Crystal patents

Co-crystals, as a class of compounds, represent compositions of matter which are within the statutory classes of patentable subject matter. Most countries also allow claims for methods of making a co-crystal and often methods of using them, as well as pharmaceutical compositions containing them. The basis for this patentability is that a new co-crystal is a new composition of matter between an API and a co-former(s) with a unique binding interaction between them. The crystalline nature of the co-crystal composition may, and in most countries does, add to co-crystal patentability. 

Co-crystal patents usually contain experimental examples that describe the preparation of the co-crystal and the characterization of the co-crystal. Characterization of the co-crystal describes the co-crystal itself and its various properties which include its sohd state characteristics and stoichiometry. Typically, the sohd state characteristics of a crystalline solid are shown by one or more of the foUowing analytical techniques X-ray powder diffraction pCRPD), single crystal X-ray diffraction (SCXD), Raman spectroscopy, infrared (IR) spectroscopy, sohd state nuclear magnetic resonance spectroscopy (SSNMR), and differential scanning calorimetry (DSC). The stoichiometry of a co-crystal may be estabhshed through solution techniques such as comparison of peak integrations in a solution NMR spectrum, data... 

Co-crystal patents, then, describe and disclose a co-crystal as a new composition of matter. Similar to the traditional composition of matter patents, they establish the existence and identity of the co-crystal. Because of a cocrystal s unique bonding interaction between the API and co-former(s), a cocrystal patent takes as prior art its constituent parts and establishes those by comparison. The properties and advantages of the co-crystal and the arguments for its patentability are also made in comparison with the API and its properties. It is from these comparisons that effective co-crystal patents are constructed. 

This chapter has merely surveyed some ways in which co-crystals may translate into new patents and commercial value and has discussed some considerations for accomplishing this. It is clear that the success of co-crystals in commercialization and as new patents is tied to their unique chemical composition, crystalline structure, and properties. Engineering pharmaceutical properties using co-crystals can create new commercial value for an API and extend its patent life. This value comes from the composition of the co-crystal as well as from its crystalline form. Patenting co-crystals captures that value in the form of intellectual property. Yet, co-crystal patents have their own unique aspects to be addressed as can be seen from the discussion of the definition of cocrystal , the patentability of co-crystals, and the information needed for... 

This assumes that the API and co-former are known compounds prior to filing of the co-crystal patent application. 

JB Harris, CN Keulemans, LA Milton, EJG Roest. Dry fractionation process for separation of polymorphic fats and oils as stable crystals. Patent WO 9605279,1996. RW Hartel, L Baomin, S Yuping. Continuous crystalhsation system with controlled nucleation for milk fat fractionation. Patent Appl WO 9851753 [US 46166 (19970512)], 1998. 

Fergason J L 1984 Encapsulated liquid crystal and method US Patent 4 435 047... 

A higher density sol—gel abrasive, produced by the introduction of seed crystaUites formed by wet-milling with high alumina media or by introduction of submicrometer a-alumina particles, was patented (28) and designated Norton SG. The microstmcture of this abrasive consists of submicrometer a-alumina crystals (Fig. 1) and its bulk density approaches that of fused alumina. Norton SG has proven to be an exceptional performer in coated and bonded abrasive products it was awarded the 1989 ASM Engineering Materials Achievement Award (29). 

Several recent patents describe improvements in the basic belt process. In one case a higher soHds polymerization is achieved by cooling the starting monomer until some monomer crystallizes and then introducing the resulting monomer slurry onto the belt as above. The latent heat of fusion of the monomer crystals absorbs some of the heat of polymerization, which otherwise limits the soHds content of the polymerization (87). In another patent a concave belt is described which becomes flat near the end. This change leads to improved release of polymer (88). 

Liquid Crystals. Based on worldwide patent activity, numerous compounds containing fluoroaromatic moieties have been synthesized for incorporation into liquid crystals. For example, fluoroaromatics are incorporated in ZLI-4792 and ZLI-4801-000/-100 for active matrix displays (AMD) containing super fluorinated materials (SFM) (186,187). Representative stmctures are as follows. 

