US3687932A - Crystalline cytidine-5{40 -diphosphate choline monohydrate and production thereof - Google Patents

Crystalline cytidine-5{40 -diphosphate choline monohydrate and production thereof Download PDF

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Publication number
US3687932A
US3687932A US31547A US3687932DA US3687932A US 3687932 A US3687932 A US 3687932A US 31547 A US31547 A US 31547A US 3687932D A US3687932D A US 3687932DA US 3687932 A US3687932 A US 3687932A
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choline
cdp
monohydrate
crystalline
angstrom
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Hideo Nakamachi
Kazuhide Kamiya
Masao Nishikawa
Shoichiro Fujii
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Takeda Pharmaceutical Co Ltd
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Takeda Chemical Industries Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • H I N CHz0-iO-i0OH2-CHzN CHa H ii @i is useful, for example, as an agent for the treatment of the disturbance of consciousness or neuro-psychiatic symptoms accompanying head injuries and cerebral operations.
  • GDP-Choline is very readily soluble in water and has such slight solubility gradients to temperature in various organic solvent that, by the known method, the compound has not been crystallized but has merely been obtained in the form of either an oil or an amorphous powder. Therefore, it has heretofore been common practice to recover the compound by lyophilization from the reaction mixture.
  • the lyophilized CDP-Choline thus obtained still has an amorphous structure and is accompanied with many disadvantages which make it unsatisfactory in practical use. Those disadvantages are:
  • the moisture content of the preparation is not constant.
  • the preparation is vulnerable to contamination with impurities, especially with pyrogens.
  • CDP- Choline monohydrate novel cytidine-5'-diphosphate choline monohydrate (hereinafter referred to as CDP- Choline monohydrate) is produced as stable crystals in a good yield and that thus-obtained crystalline CDP- Choline monohydrate is not only attractive to look at but also has extremely excellent qualities for practical handling and use.
  • the principal object of the present invention is to provide novel crystalline CDP-Choline monohydrate with excellent properties for practical use.
  • Another object of the present invention is to provide an industrially feasible method for producing the said crystalline CDP-Choline monohydrate.
  • Crystalline CDP-Choline monohydrate of the invention is produced by subjecting CDP-Choline to further specified crystallization procedure.
  • the industrially feasible crystallization method comprises adding a hydrophilic organic solvent to an aqueous solution system of GDP-Choline.
  • the aqueous solution system of CDP-Choline may be those which are prepared by dissolving GDP-Choline in any of the amorphous forms, e.g. lyophilized preparation or oily form, into water, or those obtained in the per se known syntheses procedure of CDP-Choline.
  • concentration of GDP-Choline in the aqueous solution is higher than about 50 to 60 percent by weight relative to the aqueous solution system, there is found a tendency toward the precipitation of CDP- Choline itself as an oily substance along with crystals of CDP-Choline monohydrate thus lowering the yield of crystalline GDP-Choline monohydrate.
  • the concentration of CDP-Choline is not higher than about 20 percent by weight, the yield of crystalline CDP-Choline monohydrate is relatively low. Therefore, the advantageous concentration of GDP-Choline in the aq ueous solution system is higher than about 20 percent but lower than about 60 percent by weight.
  • the aqueous solution system of CDP-Choline may contain a hydrophilic organic solvent in a small amount which is sufficient to avoid precipitation of CDP- Choline as the raw material.
  • hydrophilic organic solvent use may be made of various organic solvents miscible with water, such as methyl alcohol, ethyl alcohol, acetone, dioxane, dimethyl sulfoxide, an optional mixture thereof and the like.
  • some solvents such as methyl alcohol and dimethyl sulfoxide are particularly conducive to the rapid crystallization of CDP-Choline monohydrate and other solvents such as acetone and dioxane are excellent in giving a high yield of the objective crystalline CDP-Choline monohydrate. It is therefore especially advantageous to firstly add the former e.g.
  • CDP-Choline methyl alcohol and/or dimethyl sulfoxide to the aqueous solution system of CDP-Choline to promote the crystallization of CDP- Choline monohydrate, and then, to add the latter e.g. acetone and/or dioxane to provide for an increased yield of crystalline CDP-Choline monohydrate.
  • ethyl alcohol When ethyl alcohol is employed as the hydrophilic organic solvent, the formation of crystalline CDP- Choline monohydrate may be promoted by the addition of an aqueous solution of ethyl alcohol in the concentration of about percent, e.g. in the range of about 70 to percent.
