Title of Invention

POLYETHYLENE GLYCOL COMPOUNDS AND PROCESS FOR MAKING

Abstract

A substituted polyethylene glycol compound and process for making. The compound has the formula RO(C2H40)nH wherein R represents a Cj.y hydrocarbon group and n represents the average number of moles of C2H4O groups, ranging from 500 to 2000. The compound has a ratio of weight average molecular weight to a number average molecular weight in the range of from 1 to 1.1. The compound contains less than ten weight percent polyethylene glycol. The gist of the process is the use of an aprotic polar solvent. When the aprotic polar solvent is a polyether solvent, then the n value of the compound ranges from 100 to 2000.

Full Text

UNITED STATES PATENT APPLICATION FOR DISPOSABLE CUP LID INVENTORS: ROBERT W. HOLLIS WESTON S. KOENNECKE JOHN RUSSELL GEER III PRIORITY CLAIM [0001] This application is a continuation-in-part application of, claims priority to and the benefit of U.S. Patent Application No. 11/382,409, filed May 9, 2006, which is a non-provisional application of, claims priority to and the benefit of U.S. Provisional Patent Application No. 60/681,851, filed May 16, 2005, the entire contents of which are incorporated herein. BACKGROUND [0002] The use of disposable cup lids on disposable, single use hot drink cups has been known for many years. In the North American markets alone, every day literally millions of such disposable cups and cup lids are distributed by fast food restaurants, coffee shops and convenience stores for single use purposes. These cups and cup lids are usually disposed of after the single use. [0003] Generally, these lids permit the beverages to be consumed while reducing the likelihood of spillage of the beverages contained within these cups. Such spillage may occur accidentally, such as by simple clumsiness on the part of the person handling the cup or by exposure to other causes, such as the result of a rough vehicle ride or the attempt by a person to walk or run while holding the cup. While a fully closed lid prevents substantial spilling, many people also desire to drink from the cups without removing the lid entirely. Therefore, various different cup lids have been made or proposed which allow people to drink the beverages in the cups without completely opening or removing the lids. [0004] One such type of lid includes a small openable portion. This feature limits exposure of the beverage to ambient conditions and reduces the area through which the beverage may spill while still allowing a person to drink the beverage in the cup. The openable portion is usually recloseable, at least in theory. [0005] However, the openable portion often interferes with a person's ability to drink the beverage. That is, the openable portion generally extends upwardly above a central region of the cup lid and often interferes with the upper lip or nose of a person consuming a beverage from a cup on which the cup lid is placed. Additionally, the openable portion associated with such a cup lid sometimes does not stay in its secured open position, often releasing from its secured position while a person is drinking. Moreover, the angle of the opening of such lids do not comfortably conform to a person's mouth and/or lip& in a manner that easily facilitates consumption of a beverage. These concerns may result in a decision by a person to decide to discard the cup lid in its entirety, which in turn leads to faster cooling of the hot drink and an increased risk of spillage. [0006] Another type of lid includes a small fixed opening through which a person drinks the beverage. While these lids minimize spillage, because of the small sizing of the opening, these lids must be removed from the cup in order to add condiments, such as milk, cream and/or sugar, to the beverage contained in the cup. Such a removal of the lid increases the risk of spillage when the condiments are being added, when the lid is being resecured to the cup or if the lid is not properly resecured to the lid. [0007] Accordingly, a need exists to provide a disposable drinking cup lid which prevents spillage of the contents of the drinking cup while providing an enhanced drinking experience. POLYETHYLENE GLYCOL COMPOUNDS AND PROCESS FOR MAKING BACKGROUND The instant invention relates to polyethylene glycol compounds and a process for making such compounds. More particularly, the instant invention relates to high molecular weight polyethylene glycol compounds having narrow molecular weight distribution and a process for making such compounds. The polyethylene glycol compounds of the instant invention are useful for chemical modification of physiologically active materials, which modified materials are applicable, for example, in drug delivery systems. Biologically active compounds conjugated