Fluorinated biphenyls have been incorporated into numerous Hquid crystal stmctures as attested by patents and pubHcations from the following organizations E. Merck GmbH (257,258) Sharp (258) Hoffmann-LaRoche (259) Kanto Chemical (260) U.K. Defence Secretariat (261) Dainippon (262) Chisso (263) Sanyo Chemical (264) and the University of Hull (265). Seiko Epson has also patented fluorinated terphenyls for Hquid crystal appHcations (266). 

It should be possible to form linear noncross-linked polymers of melamine—formaldehyde or phenol—formaldehyde by reaction of one mole of the patent with one mole of formaldehyde, but this is generally not the case. The melamine crystal itself is very insoluble in water and only becomes soluble as the formaldehyde molecules add on. If much less than 1.5 moles of formaldehyde pet mole of melamine ate used, the aqueous resin solution is very unstable. 

Naphthalenol. 2-Naphthol or p-naphthol or 2-hydroxynaphthalene/7i3 -/5 -i7 melts at 122°C and boils at 295°C, and forms colorless crystals of characteristic, phenoHc odor which darken on exposure to air or light. 2-Naphthol [135-19-3] is manufactured by fusion of sodium 2-naphthalenesulfonate with sodium hydroxide at ca 325°C, acidification of the drowned fusion mass which is quenched ia water, isolation and water-washing of the 2-naphthalenol, and vacuum distillation and flaking of the product. A continuous process of this type has been patented (69). The high sulfate content ia the primary effluent from 2-naphthol production is greatiy reduced ia modem production plants by the recovery of sodium sulfate. 

There are two commercial solvent crystaUi2ation processes. The Emersol Process, patented in 1942 by Emery Industries, uses methanol as solvent and the Armour-Texaco Process, patented in 1948, uses acetone as solvent. The fatty acids to be separated are dissolved in the solvent and cooled, usually in a double-pipe chiller. Internal scrapers rotating at low rpm remove the crystals from the chilled surface. The slurry is then separated by means of a rotary vacuum filter. The filter cake is sprayed with cold solvent to remove free Hquid acids, and the solvents are removed by flash evaporation and steam stripping and recovered for reuse (10). 

A number of patents utilize dibasic calcium hypochlorite and concentrated NaOCl solution to produce Ca(OCl)2 Coarse dibasic crystals... 

When a potential is appHed across the ceU, the sodum and other cations are transported across the membrane to the catholyte compartment. Sodium hydroxide is formed in the catholyte compartment, because of the rise in pH caused by the reduction of water. Any polyvalent cations are precipitated and removed. The purified NaOH may be combined with the sodium bicarbonate from the sodium dichromate process to produce soda ash for the roasting operation. In the anolyte compartment, the pH falls because of the oxidation of water. The increase in acidity results in the formation of chromic acid. When an appropriate concentration of the acid is obtained, the Hquid from the anolyte is sent to the crystallizer, the crystals are removed, and the mother Hquor is recycled to the anolyte compartment of the ceU. The electrolysis is not allowed to completely convert sodium dichromate to chromic acid (76). Patents have been granted for more electrolytic membrane processes for chromic acid and dichromates manufacture (86). 

Oxahe acid, citric acid Promotes chunky crystals 1000 ppm U.S. Patent 2,228,742... 

However the acid is prepared, the sodium salt may be prepared as described in U.S. Patent 3,503,967 Five liters of methylene chloride were added to a clean dry vessel equipped with stirrer. 7-[a(4-pyridylthio)acetamido] cephalosporanic acid (1,000 g) was added to the vessel, followed by 350 ml of triethylamine. The resultant solution was treated with decolorizing charcoal for 15 minutes and filtered. A solution of sodium-3-ethyl-hexanoate (27.3%) in butanol-methylene chloride was added to the filtrate with stirring. Seven thousand five hundred milliliters of acetone was added. Crystallization occurred while stirring was continued several hours under dry conditions. The crystals were collected by filtration, washed with large volumes of acetone, and then dried in vacuo at 50°C to yield about 950 g of the title compound. 

B) A solution of BB g of 5-chloro-2,4-disulfamylaniline in 1.1 liters of BB% formic acid was heated under reflux for 2 hours. After removal of 200 ml of solvent by distillation, one liter of water was added and the product collected, washed with water and dried. Crystallization from dilute alcohol afforded 6-chloro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide as colorless needles, MP 342.5° to 343°C, as described in U.S. Patent 2,BOB,194. 

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