Squalamine solid forms and methods of making the same

Abstract

Provided herein are crystalline solid forms of squalamine phosphate designated as Form 1 and Form 2, compositions containing one or both forms, and methods of their preparation and of their use.

1 . An isolated solid form of squalamine phosphate designated as Form 1. 
     
     
         2 . The solid form of squalamine phosphate of  claim 1  having:
 (a) an X-ray powder diffraction pattern comprising peaks, in terms of 2-theta, at about 15.7° and at about 23.7°; 
 (b) an X-ray powder diffraction pattern comprising peaks, in terms of 2-theta, at about 11.7°, about 15.7°, about 19.7°, and about 23.7°; 
 (c) an X-ray powder diffraction pattern substantially as shown in  FIG. 8 ; 
 (d) a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 96.6° C.; 
 (e) a differential scanning calorimetry (DSC) thermogram substantially as shown in  FIG. 9 ; and/or 
 (f) a thermogravimetric analysis (TGA) substantially as shown in  FIG. 10 . 
 
     
     
         3 . The squalamine phosphate solid form of  claim 1 , which is substantially purified. 
     
     
         4 . The squalamine phosphate solid form of  claim 1 , which:
 (a) has a water content of less than about 8%; or   (b) has a water content of about 6-8%.   
     
     
         5 . The squalamine phosphate solid form of  claim 1 , in a crystalline form, characterized by an X-ray powder diffraction pattern comprising the following peaks: about 15.7° 2-theta and about 23.7° 2-theta, as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.5406 Å. 
     
     
         6 .- 10 . (canceled) 
     
     
         11 . A pharmaceutical composition comprising the solid form of squalamine phosphate designated as Form 1 according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         12 . The pharmaceutical composition of  claim 11 , comprising at least about 90% by weight of the solid form of squalamine phosphate designated as Form 1. 
     
     
         13 .- 15 . (canceled) 
     
     
         16 . A method of treating a subject in need in need having a condition susceptible to treatment with an aminosterol, wherein the method comprises administering a therapeutically effective amount of:
 (a) a pharmaceutical composition comprising a solid form of squalamine phosphate designated as Form 1;   (b) a pharmaceutical composition comprising a solid form of squalamine phosphate designated as Form 2; or   (c) a pharmaceutical composition comprising a combination of a solid form of squalamine phosphate designated as Form 1 and a solid form of squalamine phosphate designated as Form 2.   
     
     
         17 . The method of  claim 16 , wherein the subject in need has a condition selected from the group consisting of viral infections, neurological disorders, gastrointestinal disorders, antimicrobial infections, Gram-negative bacterial infections, Gram-positive bacterial infections, Mycobacteria infections, fungal infections, protozoan infections, vascular disorders of the eye, including macular degeneration, retinopathy of prematurity, corneal neovascularization, diabetic retinopathy, weight loss or weight management, diseases where sodium-hydrogen exchanger (“NHE-3”) plays a critical role, treatment of fibrodysplasia ossificans progressiva, and neovascularization disorders. 
     
     
         18 . The method of  claim 17  wherein:
 (a) the viral infection is caused by a virus selected from the group consisting of Yellow Fever, Cytomegalovirus, Eastern Equine Encephalitis virus, Hepatitis B virus, Hepatitis Delta virus, Dengue virus, and Human Immunodeficiency virus; or 
 (b) the viral infection is caused by a virus selected from the group consisting of “African Swine Fever Viruses,” Arbovirus, Adenoviridae, Arenaviridae, Arterivirus, Astroviridae, Baculoviridae, Bimaviridae, Birnaviridae, Bunyaviridae, Caliciviridae, Caulimoviridae, Circoviridae, Coronaviridae, Cystoviridae, Dengue, EBV, HIV, Deltaviridae, Filviridae, Filoviridae, Flaviviridae, Hepadnaviridae (Hepatitis), Herpesviridae (such as, Cytomegalovirus, Herpes Simplex, Herpes Zoster), Iridoviridae, Mononegavirus (e.g., Paramyxoviridae, Morbillivirus, Rhabdoviridae), Myoviridae, Orthomyxoviridae (e.g., Influenza A, Influenza B, and parainfluenza), Papiloma virus, Papovaviridae, Paramyxoviridae, Prions, Parvoviridae, Phycodnaviridae, Picomaviridae (e.g., Rhinovirus, Poliovirus), Poxviridae (such as Smallpox or Vaccinia), Potyviridae, Reoviridae (e.g., Rotavirus), Retroviridae (HTLV-I, HTLV-II, Lentivirus), Rhabdoviridae, Tectiviridae, Togaviridae (e.g., Rubivirus), herpes, pox, papilloma, corona, influenza, hepatitis, sendai, sindbis, vaccinia viruses, west nile, hanta, viruses which cause the common cold, and any combination thereof. 
 
     
     
         19 . The method of  claim 16 , wherein the condition is selected from the group consisting of AIDS, viral meningitis, Dengue, EBV, hepatitis, a chronic disease suspected to be of viral origin, multiple sclerosis, Type I diabetes, Type II diabetes, atherosclerosis, cardiomyopathies, Kawaski disease, aplastic anemia, and any combination thereof. 
     
     
         20 . The method of  claim 16 , wherein the condition is a neurological disorder selected from the group consisting of Parkinson's disease, autism, multiple system atrophy, depression, Alzheimer's disease, Huntington's Disease, schizophrenia, multiple sclerosis, and degenerative processes associated with aging, autonomic system instability, circadian rhythm disruption, delays in sleep onset, fragmentation of sleep, reduced REM sleep, reduced total sleep time, REM-behavior disorder, sleep breathing disorder including snoring and sleep apnea, hallucinations, narcolepsy, and day-time sleepiness. 
     
     
         21 . The method of  claim 16 , wherein the condition is a gastrointestinal disorder selected from the group consisting of constipation, inflammatory bowel disease, and irritable bowel syndrome. 
     
     
         22 . The method of  claim 16 , wherein the method further comprising administering an additional active agent to the subject, wherein the additional active agent is administered via a method selected from the group consisting of
 (a) concomitantly;   (b) as an admixture;   (c) separately and simultaneously or concurrently; or   (d) separately and sequentially.   
     
     
         23 . The method of  claim 16 , wherein the subject is human. 
     
     
         24 . A process for preparing the squalamine phosphate solid form of  claim 1 , the process comprising:
 (a) combining a solution of squalamine lactate with an aqueous solution of sodium phosphate dibasic and sodium phosphate monobasic to form a combined mixture;   (b) heating the combined mixture before allowing the combined mixture to cool; and   (c) isolating the combined mixture to isolate the squalamine phosphate solid form.   
     
     
         25 . The process of  claim 24 , comprising one or more of the following:
 (a) the combining step is performed at a temperature of about 55° C. to about 70° C.;   (b) the combining step is performed at 60±5° C.;   (c) the solution of squalamine lactate is a methanol solution of squalamine lactate;   (d) the heating step is performed at 70±5° C.;   (e) the process further comprising stirring the combined mixture after cooling but before the isolating step; and/or   (f) the isolating step comprises filtering the combined mixture and washing filtered solids with acetone.   
     
     
         26 . A solid form of squalamine phosphate designated as Form I prepared by the process of  claim 24 . 
     
     
         27 .- 29 . (canceled)