with polyoxyalkylenes can provide enhanced biocompatibility for the compound, See, for example, USP 5,366,735 and USP 6,280,745. A review of this subject by Zalipsky, in Bioconjugate Chem., 1995, 6, pi 50-165, identified polyethylene glycol as one of the best biocompatible polymers to conjugate with a biologically active compound (such as a drug, a protein, a peptide or an enzyme) to produce a conjugate having improved properties such as compatible solubility characteristics, reduced toxicity, improved surface compatibility, increased circulation time and reduced immunogenicity. Polyethylene glycol (PEG) is a linear polyoxyalkylene terminated at the ends thereof with hydroxyl groups and generally represented by the formula: HO(CH2CH20)nH. As discussed by Henmanson in Chapter 15 of Bioconjugate Techniques (1996), monomethoxy polyethylene glycol (mPEG) generally represented by the formula: CH30(CH2CH20)nH, is usually used to prepare a polyethylene glycol conjugate with a biologically active compound typically by way of a coupling reaction between an amine group of the biologically active compound and an amine receptive derivative (such as trichloro-s-triazine activated mPEG) formed via the remaining terminal hydroxyl group of the monomethoxy polyethylene glycol. More recently, so called "second generation" PEGylation chemistry has been developed to, for example, minimize problems of diol impurity contamination of mPEG, to increase the molecular weight of the mPEG and to increase stability of the conjugate, see Roberts et al, Advanced Drug Delivery Reviews 54 (2002) p459-4. United States Patent 6,455,639 (herein fully incorporated by reference) described an increased molecular weight mPEG having narrow molecular weight distribution. However, the highest molecular weight disclosed in the '639 patent was 20,861 (weight average molecular weight). It would be a further advance in the art if even higher molecular weight, narrow molecular weight distribution mPEG were discovered along with a processes to produce such a material. wherein R represents a C1-7 hydrocarbon group, n represents the average number of moles of C2H4O groups, ranging from 500 to 2000 and Y represents hydrogen or an alkali metal, the substituted polyethylene glycol compound having a ratio of weight average molecular weight to number average molecular weight in the range of from 1 to 1.1, the weight average molecular weight and the number average molecular weight of the substituted polyethylene glycol compound being determined by gel permeation chromatography, comprising the steps of: (a) forming a reaction mixture comprising an alcohol represented by the formula R(OCH2CH2)0-20OH, where R represents a C1-7 hydrocarbon group, an alkoxide of the alcohol and an aprotic polar solvent, the reaction mixture being at a temperature in the range of from about 80 to about 140 degrees Celsius, the water concentration of the reaction mixture being less than ten parts per million by weight, the mole ratio of the alkoxide of the alcohol to the alcohol being in the range of from about 0.01 to about 100; (b) contacting the reaction mixture with ethylene oxide so that the ethylene oxide reacts therein to form the substituted polyethylene glycol compound. In another embodiment, the instant invention is also a process for the preparation of a substituted polyethylene glycol compound having the formula RO(C2H40)nY wherein R represents a C1-7 hydrocarbon group, n represents the average number of moles of C2H4O groups, ranging from 100 to 2000 and Y represents hydrogen or an alkali metal, the substituted polyethylene glycol compound having a ratio of weight average molecular weight to number average molecular weight in the range of from 1 to 1.1, the weight average molecular weight and the number average molecular weight of the substituted polyethylene glycol compound being determined by gel permeation chromatography, comprising the steps of: (a) forming a reaction mixture comprising an alcohol represented by the formula R(OCH2CH2)o-2oOH, where R represents a C1.7 hydrocarbon group, an alkoxide of the alcohol and a polyether solvent, the reaction mixture being at a temperature in the range of from about 80 to about 140 degrees Celsius, the water concentration of the reaction mixture being less than ten parts per million by weight, the mole ratio of the alkoxide of the alcohol to the alcohol being in the range of from about 0.01 to about 100; (b) contacting the reaction mixture with ethylene oxide so that the ethylene oxide reacts therein to form the substituted polyethylene glycol compound. of the total moles of polyethylene glycol and the substituted polyethylene glycol compound. A specific critical condition liquid chromatography method for the determination of polyethylene glycol is