US 2005O250845A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0250845 A1 Vermeersch et al. (43) Pub. Date: Nov. 10, 2005 (54) PSEUDOPOLYMORPHIC FORMS OF A HIV (86) PCT No.: PCT/EP03/50176 PROTEASE INHIBITOR (30) Foreign Application Priority Data (75) Inventors: Hans Wim Pieter Vermeersch, Gent (BE); Daniel Joseph Christiaan May 16, 2002 (EP)........................................ O2O76929.5 Thone, Beerse (BE); Luc Donne O O Marie-Louise Janssens, Malle (BE) Publication Classification Correspondence Address: (51) Int. Cl." ............................................ A61K 31/353 PHILIP S. JOHNSON (52) U.S. Cl. ............................................ 514/456; 549/396 JOHNSON & JOHNSON ONE JOHNSON & JOHNSON PLAZA NEW BRUNSWICK, NJ 08933-7003 (US) (57) ABSTRACT (73) Assignee: Tibotec Parmaceuticeals New pseudopolymorphic forms of (3R,3aS,6aR)-hexahy (21) Appl. No.: 10/514,352 drofuro2,3-blfuran-3-yl (1S,2R)-3-(4-aminophenyl)sul fonyl(isobutyl)amino-1-benzyl-2-hydroxypropylcarbam (22) PCT Fed: May 16, 2003 ate and processes for producing them are disclosed. Patent Application Publication Nov. 10, 2005 Sheet 1 of 18 US 2005/0250845 A1 E. i Patent Application Publication Nov. 10, 2005 Sheet 2 of 18 US 2005/0250845 A1 e Patent Application Publication Nov. 10, 2005 Sheet 3 of 18 US 2005/0250845 A1 Patent Application Publication Nov. 10, 2005 Sheet 4 of 18 US 2005/0250845 A1 92 NO C12S)-No S. C19 Se (Sb so woSC2 AS27 SN22 C23 Figure 4 Patent Application Publication Nov. 10, 2005 Sheet 5 of 18 US 2005/0250845 A1 -- 1800 1600 1400 1200 1000 800 soc wavenumbers (cm) Figure 5 - P1 : - P8'i P19 ... P25 ... --27 - P50 P68 - P69 ; - - P72 ... P81 600 wavenumbers (cm) Figure 6 Patent Application Publication Nov. 10, 2005 Sheet 6 of 18 US 2005/0250845 A1 0.30 0.20 0.15 0.10 | wavenumbers (cm) Figure 7 Patent Application Publication Nov. 10, 2005 Sheet 7 of 18 US 2005/0250845 A1 ss s i s S& S. s s Patent Application Publication Nov. 10, 2005 Sheet 8 of 18 US 2005/0250845 A1 Figure 9 100 50 4000 3000 2000 ico Wavenumber (cm-1) Figure 10 OO BO 70 6 O 4. 30 ' ' ' ' " ' zo: '' 1 40 3000 2000 000 Wavenumber (cm-1) Patent Application Publication Nov. 10, 2005 Sheet 9 of 18 US 2005/0250845 A1 s s ----.k ----. ... k - Y A. - - - - - - an as assis a st oist : Eig --------- ...i.d." missingings."Eifelot...t. HESHit iss". is is a po P. HEEEE it. EHESE ...s. k: Patent Application Publication Nov. 10, 2005 Sheet 10 of 18 US 2005/0250845 A1 H. wo w f as a on a ... f1-7-- a slag Lif 3. w oOoko. t os:nEE. O e-af f t l o . s. c ad c a r Patent Application Publication Nov. 10, 2005 Sheet 11 of 18 US 2005/0250845 A1 nun be as an as ss ea?ons - sma manup sa apooroones as sa as as so n - a se - wns a ty. ) i. was a 4 pa g 1.4----...-k---------- Patent Application Publication Nov. 10, 2005 Sheet 12 of 18 US 2005/0250845 A1 HELE hirlift it, ill HEB5KH r f Riis II.it. t tIt 11 HiFi.Hi. HHBHAHESH III 4. 1911 : sr. P. g. st Iser is lap in traitress...F. : -et-see...- :-...s:4:ll...: --- f; a ; E f : : s : R i s is , A R : . m a on a Patent Application Publication Nov. 10, 2005 Sheet 13 of 18 US 2005/0250845 A1 Figure 15 | | | | | | | |A| | | | HH EHSEEEIA-4'---- g S s 7. s 20 5 4. s as so 75 o 2s 5 175 2. 25 25 2S SD Temperature (C) sign Patent Application Publication Nov. 10, 2005 Sheet 14 of 18 US 2005/0250845 A1 Figure 17 1. g ar S. t S. fasidual SA S3 tour e Octing Residia: 2S3tti (185rig S.2 SA Time (nar) Figure 18 AdsorptionDesorption isotherm at 25C - I-25 a g 5 e - -e-Dried chor at a cy -o- first sector -2. 2D S. S. 8 9. f % Relative Humidity Patent Application Publication Nov. 10, 2005 Sheet 15 of 18 US 2005/0250845 A1 Figure 19 Adsorption/Oesorption isotherm at 25"C ar r1 . - - s A - - w - a hydratation test 2. s f A. r Rhiwat Figure 20 Adoption-Dorption totype III at 250 thout Oc --- First 8 aerodrun c t r Rav Hart Patent Application Publication Nov. 10, 2005 Sheet 16 of 18 US 2005/0250845 A1 Figure 21 SOO 4000 3000 2000 1000 Wavenumber (cm-1) O 3000 2000 1000 Wavenumber (cm-1) Patent Application Publication Nov. 10, 2005 Sheet 17 of 18 US 2005/0250845 A1 Figure 23 g 3. 3. t 1. 125 eno tip Temperate (C) Figure 24 1. sy 3. 