Dihydrogen Citrate

A solution of 163 g (0.1 mol) of 2-amino-5-chloroben2oxazole in 200 ml of 1 N HCI is refluxed until precipitation is complete. The resulting solid is collected by filtration, dissolved in 200 ml of 1 N NaOH and the solution extracted with 50 ml of ether. Acidification of the alkaline solution gives a precipitate which is purified by crystallization from acetone to give 2-hydroxy-5-chlorobenzoxazole melting at 191° to 191.5°C. 

Patent 2395/877 July 21,1959 assigned to McNeil Laboratories, Inc. 

Chemical Name (2-Hydroxyethyl)trimethylammonium citrate Common Name — 

Trimethyl amine Ethylane oxide Citric acid 

DiSalvo.WA. and Kapp, R. U.S. Patent 2/870,198 January 20,1959 assigned to Nopco Chemical Co. 

Trimethyl amine Ethylene oxide Citric acid 

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Choline Dihydrogen Citrate. This compound [77-91 -8] is a white, crystalline, granular substance possessing an acid taste, mp 105—I07.5°C, and is freely soluble in water, very slightly soluble in alcohol, and practically insoluble in benzene, chloroform, and ether. The pH of a 25% solution is about 4.25. 

Choline dihydrogen citrate (CH2)3N(CH2CH20H)C H202, is prepared by methods similar to those for preparing choline chloride. It has the same pharmacological action as the chloride, but contains a lower proportion of choline. It is not as dehquescent as the chloride, and absorbs moisture from the atmosphere only at relative humidities greater than 56% at 25.5°C. It is mote palatable than the chloride. 

As a therapeutic agent, ch oline is adininistered orally in the form of symps or elixers containing the chloride, citrates or bitartrate, or in the form of compressed tablets or capsules of the dihydrogen citrate. Choline is also given in small doses as a nutritional supplement in combination with a variety of other materials. In dry pharmaceutical-dosage forms, the dihydrogen citrate is usually preferred because of its lower tendency to absorb atmospheric moisture. Both salts have been used parenteraHy. 

Market prices for ch oline products in 1992 were as follows 70% ch oline chloride(FeedGrade), 0.77/kg choline dihydrogen citrate, 7.20/kg and choline hydrogen tartrate, 9.50/kg. 

Chemical Name 2-[4-(2-Chloro-1,2-diphenylethenyl)-phenoxy] N,N-dlethylethanamine dihydrogen citrate... 

A mixture of 20 g of 1. [p.((3.diethylaminoethoxy)phenyl]-1,2-diphenylethanol in 200 cc of ethanol containing an excess of hydrogen chloride was refluxed 3 hours. The solvent and excess hydrogen chloride were removed under vacuum, and the residue was dissolved in a mixture of ethyl acetate and methylene chloride. 1-[p-((3.diethylaminoethoxv)phenyl] -1,2-diphenylethylene hydrochloride was obtained, melting at 148° to 157°C. This hydrochloride salt was treated with N-chlorosuccinimide in dry chloroform under reflux. The product then obtained was converted to the free base and treated with citric acid. The dihydrogen citrate salt of 1-[p-((3-diethylaminoethoxy)phenyl]-1,2-diphenylchloroethylene was obtained, melting at 116.5° to 118°C. 

As described in U,S. Patent 2,575,611, 107 parts of freshly prepared ferric hydroxide are added to 295 parts of choline dihydrogen citrate dissolved in 200 parts of distilled water and heated to approximately 80°C until a homogeneous solution occurs. The resulting reddish brown solution may be used as such or it may be dried by evaporating the water,... 

Choline theophyllinate Choline chloride Carbachol Choline salicylate Choline dihydrogen citrate Ferrocholinate Chromic acid... 

Butamirate citrate Choline dihydrogen citrate Clomiphone dihydrogen citrate Orphenadrine citrate Perisoxal citrate Proxazole citrate Copper (powder)... 

Benactyzine hydrochloride Benoxinate hydrochloride Caramiphen edisylate Chloroprocaine HCI Dicyclomine HCI Valethamate bromide 4-( -Diethylaminoethoxy) benzophenone Clomiphene dihydrogen citrate 2-(2-Diethylaminoethyl) acetic acid ethyl ester Chromonar HCI 2-Diethylaminoethyiamine Ambenonium chloride Chlorisondamine chloride Diethylaminoethyl chloride Captodiamine Dlltiazem HCI Flurazepam Penthienate bromide Tiropramide Tripara nol... 

Triethylenemelamine Ethylene oxide Chlorambucil Choline dihydrogen citrate Etofibrate Melphalan Nimorazole Nonoxynol Tyloxapol Uracil mustard... 

C5H15NO2 123-41-1) see Acetylcholine chloride Choline chloride Choline dihydrogen citrate Choline stearate choline naphthalene-1,5-disulfonate (C20H34N2O8S2) see Aclatonium napadisilate choline tosylate... 

QHj07 77-92-9) see Choline dihydrogen citrate citric acid monohydrate (C H Oj, 5949-29-1) see Mosapride citrate (-l-)-citronellal... 

Q dD Predict whether sodium dihydrogen citrate, NaH2CeH507,... 

Potassium dihydrogen citrate [866-83-1 ] M 230.2. Crystd from water. Dried at 80°. 

Buprenorphine, the other option for transdermal application on account of its potency, is more difficult to apply dermally in therapeutic doses (Roy et al., 1994 Grond et al., 2000). A surrogate parameter for skin penetration, provided the other prerequisites are fulfilled (Fig. 7), is the melting point of the active substance. With buprenorphine base this is 209°C and about 260°C for buprenorphine hydrochloride, compared with, for example, 83°C for fentanyl base and 150°C for fentanyl dihydrogen citrate. The DDS developer LTS devised a technical solution for reliable transdermal buprenorphine administration in the form of a matrix patch (Fig. 9). 

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