outlined below. The process of the instant invention in one embodiment is a process for the preparation of a substituted polyethylene glycol compound having the formula RO(C2H40)nY wherein R represents a C1-7 hydrocarbon group, n represents the average number of moles of C2H4O groups, ranging from 500 to 2000 and Y represents hydrogen or an alkali metal, the substituted polyethylene glycol compound having a ratio of weight average molecular weight to number average molecular weight in the range of from 1 to 1.1, the weight average molecular'weight and the number average molecular weight of the substituted polyethylene glycol compound being determined by gel permeation chromatography, comprising the steps of: (a) forming a reaction mixture comprising an alcohol represented by the formula R(OCH2CH2)o-2oOH, where R represents a C1-7 hydrocarbon group, an alkoxide of the alcohol and an aprotic polar solvent, the reaction mixture being at a temperature in the range of from about 80 to about 140 degrees Celsius, the water concentration of the reaction mixture being less than ten parts per million by weight, the mole ratio of the alkoxide of the alcohol to the alcohol being in the range of from about 0.01 to about 100; (b) contacting the reaction mixture with ethylene oxide so that the ethylene oxide reacts therein to form the substituted polyethylene glycol compound. The process of the instant invention in another embodiment is process for the preparation of a substituted polyethylene glycol compound having the formula RO(C2H40)nY wherein R represents a C1.7 hydrocarbon group, n represents the average number of moles of C2H4O groups, ranging from 100 to 2000 and Y represents hydrogen or an alkali metal, the substituted polyethylene glycol compound having a ratio of weight average molecular weight to number average molecular weight in the range of from 1 to 1.1, the weight average molecular weight and the number average molecular weight of the substituted polyethylene glycol compound being determined by gel permeation chromatography, comprising the steps of: (a) forming a reaction mixture comprising an alcohol represented by the formula R(OCH2CH2)o-2oOH, where R represents a C1.7 hydrocarbon group, an alkoxide of the alcohol and a polyether solvent, the reaction mixture being at a temperature It is theorized (although it should be understood that applicants are not to be held to such theory) that the use of the preferred polyether aprotic polar solvents (such as bis(2-methoxyethyl) ether) and/or the use of the preferred polyether alcohols (such as diethyleneglycol methyl ether) promote dissociation of the alcohol alkoxide into its respective ions because such solvents and alcohols tend to complex the alkali metal of the alcohol alkoxide. An additional benefit of the use of the preferred polyether aprotic polar solvents that applicants theorize (without being held to such theory) is the like nature of the solvent in relation to the growing polymer chain, thereby further promoting the obtention of higher molecular weight polymer. With regard to molecular weight distribution, it is theorized (although again it should be understood that applicants are not to be held to such theory) that by using such solvents and alcohols in anionic ethylene oxide polymerizations, the rate of initiation becomes faster with respect to the rate of propagation and that the rate of termination is very small with respect to the rate of propagation. In the typical anionic ethylene oxide polymerization, the rate of initiation is slower that the rate of propagation, and the molecular weight distribution is expected to broaden. However, due to their ability to complex cations, a polyether solvent and a polyether alcohol in the process of the instant invention is theorized to increase the rate of initiation with respect to the rate of propagation and thus promote a narrower molecular weight distribution of the substituted polyethylene glycol compound. A narrow molecular weight distribution of the substituted polyethylene glycol compound is desired for the above discussed PEGylation applications. Since water initiates ethylene oxide polymerization to form polyethylene glycol ("diol") and since diol is undesired in the substituted polyethylene glycol compound of the instant invention, it is beneficial to minimize the water concentration of the reaction mixture during step (b) of the process of the instant invention. When water is present at the beginning of the reaction, the molecular weight of the PEG will be about two times greater than the molecular weight of the substituted polyethylene compound. There are several potential sources of water, including water in the solvent, alcohol and ethylene oxide; water entering the reactor from outside the reactor, hydroxide in the