95. g s 4. Temperature (C) Patent Application Publication Nov. 10, 2005 Sheet 18 of 18 US 2005/0250845 A1 Figure 25 Adsorption Oesorption isothem at 25°C 15 - -HD fied (boratic morfit Evenate s oil -- -...Eu. Ur brative humidity US 2005/0250845 A1 Nov. 10, 2005 PSEUDOPOLYMORPHC FORMS OF A HIV acceptable purity. There are established guidelines that PROTEASE INHIBITOR define the limits and qualification of impurities in new drug Substances produced by chemical Synthesis, i.e. actual and TECHNICAL FIELD potential impurities most likely to arise during the Synthesis, 0001. This invention relates to novel pseudopolymorphic purification, and Storage of the new drug Substance. Guide forms of (3R,3aS,6aR)-hexahydro-furo2,3-blfuran-3-yl(1S, lines are instituted for the amount of allowed degradation 2R)-3-(4-aminophenyl)sulfonyl(isobutyl)amino-1-ben products of the drug Substance, or reaction products of the Zyl-2-hydroxypropylcarbamate, a method for their prepara drug Substance with an excipient and/or immediate con tion as well as their use as a medicament. tainer/closure System. BACKGROUND OF THE INVENTION 0006 Stability is also a parameter considered in creating 0002 Virus-encoded proteases, which are essential for pharmaceutical formulations. A good Stability will ensure Viral replication, are required for the processing of viral that the desired chemical integrity of drug Substances is protein precursors. Interference with the processing of pro maintained during the shelf-life of the pharmaceutical for tein precursors inhibits the formation of infectious virions. mulation, which is the time frame over which a product can Accordingly, inhibitors of Viral proteases may be used to be relied upon to retain its quality characteristics when prevent or treat chronic and acute viral infections. (3R,3aS, Stored under expected or directed Storage conditions. During 6aR)-hexahydrofuro2,3-blfuran-3-yl(1S,2R)-3-(4-ami this period the drug may be administered with little or no nophenyl)sulfonyl(isobutyl)amino-1-benzyl-2-hydrox risk, as the presence of potentially dangerous degradation ypropylcarbamate has HIV protease inhibitory activity and products does not pose prejudicial consequences to the is particularly well suited for inhibiting HIV-1 and HIV-2 health of the receiver, nor the lower content of the active viruses. The structure of (3R,3aS,6aR)-hexahydrofuro 2,3- ingredient could cause under-medication. blfuran-3-yl(1S,2R)-3-(4-phenyl)sulfonyl(isobuty 0007 Different factors, such as light radiation, tempera l)amino-1-benzyl-2-hydroxypropylcarbamate, is shown ture, oxygen, humidity, pH Sensitivity in Solutions, may below: influence Stability and may determine shelf-life and Storage conditions. Formula (X) 0008 Bioavailability is also a parameter to consider in drug delivery design of pharmaceutically acceptable formu lations. Bioavailability is concerned with the quantity and rate at which the intact form of a particular drug appears in the Systemic circulation following administration of the drug. The bioavailability exhibited by a drug is thus of relevance in determining whether a therapeutically effective CH concentration is achieved at the site(s) of action of the drug. N N 0009 Physico-chemical factors and the pharmaco-tech OH en CH3 nical formulation can have repercussions in the bioavail ability of the drug. AS Such, Several properties of the drug Such as dissociation constant, dissolution rate, Solubility, polymorphic form, particle size, are to be considered when improving the bioavailability. 0010. It is also relevant to establish that the selected pharmaceutical formulation is capable of manufacture, more Suitably, of large-scale manufacture. 0003 Compound of formula (X) and processes for its 0011. In view of the various and many technical require preparation are disclosed in EP 715618, WO99/67417, U.S. ments, and its influencing parameters, it is not obvious to Pat. No. 6,248,775, and in Bioorganic and Chemistry Let foresee which pharmaceutical formulations will be accept ters, Vol. 8, pp. 687-690, 1998, “Potent HIV protease able. AS Such, it was unexpectedly found that certain modi inhibitors incorporating high-affinity P-igands and (R)- fications of the solid state of compound of formula (X) (hydroxyethylamino)sulfonamide isostere”, all of which are positively influenced its applicability in pharmaceutical for incorporated herein by reference. mulations. 0004 Drugs utilized in the preparation of pharmaceutical formulations for commercial use must meet certain Stan SUMMARY OF THE INVENTION dards, including GMP (Good Manufacturing Practices) and 0012 Present invention concerns pseudopolymorphic ICH (International Conference on Harmonization) guide forms of compound of formula (X) for the preparation of lines. Such standards include technical requirements that pharmaceutical formulations. Such pseudopolymorphic encompass a heterogeneous and wide range of physical, forms contribute to pharmaceutical formulations in chemical and pharmaceutical parameters. It is this variety of improved stability and bioavailability. They can be manu parameters to consider, which make pharmaceutical formu factured in Sufficient high purity to be acceptable for phar lations a complex technical discipline. maceutical use, more particularly in the manufacture of a 0005 For instance, and as example, a drug utilized for the medicament for inhibiting HIV protease activity in mam preparation of pharmaceutical formulations should meet an mals.