  • the amount of the hydrophilic organic solvent to be added into the aqueous solution system of GDP-Choline may vary somewhat with the kinds of the hydrophilic organic solvents and whether or not the aqueous solution system previously contains a hydrophilic organic solvent, it is generally sufficient to add the hydrophilic organic solvent in an amount to make its total amount about 5 to about 20 times the volume of water contained in the aqueous solution system. Usually, it is a good expedient to add a hydrophilic organic solvent, after no more precipitates form in the resulting mixture, in a further amount corresponding to about 30 percent of that so far contained in the aqueous solution system.
  • CDP-Choline monohydrate it is possible to allow CDP-Choline monohydrate to crystallize out in an extremely shortened period of time by adding previously prepared crystalline CDP-Choline monohydrate as seed crystals especially when the resulting mixture shows signs of turbidity in the process of adding a hydrophilic organic solvent to an aqueous solution system of GDP-Choline.
  • crystalline CDP-Choline monohydrate is produced by keeping the amorphous CDP-Choline, e.g. the lyophilized CDP- Choline, standing at a relative humidity of not less than about 32 percent and at a temperature in the range of from about 17 to about 70C.
  • the amorphous CDP-Choline absorbs a substantial amount of water and is dissolved in the moisture to form a liquid state, but further keeping the same standing under the above-mentioned conditions yields crystalline CDP-Choline monohydrate with the evaporation of an excess of the absorbed water.
  • the speed of the formation of crystalline CDP- Choline monohydrate increases with elevated temperature, but at a temperature above about 70C the speed is too high to allow the monohydration to proceed into the inside of the amorphous CDP-Choline.
  • a mere skin of the monohydrate is formed only in the surface layer of the amorphous CDP-Choline.
  • the thermal decomposition of CDP-Choline is also promoted to detract from the yield of crystalline CDP- Choline monohydrate.
  • a temperature lower than about 17C is not advantageous since CDP-Choline monohydrate is formed too slowly.
  • the formation speed of crystalline CDP-Choline monohydrate may be increased by adding previously prepared crystalline CDP-Choline .monohydrate as seed crystals.
  • FIG. 1 of the accompanying drawing is a reproduction of a photograph of crystals of CDP-Choline monohydrate of the present invention magnified 40 diameters with a microscope.
  • CDP-Choline monohydrate shows a well defined X ray difiraction pattern which indicates that this compound is highly crystalline.
  • the X-ray diffraction pattern of CDP-Choline monohydrate measured by the powder method is as shown in FIG. 2 of the accompanying drawing, and the significant lattice spacings are as follows:
  • CDP-Choline monohydrate of the present invention is essentially characterized by the above-listed lattice spacings.
  • FIG. 7 of the accompanying drawing is to illustrate the stereo model of CDP-Choline molecule in the crystal of CDP-Choline monohydrate projected in direction of the c-axis.
  • Crystalline CDP-Choline monohydrate of the present invention offers the following advantages over the conventional preparations of CDP-Choline.
  • the lines designated A, B, C and D show, respectively, the moisture absorption equilibrium curve of a lyophilized preparation of CDP-Choline as measured at C, that of the said preparation as measured at 40C, that of crystalline CDP-Choline monohydrate as measured at 40C.
  • crystalline CDP- Choline monohydrate remains stable up to the relative humidity of 75 percent even at 40C, and at the temperature of 20C, shows no change even when the relative humidity is as high as 95 percent.
  • the lyophilized preparation of CDP-Choline is highly hygroscopic and liable to deliquescence. In addition, this hygroscopicity gains with increasing temperatures.
  • CDP- Choline not only requires the utmost care in its production but lends to itself only poorly to the uniformity of quality. This is sharp contrast of crystalline CDP- Choline monohydrate which, even if not stored in an air-tight or closed container, does not undergo a change of any appreciable degree in quality, and therefore, which requires no special care in handling.
  • the melting point (decomposition point) of the lyophilized CDP-Choline varies considerably with differences in moisture content, and even a freshly prepared sample melts (decomposes) gradually between 190C and 196C (uncorrected). which is higher than said range by at least about 30C. Furthermore, crystalline CDP-Choline monohydrate is more stable against heat than the lyophilized preparation of CDP-Choline.
  • the following table shows the respective colorations in terms of reflectivity at 360 my. of the said two compounds on heating at 80C for 70 hours.
  • CDP-Choline monohydrate retains its water of crystallization up to higher than about 100C and it abruptly loses its water of crystallization at about 110 to about 120C becoming an anhydrate as shown in FIG. 6 of the accompanying drawing.
  • crystalline CDP-Choline monohydrate does not suffer changes in amount of its water of crystallization by the general differences in drying conditions and, therefore, lends itself better to the maintenance of product uniformity.
  • the anhydrate obtained by heating crystalline CDP- Choline monohydrate to a temperature higher than about 120C has a crystalline structure different from that of CDP-Choline monohydrate.
