<12) United States Patent <16 Patent N0.: US 6,849,736 B2 Wizel et al. (45) Date of Patent: Feb. 1, 2005 (54) CRYSTALLINE FORMS OF VALACYCLOVIR 4,957,924 A * 9/1990 Beauchamp .............. .. 544/276 222282: 181222 “I 2:24:22 , , zeno et a (75) Inventors: Shlomit Wizel, Petah Tiqva (IL); 2 : I]aIeSI0fr@/Ital-1 Judith Aronhime, Rehovot (IL); ’ ’ 7°“ ° 2' 2.1.5/z1"!£2i2Ii 253882 ssmsi. 222822 Even-Yeouda (IL); Ben-Zion Dolitzky, g ' """""" " Petach Tiqva (IL); Marina Yu Etinger, FOREIGN PATENT DOCUMENTS N°Sl_1°r (IL); M'°ha°.l Y“Z.ef°V'°h.’ Halfa wo wo 9725989 A1 * 7/1997 ........ .. A61K/31/52 (ILL Gennady A‘ N‘s“°"‘°h> Halfa wo wo 9727194 A1 * 7/1997 ....... .. C07D/473/00 (IL); Boris I’e1‘I$Ik°"> Neshef (IL); wo wo 9803553 A1 * 1/1998 ....... .. C07D/473/00 Boris Tishin, Haifa (IL); Dina Blasberger, Raanana (IL) QTIIER PUBLICATIONS (73) Aaaiaaaai Tava Pharmaaaatiaai Iadaatriaa Ltd‘, Goodman & Gilman’s, Tl1€rhPl121I'II121COlOg1C21lB21S1S of Thera. peutics, pp. 1193-1198 (9 ed. 1996). Petah Tlqva (IL) G.M. Wall, “Pharmaceutical Applications of Drug Crystal ( ,. ) Notice: Sub]-act to any disclaimer, the term or this Studies,” Pharmaceutical Manufacturing, vol. 3, No. 2, Feb. patent is extended or adjusted under 35 _I9I‘?I?i1e1)>I1iafi32m1:12W McCrone “PharmaceuticalA lications U'S'C' 154(b) by 0 dayS' of Polymorphism ” Journal of Pharmaceutical Scilz-ices vol 58, N6. 8, Aug. 1969, pp. 911-929. ’ (21) App1' NO‘: 10/239729 J .K. Haleblian, “Characterization of Habits and Crystalline (22) Fried; Sop_ 6, 2002 Modification of Solids and Their Pharmaceutical Applications,” Journal of Pharmaceutical Sciences, vol. 64, No. 8, (65) Prior Publication Data Aug 1975, Po 12o9_1233_ Us 2003/0114470 A1 Jim 197 2003 Pharmacopeial Forum, vol. 24, No. 1, (Jan.-Feb. 1998) p. 5438-5440. Related U.S. Application Data 4 Cited by examiner (60) Provisional application No. 60/317,850, filed on Sep. 7, _ _ 2001, provisional application No. 60/342,273, filed on Dec. Primary EXflmln€V—M3fI< L- B@fCh 21, 2001, pIOViSiOH8.l 8.ppliC8.[iOl1 NO. 60/386,505, filéd on Affgr}/[ex Or Firm_K@nyQn & Kenygn Jun. 5, 2002, and provisional application No. 60/403,838, filed on Aug. 14, 2002. (57) ABSTRACT (51) Int. Cl.7 ................... .. C07D 473/18; A61K 31/522 provided are novel polymorphs and Psoudopoiyrnorphs of (52) U.S. Cl. ..................................................... .. 544/276 valacyclovir hydrochloride and pharmaceutical oomr,oSi_ (58) Field of Search .................... .. 544/276; 514/263.38 tions containing these. Also provided are methods for mak_ ing the novel polymorphs and pseudopolymorphs, which (56) References Clted include valacyclovir hydrochloride monohydrate and vala
U.S. PATENT DOCUMENTS 4,199,574 A 4/1980 Schaeffer
cyclovir hydrochloride dihydrate.
26 Claims, 10 Drawing Sheets
