Cocrystal forms of ((1s,2s,4r)-4-{4-[(1S)-2,3-dihydro-1h-inden-1-ylamino]-7h-pyrrolo [2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl) methyl sulfamate, formulations and uses thereof

Microscale Cocrystal Formation of MLN4924

[0422]A cocrystal formation of MLN4924 was performed using twenty-five coformers including acetic acid, benzoic acid, camphoric acid, caproic acid, trans-cinnamic acid, ethylenediamine, fumaric acid, gentisic acid, D-glucuronic acid, glycolic acid, hippuric acid, DL-lactic acid, L-lysine, L-malic acid, malonic acid, DL-mandelic acid, meglumine, orotic acid, oxalic acid, piperazine, L-proline, L-pyroglutamic acid, saccharin, succinic acid, and vanillin. Crystallization techniques included evaporation, precipitation using an anti-solvent, slow cooling, vapor diffusion, slurrying, and liquid-assisted grinding. MLN4924 was used as starting material for the cocrystal formation experiments. XRPD data of isolated solids were compared to the pattern of MLN4924 free base, to each other, and to the patterns of respective coformers which are solid at ambient temperature.

[0423]Cocrystal formation experiments were first conducted on microscale in a 96-well p

Medium Scale Cocrystal Formation of MLN4924

[0424]Medium scale experiments then followed which allowed for a wider range of experimental techniques to be employed (Table 18). Isolated solids which exhibited a unique XRPD pattern were further characterized by proton spectroscopy to determine chemical composition and stoichiometry. Thermal analysis were conducted on selected solids.

[0425]Overall, sixty single or multi-step medium scale (˜50 mg to ˜200 mg) experiments were performed targeting various cocrystals of MLN4924 free base. Twenty coformers were studied including mono-, di-, and aromatic carboxylic acids (acetic acid, benzoic acid, trans-cinnamic acid, fumaric acid, gentisic acid, D-glucuronic acid, glycolic acid, hippuric acid, malonic acid, DL-mandelic acid, orotic acid, oxalic acid, L-pyroglutamic acid, and succinic acid), bases (ethylenediamine, meglumine, and piperazine), amino acids (L-lysine and L-proline), and saccharin. Crystallization techniques included evaporation, coo

Preliminary Evaluation of Selected MLN4924 Cocrystals

[0434]The aqueous solubility of new materials was estimated in water using a solvent addition method (Table 19). All new materials that were confirmed to contain a stoichiometric ratio of MLN4924 to coformer were estimated to have a solubility of less than 1 mg / mL.

TABLE 19Aqueous Solubility Estimates of MLN4924 Cocrystal CandidatesSolubilityMaterial testedCoformerX:Y aEstimateb(mg / mL)Form AGlycolic acid1:1 cForm BHippuric acid1:1Form FSaccharin  1:1 dForm GPiperazine2:1Form HGentisic acid  1:1 dForm JGentisic acid1:1Form LGentisic acid1:1Form MMalonic acid1:1Form NGentisic acid1:1 ca API:coformer stoichiometry as confirmed by proton NMR spectroscopy unless otherwise notedbValues are rounded to nearest whole number. If dissolution did not occur asdetermined by visual assessment value is reported as “cFew solids remainedd Ratio reported is from experimental conditions and was not confirmed by proton NMR

[0435]Each cocrystal was also