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(19) United States (12) Patent Application Publication (10) Pub US 20050181041A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0181041 A1 Goldman (43) Pub. Date: Aug. 18, 2005 (54) METHOD OF PREPARATION OF MIXED Related US. Application Data PHASE CO-CRYSTALS WITH ACTIVE AGENTS (60) Provisional application No. 60/528,232, ?led on Dec. 9, 2003. Provisional application No. 60/559,862, ?led (75) Inventor: David Goldman, Portland, CT (US) on Apr. 6, 2004. Correspondence Address: Publication Classi?cation LEYDIG VOIT & MAYER, LTD (51) Int. Cl.7 ....................... .. A61K 31/56; A61K 38/00; TWO PRUDENTIAL PLAZA, SUITE 4900 A61K 9/64 180 NORTH STETSON AVENUE (52) US. Cl. ............................ .. 424/456; 514/179; 514/2; CHICAGO, IL 60601-6780 (US) 514/221 (73) Assignee: MedCrystalForms, LLC, Hunt Valley, (57) ABSTRACT MD This invention pertains to a method of preparing mixed phase co-crystals of active agents With one or more materials (21) Appl. No.: 11/008,034 that alloWs the modi?cation of the active agent to a neW physical/crystal form With unique properties useful for the delivery of the active agent, as Well as compositions com (22) Filed: Dec. 9, 2004 prising the mixed phase co-crystals. Patent Application Publication Aug. 18, 2005 Sheet 1 0f 8 US 2005/0181041 A1 FIG. 1a 214.70°C z.m."m.n... 206.98°C n..0ao 142 OJ/g as:20m=3: -0.8 -1.0 40 90 1:10 2110 Temperture (°C) FIG. 1b 0.01 as:22“.Km: 217 095 24221.4 39Jmum/Q -0.8 35 155 255 255 Temperture (°C) Patent Application Publication Aug. 18, 2005 Sheet 2 0f 8 US 2005/0181041 A1 Patent Application Publication Aug. 18, 2005 Sheet 3 0f 8 US 2005/0181041 A1 FIG.2b 20252-Theta(°) Q 05 150 o 20.0~ .. (SIUHOOMHSUBWI X10"3 Patent Application Publication Aug. 18, 2005 Sheet 4 0f 8 US 2005/0181041 A1 ,0 v FIG.20 252-Theta(°) 2'0 20.0 150 5.0 (SIUHOOMMSUGIUI x10"3 Patent Application Publication Aug. 18, 2005 Sheet 5 0f 8 US 2005/0181041 A1 4'0 40 3'5 35 30 30 25 25 2-Theta(°) 2-Theta(°) 1'01'5'i 020 "01o1520 FIG3aI FIG.3b Q O O0 00 00 O 5I o. 5. 500 500 3500 n 1000 5000 4500 §§§§§§§ Patent Application Publication Aug. 18, 2005 Sheet 6 0f 8 US 2005/0181041 A1 96 <1LFI 9 ~52 ——E—SucroseEsterMethE4M +50%Phospholipon ——A——25%Phospholipon —e—Control 4 FIG.4 Time(minutes) Patent Application Publication Aug. 18, 2005 Sheet 7 0f 8 US 2005/0181041 A1 IT(Kb: |I|93E M.£63|<| £9;illI ixi6E8 353|o| @wm?'T @EElit 813III _ omoorom?cow __ 3235:;9:2. codI oo.m cod Patent Application Publication Aug. 18, 2005 Sheet 8 0f 8 US 2005/0181041 A1 ovw $935.5mEc. I ow cm oq PGAIOSSK] 0/0 US 2005/0181041 A1 Aug. 18, 2005 METHOD OF PREPARATION OF MIXED PHASE active agent, lack the high concentrations that the mixed CO-CRYSTALS WITH ACTIVE AGENTS phase co-crystals enable, and lack the multi-functional aspects that mixed phase co-crystals offer With respect to CROSS-REFERENCE TO RELATED PATENT improved drug delivery. APPLICATIONS [0006] Co-crystalliZation of chemically related materials [0001] This patent application claims the bene?t of US. is illustrated by the preparation of co-crystalliZed sugars Provisional Patent Application No. 60/559,862, ?led Apr. 6, (US. Pat. Nos. 4,101,680 and 4,338,339), of acetylenic 2004 and US. Provisional Patent Application No. 60/528, compounds (US. Pat. No. 4,384,980), and sugar alcohols 232, ?led Dec. 9, 2003, Which are incorporated by reference (US. Pat. Nos. 5,679,398; 5,958,471 and 6,083,438). The herein. simple co-crystals therein described do not have the broad utility that mixed phase co-crystals have for the enhance FIELD OF THE INVENTION ment of properties of Widely different structures and physico-chemical properties. [0002] This invention pertains to methods of preparing an active agent as mixed phase co-crystals that have unique [0007] Incorporation of minor components by a process physical properties that differ from the active agent in pure described as ‘co-crystallization’ that yields a product of form, as Well as compositions comprising mixed phase indeterminate crystalline structure is illustrated by US. Pat. co-crystals. The formulated mixed phase co-crystals are Nos. 6,376,481, and 6,267,963 (sterol esters); US. Pat. No. heterogenous and contain crystalline regions Within the 6,214,402 (dilution of sWeetener); US. Pat. No. 4,751,294 particles/granules produced. Mixed phase co-crystals are (stabiliZation by a base); US. Pat. No. 5,910,523 (nanocom useful for systemic delivery of the active agent as human and posites); US. Pat. No. 5,876,506 (mesomorphic sugar), US. animal pharmaceuticals, dietary supplements, and agro Pat. No. 5,075,291 (uniform dispersion of drug in sugar chemicals. Furthermore, mixed phase co-crystals have util alcohol); and US. Pat. No. 5,451,416. These materials of ity in imparting desirable physical and stability properties indeterminate