base; and water generated by dehydration of a polyethylene glycol alcohol. The polymerization solvent may be dried by, for example, addition of activated molecular sieves. The sieves are removed by filtration before the solvent is added to the polymerization reactor. Alternatively or additionally, the polymerization solvent may be Liquid chromatography under critical conditions has been used to determine polyethylene glycol in mPEG (see, for example, Kazanskii et al.5 Polymer Science, Series A, Vol 42, No. 6 (2000), p585-595. However, the degree of resolution of the polyethylene glycol and mPEG peaks is usually poor (see Fig. 2 of the Kazanskii et al. reference). The degree of resolution of the polyethylene glycol and mPEG peaks in liquid chromatography under critical conditions can be significantly improved by derivatizing the polyethylene glycol and mPEG with, for example, dinitrobenzoyol chloride. The amount of polyethylene glycol in the instant invention is determined by the following procedure: (a) 0.1 gram of the compound is mixed with one milliliter of dry acetonitrile containing 150 microequivalents of 4^imethylaminopyridine and one milliliter >of dry acetonitrile containing 150 microequivalents of dinitrobenzoyol chloride, which mixture is heated at 100 degrees Celsius for 15 minutes, and then quenched with three milliliters of water to produce a sample for injection; (b) 5 microliters of the sample for injection is injected into a moblile phase of 52%A and 48%B (where A is 47% acetonitrile in water and B is 43% acetonitrile in water) at a mobile phase flow rate of 0.75 milliliters per minute and flowed through a 5 micrometer packing diameter Zorbax Brand SB300 CI 8 reverse phase column at a column temperature of 32 degrees Celsius, the column having an internal diameter of 4.6 millimeters and a length of 150 millimeters, followed by a UV detector (absorbance at 230 nanometers) to produce a chromatogram; (c) the chromatogram having a peak at about 2.5 minutes (primarily related to excess dinitrobenzoyol chloride), a peak at about 4.5 minutes for the derivatized substituted polyethylene compound of the instant invention and a well resolved peak at about 9.5 minutes for the derivatized polyethylene glycol (derivatized diol). The mole percent amount of polyethylene glycol of the total moles of polyethylene glycol and the substituted polyethylene glycol compound of the instant invention is defined herein as: one half the area of the derivatized polyethylene glycol peak divided by the sum of one half the area of the derivatized polyethylene glycol peak and the area of the peak for the derivatized substituted polyethylene compound of the instant invention, multiplied by 100. It should be understood that the above procedure relates to a specific reverse phase column operated under specific critical conditions and that, as is well known in the art of liquid chromatography under critical conditions, it will probably be necessary to determine the critical conditions for another specific system, which critical conditions will probably be hours. The resulting mPEG product is characterized by GPC analysis to determine the polymer characteristics such as molecular weight and polydispersity (D). The peak molecular weight (Mp) is 28,613. The number average molecular weight (Mn)is 28,176. The weight average molecular weight (Mw) is 28,910. The molecular weight dispersion (Mw/Mn) is 1.026. PEG diol content is determined by liquid chromatography under critical conditions. ADDITIONAL EXAMPLES The following Table 1 lists various reaction recipies using the system outlined in the above example (Batch 4046 is the above example). The following Table 2 lists the analysis results for the various batches of Table 1. In the above tables, wt is weight; g is grams; KH is potassium hydride; Eq is equivalent; EO is ethylene oxide; Rxn Time is reaction time; kg is kilograms; Theor MW is theoretical molecular weight; Mn is number average molecular weight; Mw is weight average molecular weight; Mp is peak molecular weight; D is molecular weight distribution ratio or Mw divided by Mn; Mol% is mole percent; and ppm is parts per million by weight. In conclusion, it should be readily apparent that although the invention has been described above in relation with its preferred embodiments, it should be understood that the instant invention is not limited thereby but is intended to cover all alternatives, modifications and equivalents that are included within the scope of the invention as defined by the following claims. WHAT IS CLAIMED IS: 1. A substituted polyethylene glycol compound having the formula RO(C2H40)nH wherein R represents a C\.