Crystalline forms of valacyclovir hydrochloride

Abstract

Provided are novel polymorphs and pseudopolymorphs of valacyclovir hydrochloride and pharmaceutical compositions containing these. Also provided are methods for making the novel polymorphs and pseudopolymorphs, which include valacyclovir hydrochloride monohydrate and valacyclovir hydrochloride dihydrate.

1 . Valacyclovir hydrochloride form I.  
     
     
         2 . Valacyclovir hydrochloride form I of  claim 1  characterized by x-ray diffraction reflections at about 3.7°, 8.6°, 10.6°, 10.9°, 16.5°, 24.0° and 27.2°±0.2° 2θ.  
     
     
         3 . Valacyclovir hydrochloride form I of  claim 2  further characterized by x-ray diffreaction reflections at about 9.5°, 10.9°, 20.1°, 21.4°, and 26.7°±0.2° 2θ.  
     
     
         4 . Valacyclovir hydrochloride form I of  claim 2  further characterized as having a weight loss of between about 6% and about 9% as measured by thermogravimetric analysis over the temperature range between about 25° C. and about 125° C.  
     
     
         5 . Valacyclovir hydrochloride in form I of  claim 1  characterized by the x-ray diffraction pattern substantially as shown in  FIG. 1 .  
     
     
         6 . (canceled)  
     
     
         7 . Valacyclovir hydrochloride form II.  
     
     
         8 . Valacyclovir hydrochloride form II of  claim 7  characterized by x-ray diffraction reflections at about 6.6°, 19.0°, 21.5°, 27.4°, and 28.5°±0.2° 2θ.  
     
     
         9 . Valacyclovir hydrochloride form II of  claim 8  further characterized by x-ray diffraction reflections at about 9.2°, 15.6°, and 26.3°±0.2° 2θ.  
     
     
         10 . Valacyclovir hydrochloride in form II of  claim 8  further characterized as having an endothermic peak at about 214° C. by differential thermal analysis.  
     
     
         11 . Valacyclovir hydrochloride form II of  claim 7  characterized by the x-ray diffraction pattern substantially as shown in  FIG. 3 .  
     
     
         12 . Valacyclovir hydrochloride form IV.  
     
     
         13 . Valacyclovir hydrochloride form IV of  claim 12  characterized by the x-ray diffraction pattern substantially as shown in  FIG. 6 .  
     
     
         14 . Valacyclovir hydrochloride form IV of  claim 12  characterized by x-ray diffraction reflections at about 3.6°, 10.7°, 15.1°, 26.9°, and 28.1°±0.2° 2θ.  
     
     
         15 . Valacyclovir hydrochloride in form IV of  claim 14  further characterized by x-ray diffraction reflections at about 7.2°, 8.6°, 9.5°, 13.3°, 15.2°, 27.3°, and 28.1°±0.2° 2θ.  
     
     
         16 . Valacyclovir hydrochloride form IV of  claim 14  further characterized as having a water content between about 8% and about 11% as measured by thermogravimetric analysis over the temperature range between about 25° C. and about 130° C.  
     
     
         17 . Valacyclovir hydrochloride form V.  
     
     
         18 . Valacyclovir hydrochloride in form V of  claim 17  characterized by the x-ray diffraction pattern substantially as shown in  FIG. 7 .  
     
     
         19 . Valacyclovir hydrochloride in form V of  claim 17  characterized by x-ray diffraction reflections at about 6.7°, 15.7°, 16.2°, and 22.6°±0.2° 2θ.  
     
     
         20 . Valacyclovir hydrochloride in form V of  claim 19  further characterized by additional x-ray diffraction reflections at about 3.4°, 9.5°, 13.5°, 21.9°, 27.2°, and 28.6°±0.2° 2θ.  
     
     
         21 . Valacyclovir hydrochloride in form V of  claim 19  further characterized as having a weight loss of between abut 5% and about 7% as measured by thermogravimetric analysis over the temperature range between about 25° C. and about 130° C.  
     
     
         22 . Valacyclovir hydrochloride in form V of  claim 21  further characterized by a broad endothermic peak at about 95° C. and a sharp endothermic peak at about 180° C. in differential thermal analysis.  
     
     
         23 . Valacyclovir hydrochloride in form VI.  
     
     
         24 . Valacyclovir hydrochloride form VI of  claim 23  characterized by the x-ray diffraction pattern substantially as shown in  FIG. 9 .  
     
     
         25 . Valacyclovir hydrochloride in form VI of  claim 23  characterized by x-ray diffraction reflections at about 6.2°, 9.2°, 12.1°, 20.2° and 25.7°±0.2° 2θ.  
     
     
         26 . Valacyclovir hydrochloride in form VII.  
     
     
         27 . Valacyclovir hydrochloride form VII of  claim 26  characterized by x-ray diffraction reflections at about 3.5°, 10.3°, 13.6°, 26.2° and 28.1°±0.2° 2θ.  
     
     
         28 . The valacyclovir hydrochloride in form VII of  claim 26  characterized by the x-ray diffraction pattern substantially as shown in  FIG. 10 .  
     
     
         29 . A method of making valacyclovir hydrochloride form I comprising the step of slurrying valacyclovir hydrochloride in a slurry solvent selected from the group consisting of ethyl acetate, acetone, methyl ethyl ketone, dioxane, methylene chloride, t-butyl methyl ether, and tetrahydrofurane.  
     
     
         30 . The method of  claim 29  further comprising the steps of: 
 isolating valacyclovir hydrochloride in form I from the slurry and drying valacyclovir form I at a temperature between about 50° C. and about 70° C.    
     
     
         31 - 41 . (canceled)  
     
     
         42 . A method of making valacyclovir hydrochloride in form V comprising the step of mixing a solution of valacyclovir hydrochloride in water with a lower aliphatic alcohol.  
     
     
         43 . The method of  claim 42  wherein the lower aliphatic alcohol is iso-propanol.  
     
     
         44 - 51 . (canceled)  
     
     
         52 . A method of making valacyclovir hydrochloride in form I comprising the steps of dissolving valacyclovir hydrochloride in a solvent, and evaporating the solution at a reduced pressure.  
     
     
         53 . The method of  claim 52  wherein the solvent is a polar organic solvent having 4 or fewer carbon atoms.  
     
     
         54 . The method of  claim 53  wherein the polar organic solvent is an alcohol.  
     
     
         55 . The method of  claim 54  wherein the solvent is methanol.  
     
     
         56 . Valacyclovir hydrochloride monohydrate.  
     
     
         57 - 61 . (canceled)  
     
     
         62 . A pharmaceutical composition comprising at least one of valacyclovir hydrochloride in Forms I, II, IV, V, VI or VII.  
     
     
         63 . The pharmaceutical composition of  claim 53  further comprising at least one pharmaceutically acceptable excipient.  
     
     
         64 . (canceled)