MORPHIC FORMS OF HEXADECYLOXYPROPYL-PHOSPHONATE ESTERS AND METHODS OF SYNTHESIS THEREOF
The disclosure describes methods of synthesis of phosphonate ester compounds. The methods according to the disclosure allow for large-scale preparation of phosphonate ester compounds having high purity and stability. Also disclosed are morphic forms of phosphonate ester compounds.
1 .- 30 . (canceled)
31 . Morphic Form II of phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl) ethoxy]methyl]mono[3-(hexadecyloxy)propyl] ester, wherein the morphic Form II is characterized by an X-ray diffraction pattern that lacks prominent peaks at about 12.6 and at about 15.6 degrees 2θ.
32 . The morphic Form II of claim 31 , wherein the morphic Form II is characterized by an X-ray diffraction pattern with prominent peaks at about 2.81 and about 5.63 degrees 2θ.
33 . The morphic Form II of claim 31 , wherein the morphic Form II is characterized by an X-ray diffraction pattern with peaks expressed in degrees 2θ (±0.2) at 2.81, 5.63, 19.00, 19.57, 22.76, and 24.70.
34 . The morphic Form II of claim 31 , wherein the morphic Form II is characterized by a scanning electron microscopy image showing agglomerates with sizes from about 200 μm to about 500 μm.
35 . The morphic Form II of claim 31 , wherein the morphic Form II is characterized by a scanning electron microscopy image showing agglomerates with sizes of about 200 μm.
36 . The morphic Form II of claim 31 , wherein the morphic Form II is characterized by a scanning electron microscopy image showing agglomerates with sizes of about 500 μm.
37 . The morphic Form II of claim 31 , wherein the morphic Form II has a purity of at least 91%.
38 . The morphic Form II of claim 31 , wherein the morphic Form II has a purity of at least 98%.
39 . The morphic Form II of claim 31 , wherein the morphic Form II has a purity of at least 98.5%.
40 . The morphic Form II of claim 31 , wherein the morphic Form II is characterized by a D50 value from about 81.603 μm to about 101.748 μm.
41 . The morphic Form II of claim 31 , wherein the morphic Form II is characterized by a D50 value of about 101.748 μm.
42 . A pharmaceutical composition comprising morphic Form II of phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl) ethoxy]methyl]mono[3-(hexadecyloxy)propyl] ester, wherein the morphic Form II is characterized by an X-ray diffraction pattern that lacks prominent peaks at about 12.6 and at about 15.6 degrees 2θ, and a pharmaceutically acceptable carrier.
43 . The pharmaceutical composition of claim 42 , wherein the composition is intended for intravenous administration.
44 . The pharmaceutical composition of claim 42 , wherein the composition comprises water.
45 . The pharmaceutical composition of claim 42 , wherein the morphic Form II is characterized by an X-ray diffraction pattern with prominent peaks at about 2.81 and about 5.63 degrees 2θ.
46 . The pharmaceutical composition of claim 42 , wherein the morphic Form II is characterized by an X-ray diffraction pattern with peaks expressed in degrees 2θ (±0.2) at 2.81, 5.63, 19.00, 19.57, 22.76, and 24.70.
47 . The pharmaceutical composition of claim 42 , wherein the morphic Form II is characterized by a scanning electron microscopy image showing agglomerates with sizes from about 200 μm to about 500 μm.
48 . The pharmaceutical composition of claim 42 , wherein the morphic Form II has a purity of at least 91%.
49 . The pharmaceutical composition of claim 42 , wherein the morphic Form II has a purity of at least 98%.
50 . The pharmaceutical composition of claim 42 , wherein the morphic Form II has a purity of at least 98.5%.