-j hydrocarbon group and n represents the average number of moles of C2H4O groups, ranging from 600 to 2000, the substituted polyethylene glycol compound having a ratio of weight average molecular weight to a number average molecular weight in the range of from 1 to 1.1, the weight average molecular weight and the number average molecular weight of the substituted polyethylene glycol compound being determined by gel permeation chromatography. 2. The compound of Claim 1, wherein n is in the range of from 700 to 1000. 3. A mixture comprising a substituted polyethylene glycol compound and polyethylene glycol, the substituted polyethylene glycol compound having the formula RO(C2H40)nH wherein R represents a C1.7 hydrocarbon group; and n represents the average number of moles of C2H4O groups added, ranging from 600 to 2000, the substituted polyethylene glycol compound having a ratio of weight average molecular weight to number average molecular weight as determined by gel permeation chromatography in the range of from 1 to 1.1, the amount of polyethylene glycol being less than ten mole percent of the total moles of polyethylene glycol and the substituted polyethylene glycol compound, the amount of the polyethylene glycol being determined by liquid chromatography under critical conditions. 4. The mixture of Claim 3, wherein n is in the range of from 700 to 1000. 5. The mixture of Claim 3 or 4, wherein the amount of polyethylene glycol is less than five mole percent of the total moles of polyethylene glycol and the substituted polyethylene glycol compound. 6. A process for the preparation of a substituted polyethylene glycol compound having the formula RO(C2H40)nY wherein R represents aC].? hydrocarbon group, n represents the average number of moles of C2H4O groups, ranging from 500 to 2000 and Y represents hydrogen or an alkali metal, the substituted polyethylene glycol compound having a ratio of weight average molecular weight to number average molecular weight in the range of from 1 to 1.1, the weight average molecular weight and the number average molecular weight of the substituted polyethylene glycol compound being determined by gel permeation chromatography, comprising the steps of: (a) forming a reaction mixture comprising an alcohol represented by the formula R(OCH2CH2)o_2oOH, where R represents a C1.7 hydrocarbon group, an alkoxide of the alcohol and an aprotic polar solvent, the reaction mixture being at a temperature in the range of from about 80 to about 140 degrees Celsius, the water concentration of the reaction mixture being less than ten parts per million by weight, the mole ratio of the alkoxide of the alcohol to the alcohol being in the range of from about 0.01 to about 100; (b) contacting the reaction mixture with ethylene oxide so that the ethylene oxide reacts therein to form the substituted polyethylene glycol compound. 7. The process of Claim 6, wherein the aprotic polar solvent is a polyether solvent. 8. The process of Claim 7, wherein the polyether solvent is bis(2-methoxyethyl)ether. 9. The process of Claim 6, 7, or 8, wherein the alcohol is diethyleneglycol monomethyl ether. 10. The process of any one of Claims 6 to 9, wherein the temperature of the reaction mixture is in the range of from about 90 to about 110 degrees Celsius. 11. The process of any one of Claims 6 to 9, wherein the concentration of the substituted polyethylene glycol compound in the reaction mixture at the end of step (b) is in the range of from about 20 to about 80 weight percent of the reaction mixture. 12. The process of Claim 11, wherein the concentration of the substituted polyethylene glycol compound in the reaction mixture at the end of step (b) is in the range of from about 40 to about 60 weight percent of the reaction mixture. 13. The process of any one of Claims 6 to 12, wherein the reaction mixture at the end of step (b) also contains polyethylene glycol, the amount of polyethylene glycol being less than ten mole percent of the total moles of polyethylene glycol and the substituted polyethylene glycol compound, the amount of the polyethylene glycol being determined by liquid chromatography under critical conditions. 14. The process of Claim 13, wherein the reaction mixture at the end of step (b) also contains polyethylene glycol, the amount of polyethylene glycol being less than five mole percent of the total moles of polyethylene glycol and the substituted polyethylene glycol compound, the amount of the polyethylene glycol being determined by liquid chromatography under critical conditions. 15. The process of Claim 13, wherein the reaction mixture at the end of step (b) also contains polyethylene glycol, the amount of polyethylene glycol being less than two and one half mole percent of the total moles of polyethylene glycol and the substituted polyethylene glycol compound, the amount of the polyethylene glycol being determined by liquid chromatography under critical conditions. 