structure lack the ability of mixed phase otherWise not achievable for the pure active agent or in co-crystals to maintain primary crystalline characteristics of combination as a simple formulation With the materials the active agent While imparting amorphous-like properties incorporated With the active agent. along With designed functionalities to enhance solubility, dissolution, and absorption. BACKGROUND OF THE INVENTION [0008] Complex mixtures of crystalline materials formed [0003] Co-crystals occur in nature and form spontane by melt/congealing process are described in US. Pat. Nos. ously With closely related chemical structures, such as 6,267,963 (sterol-emulsion complexes); US. Pat. Nos. chemical isomers (racemates, diasteriomers, and the like). 4,855,326 and 5,853,762 (rapidly dissolving dosage unit); Co-crystals are also found for materials that complex and US. Pat. No. 5,075,291. The process for preparing together in solution such as protein-ligands, chelates, inclu co-crystals by evaporation or cooling from a solvent system sion complexes as With cyclodextrins, and ligands. In US. is described in US. Pat. No. 4,145,214 (photoconductors); Pat. Nos. 4,971,797; 6,312,723 and 6,312,712, complexes of US. Pat. Nos. 4,751,294; 4,971,797; and 6,214,402. Appli cyclodextrin and active agents are described as being co cations for Which no active agent is incorporated are crystalliZed together from solution. These complexes lack described in US. Pat. Nos. 4,145,214 and 4,384,980. These the ?exibility to incorporate materials With broadly different materials of indeterminate structure lack the ability of mixed chemical structures and lack the multi-functional properties phase co-crystals to maintain primary crystalline character that mixed co-crystals can impart. istics of the active agent While imparting amorphous-like properties along With designed functionalities to enhance [0004] In certain cases, macromolecules (both polymers solubility, dissolution, and absorption. and biopolymers) are capable of forming co-crystals With other macromolecules. These co-crystalliZed products have [0009] In the ?eld of active agent delivery, inherent prob been used to isolate macromolecules such as proteins for lems associated With the active agent exist, such as particle structural characteriZation. An example of this is found in siZe, stability, solubility, poWder physical properties and the paper by Murphy et al. (Acta CrystallogrD Biol Crys release rates. NeW and improved methods to solve the tallogr; 55(Pt 9), 1594-1597 (1999)). These simple co problems associated With active agent delivery are needed. crystals are not useful to enhance solubility, dissolution or The invention provides such a method, as Well as mixed absorption of poorly absorbed active agents. phase co-crystal compositions comprising an active agent. These and other advantages of the invention, as Well as [0005] Minor amounts of materials can be incorporated in additional inventive features, Will be apparent from the a particle sub-structure. These components co-exist With description of the invention provided herein. crystalline phases of the particle and produce co-crystalline regions Within the particle. The resulting co-crystalliZed BRIEF SUMMARY OF THE INVENTION material has a high level of crystallinity and lacks signi?cant amounts of amorphous phase. Examples of these applica [0010] The invention is directed to a method of preparing tions can be found in patents describing the dilution of mixed phase co-crystals comprising: (a) forming a ?rst sWeetening agents in sugar carriers as in US. Pat. Nos. solution of a ?rst active agent and at least one crystal lattice 6,214,402 and 6,365,216. Incorporation of small amounts of modi?er dissolved in a solvent; (b) mixing an anti-solvent single constituents differs from mixed phase co-crystals With the ?rst solution to form a second solution; and (c) since the particles produced do not have a signi?cant amount forming a mixed phase crystalline material, Wherein the of amorphous phase as indicated by melting properties and active agent and crystal lattice modi?er are contained Within solubility. In addition, these materials do not contain an the mixed phase crystalline material. US 2005/0181041 A1 Aug. 18, 2005 [0011] The invention also is directed to a mixed phase monotropic co-crystal materials. The enhanced properties of co-crystal composition comprising a mixed phase co-crystal the mixed phase co-crystal materials are obtained even When of an active agent and at least one crystal lattice modi?er, the thermodynamically favored polymorph of the active Wherein the content of the active agent ranges from about agent is present as a component of the mixed phase co 5% to 95% by Weight of the total Weight of the material, and crystal structure.
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