a disease, comprising administer maltol. ing the solid form of claim 1 to a subject in need thereof. 10. The solid form of claim 2, wherein the coformer is 35. The method of claim34, wherein the disease is multiple oxalic acid. myeloma. 11. The solid form of claim 2, wherein the coformer is 36. The method of claim 34, wherein the disease is trans propyl gallate. fusion-dependent anemia due to Low- or Intermediate-1-risk 12. The solid form of claim 2, wherein the coformer is myelodysplastic syndromes (MDS) associated with a dele Sodium lauryl Sulfate. tion 5q cytogenetic abnormality with or without additional 13. The solid form of claim 2, wherein the coformer is cytogenetic abnormalities. L-tartaric acid. 14. The solid form of claim 2, wherein the coformer is 37. The method of claim 34, further comprising adminis Vanillic acid. tering a second active agent. 15. The solid form of claim 2, wherein the coformer is zinc 38. The method of claim 37, wherein the second active chloride. agent is dexamethasone. 16. The solid form of claim 1, wherein the molar ratio of 39. The method of claim 34, wherein the subject was pre 3-(4-amino-1-oxo-1.3 dihydro-isoindol-2-yl)-piperidine-2, viously treated with a prior therapy. 6-dione to the coformer is about 1:1. k k k k k