16. The process of any one of Claims 6-15, further comprising the step after step (b) of adding an acid to the reaction mixture so that Y is essentially hydrogen. 17. The process of any one of Claims 6-15, further comprising the step after step (b) of mixing the reaction mixture with a nonpolar solvent to precipitate the substituted polyethylene glycol compound. 18. The process of any one of Claims 6-15, further comprising the step after step (b) of mixing the reaction mixture with a mixture comprising a nonpolar solvent and an acid to precipitate the substituted polyethylene glycol compound wherein Y is essentially hydrogen. 19. A process for the preparation of a substituted polyethylene glycol compound having the formula RO(C2H40)nY wherein R represents a C1.7 hydrocarbon group, n represents the average number of moles of C2H4O groups, ranging from 100 to 2000 and Y represents hydrogen or an alkali metal, the substituted polyethylene glycol compound having a ratio of weight average molecular weight to number average molecular weight in the range of from 1 to LI, the weight average molecular weight and the number average molecular weight of the substituted polyethylene glycol compound being determined by gel permeation chromatography, comprising the steps of: (a) forming a reaction mixture comprising an alcohol represented by the formula R(OCH2CH2)o-2oOH, where R represents a Q.7 hydrocarbon group, an alkoxide of the alcohol and a polyether solvent, the reaction mixture being at a temperature in the range of from about 80 to about 140 degrees Celsius, the water concentration of the reaction mixture being less than ten parts per million by weight, the mole ratio of the alkoxide of the alcohol to the alcohol being in the range of from about 0.01 to about 100; (b) contacting the reaction mixture with ethylene oxide so that the ethylene oxide reacts therein to form the substituted polyethylene glycol compound. 20. The process of Claim 19, wherein the polyether solvent is bis(2-methoxyethyl)ether. 21. The process of Claim 19 or 20, wherein the alcohol is diethyleneglycol monomethyl ether. 22.. The process of any one of Claims 19-21, wherein the temperature of the reaction mixture is in the range of from about 90 to about 110 degrees Celsius. 23. The process of any one of Claims 19-22, wherein the reaction mixture at the end of step (b) also contains polyethylene glycol, the amount of polyethylene glycol being less than ten mole percent of the total moles of polyethylene glycol and the substituted polyethylene glycol compound, the amount of the polyethylene glycol being determined by liquid chromatography under critical conditions. 24. The process of Claim 23, wherein the reaction mixture at the end of step (b) also contains polyethylene glycol, the amount of polyethylene glycol being less than five mole percent of the total moles of polyethylene glycol and the substituted polyethylene glycol compound, the concentration of the polyethylene glycol being determined by liquid chromatography under critical conditions. 25. The process of Claim 23, wherein the reaction mixture at the end of step (b) also contains polyethylene glycol, the amount of polyethylene glycol being less than two and one half mole percent of the total moles of polyethylene glycol and the substituted polyethylene glycol compound, the amount of the polyethylene glycol being determined by liquid chromatography under critical conditions. 26. The process of any one of Claims 19-25, further comprising the step after step (b) of adding an acid to the reaction mixture so that Y is essentially hydrogen. 27. The process of any one of Claims 19-26, further comprising the step after step (b) of mixing the reaction mixture with a nonpolar solvent to precipitate the substituted polyethylene glycol compound. 28. The process of any one of Claims 19-27, further comprising the step after step (b) of mixing the reaction mixture with a mixture comprising a nonpolar solvent and an acid to precipitate the substituted polyethylene glycol compound wherein Y is essentially hydrogen.

Documents:

1286-CHENP-2007 AMENDED CLAIMS 17-04-2014.pdf

1286-CHENP-2007 AMENDED PAGS OF SPECIFICATION 17-04-2014.pdf

1286-CHENP-2007 CORRESPONDENCE OTHERS 30-07-2013.pdf

1286-CHENP-2007 EXAMINATION REPORT REPLY RECEIVED 17-04-2014.pdf

1286-CHENP-2007 OTHER PATENT DOCUMENT 17-04-2014.pdf

1286-CHENP-2007 PRIORITY DOCUMENT 17-04-2014.pdf

1286-chenp-2007-abstract.pdf

1286-chenp-2007-assignement.pdf

1286-chenp-2007-claims.pdf

1286-chenp-2007-correspondnece-others.pdf

1286-chenp-2007-description(complete).pdf

1286-chenp-2007-form 1.pdf

1286-chenp-2007-form 26.pdf

1286-chenp-2007-form 3.pdf

1286-chenp-2007-form 5.pdf

1286-chenp-2007-pct.pdf

Form 3.pdf

Petition for Annexure.pdf