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(12) Patent Application Publication (10) Pub. No.: US 2005/0181041 A1 Goldman (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2005/0181041 A1 Goldman (43) Pub US 2005O181041A1 (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 U.S. Application Data PHASE CO-CRYSTALS WITH ACTIVE AGENTS (60) Provisional application No. 60/528,232, filed on Dec. 9, 2003. Provisional application No. 60/559,862, filed (75) Inventor: David Goldman, Portland, CT (US) on Apr. 6, 2004. Correspondence Address: Publication Classification LEYDIG VOIT & MAYER, LTD (51) Int. Cl." ......................... A61K 31156; A61K 38/00; TWO PRUDENTIAL PLAZA, SUITE 4900 A61K 9/64 180 NORTH STETSON AVENUE (52) U.S. Cl. .............................. 424/456; 514/179; 514/2; CHICAGO, IL 60601-6780 (US) 514/221 (73) Assignee: MedCrystallForms, LLC, Hunt Valley, ABSTRACT MD (57) 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 modification 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 of 8 US 2005/0181041 A1 FIG. 1 a -0. 2 214.7OC 206.98°C 142.0J/g - O 40 90 140 190 240 290 Temperture (C) 0.0 FIG 1b. area 53.76°C 0.2 50.75°C 51.18J/g 2O2.23°C 194.19C 35 85 135 185 235 285 Temperture (C) Patent Application Publication Aug. 18, 2005 Sheet 2 of 8 US 2005/0181041 A1 S. 3 ls CN as Yea s s D H CN Cd N w Cd r - --- c Cd o C d ad as N w v- v (Sunoo)/AISueu x Patent Application Publication Aug. 18, 2005 Sheet 3 of 8 US 2005/0181041 A1 gs S OQf o 9 d Cd s ver (SunOO)/AISuelu Patent Application Publication Aug. 18, 2005 Sheet 4 of 8 US 2005/0181041 A1 Cd r g S. S 2 2 o s o (SunOO)/AISueu Patent Application Publication Aug. 18, 2005 Sheet 5 of 8 US 2005/0181041 A1 r w g d l t N N es es wa Xe s w- sh Cld C cN CN es s N w CY) cyd d so "" d go go is as a d - o - c to wr8 3 in 3 SVr 3 3 5 S 3 & (SunOO)/AISueu (SunOO)/AISueu Patent Application Publication Aug. 18, 2005 Sheet 6 of 8 US 2005/0181041 A1 g {d 3 d s as SS SS a O3 CNO C3 OC 9 O O o d Nc5 2.D S. 9of O O C O S C O C. C/O - O a O v th} { ?o 9 s s .S. S se CD CDE - H O N KV) S. o N O vs. CN v- d Patent Application Publication Aug. 18, 2005 Sheet 7 of 8 US 2005/0181041 A1 CC ve n w n | O d CN d val as f CD w s . LO e 5 g CD H Cd d O O d C O O Cd C d o o d Cd O v c CN v (u/6n) ouOO Patent Application Publication Aug. 18, 2005 Sheet 8 of 8 US 2005/0181041 A1 00|| OZ penOSSIO % 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 benefit of U.S. is illustrated by the preparation of co-crystallized Sugars Provisional Patent Application No. 60/559,862, filed Apr. 6, (U.S. Pat. Nos. 4,101,680 and 4,338,339), of acetylenic 2004 and U.S. Provisional Patent Application No. 60/528, compounds (U.S. Pat. No. 4,384,980), and Sugar alcohols 232, filed Dec. 9, 2003, which are incorporated by reference (U.S. 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 0002 This invention pertains to methods of preparing an physico-chemical properties. 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 U.S. Pat. co-crystals. The formulated mixed phase co-crystals are Nos. 6,376,481, and 6,267.963 (sterol esters); U.S. Pat. No. heterogenous and contain crystalline regions within the 6.214,402 (dilution of sweetener); U.S. Pat. No. 4,751,294 particles/granules produced. Mixed phase co-crystals are (stabilization by a base); U.S. Pat. No. 5,910,523 (nanocom useful for Systemic delivery of the active agent as human and posites); U.S. Pat. No. 5,876,506 (mesomorphic Sugar), U.S. 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 U.S. 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 0.003 Co-crystals occur in nature and form spontane by melt/congealing process are described in U.S. Pat. Nos. ously with closely related chemical Structures, Such as 6,267.963 (sterol-emulsion complexes); U.S. 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 U.S. 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 U.S. is described in U.S. Pat. No. 4,145,214 (photoconductors); Pat. Nos. 4,971,797; 6,312,723 and 6,312,712, complexes of U.S. 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 U.S. Pat. Nos. 4,145,214 and 4,384,980. These the flexibility 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 and biopolymers) are capable of forming co-crystals with Solubility, dissolution, and absorption. other macromolecules. These co-crystallized products have 0009. In the field 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 Crystallogr D Biol Crys release rates. New and improved methods to solve the tallog, 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. 0005 Minor amounts of materials can be incorporated in These and other advantages of the invention, as well as a particle Sub-structure. These components co-exist with additional inventive features, will be apparent from the crystalline phases of the particle and produce co-crystalline description of the invention provided herein. regions within the particle. The resulting co-crystallized material has a high level of crystallinity and lacks significant BRIEF SUMMARY OF THE INVENTION 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 first Sweetening agents in Sugar carriers as in U.S. Pat. NoS. Solution of a first active agent and at least one crystal lattice 6,214,402 and 6,365,216. Incorporation of Small amounts of modifier dissolved in a Solvent; (b) mixing an anti-Solvent Single constituents differs from mixed phase co-crystals with the first Solution to form a second Solution; and (c) Since the particles produced do not have a significant amount forming a mixed phase crystalline material, wherein the of amorphous phase as indicated by melting properties and active agent and crystal lattice modifier are contained within Solubility.
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