  • this crystalline anhydrate is kept standing overnight at 20C and at about 60 percent of relative humidity, it regains water of crystallization to form the original crystalline CDP- Choline monohydrate.
  • CDP-Choline Lyophilized preparation of CDP-Choline is not only hygroscopic as described about but has a low bulk density and a low fluidity.ln sharp contrast thereto, CDP- Choline monohydrate comes in the form of attractive crystals which have remarkably higher bulk density and a greater fluidity than the conventional preparations.
  • CDP- Choline monohydrate of the present invention is precipitated from its solution as fine crystals and, as such, is free from contamination with impurities, especially with pyrogens.
  • Crystalline CDP-Choline monohydrate is obtained by the simple procedure and low cost according to the method of the present invention in which the lyophilization process is not necessary.
  • Crystalline CDP-Choline monohydrate of the present invention shows thesame pharmacological activities as those of the conventional lyophilized preparation of CDP-Choline and is used as the agent for the treatment of the disturbance of consciousness or neuro-psychiatric symptoms accompanying head injuries and cerebral operations, and the like.
  • about 100 to about 500 milligrams is administered once or twice a day by intravenous drip, intravenous injection or intramuscular injection.
  • a dose of about 250 to about 500 milligrams is most effective.
  • EXAMPLE 2 To a solution of 4.8 parts by weight (on dry basis) of CDP-Choline in 5 parts by volume of water is added 10 parts by volume of methyl alcohol at 50C. While the mixture is stirred well at the same temperature, parts by volume of methyl alcohol is gradually added thereto dropwise over 3 hours. After the addition is completed, the mixture is further stirred at the same temperature for 1 hour, then cooled to 45C, followed by the dropwise addition of 20 parts by volume of acetone over 1 hour. The mixture is cooled to about 20C and is kept standing overnight to yield crystals of CDP-Choline monohydrate. The crystals are recovered by filtration, washed with parts by volume of acetone and dried in a current of air at 20C. Yield: 4.6 parts by weight or 92.4 percent.
  • EXAMPLE 3 To a solution of 9.5 parts by weight (on dry basis) of CDP-Choline in 10 parts by volume of water is added 20 parts by volume of methyl alcohol at 20C. While the mixture is stirred well at the same temperature, 50 parts by volume of methyl alcohol is added thereto dropwise over 1 hour. When the addition of 20 parts by volume of methyl alcohol is completed, 0.05 part by weight of crystalline CDP-Choline monohydrate is EXAMPLE 4 To a solution of 30 parts by weight (on dry basis) of CDP-Choline in 30 parts by volume of water is added 60 parts by volume of methyl alcohol at 60C. While the mixture is stirred well at the same temperature, 150 parts by volume of methyl alcohol is added thereto dropwise over 3 hours. After the addition is completed, the mixture is gradually cooled to about 20C to yield crystals of CDP-Choline monohydrate. The crystals are recovered by filtration, washed with 10 parts by volume of methyl alcohol and dried at 40C under reduced pressure.
  • EXAMPLE 5 To a solution of parts by weight (on dry basis) of GDP-Choline in 400 parts by volume of water is added 2,500 parts by volume of dimethyl sulfoxide dropwise over 2 hours, whereby crystals of CDP-Choline monohydrate are formed. The crystals are recovered by filtration and dried at 40C under reduced pressure. Yield: 97 parts by weight or 93.5 percent.
  • EXAMPLE 6 950 mg. (on dry basis) of lyophilized preparation of CDP-Choline is spread on a dish about 5 centimeters in diameter. The dish is then placed in a desiccator having a relative humidit of 62 erc nt controlled with a saturated aqueous so ution 0 so rum nitrite in its bottom.
  • the desiccator is allowed to stand in an incubator EXAMPLE 7 950 mg. dry basis) of lyophilized preparation of GDP-Choline is spread on a dish about 5 centimeters in diameter. The dish is then placed in a desiccator having a relative humidity of 84 percent controlled with a saturated aqueous solution of calcium bromide in its bottom. The desiccator is further positioned in an incubator maintained at 20 i 1C. After a week, the dish is taken out and the crystals of CDP-Choline monohydrate formed on the dish are recovered with a spoon.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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US31547A 1969-04-24 1970-04-24 Crystalline cytidine-5{40 -diphosphate choline monohydrate and production thereof Expired - Lifetime US3687932A (en)

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BE (1) BE749332A (enrdf_load_stackoverflow)
CA (1) CA954510A (enrdf_load_stackoverflow)
CH (2) CH542858A (enrdf_load_stackoverflow)
DE (1) DE2019308C3 (enrdf_load_stackoverflow)
FR (1) FR2042370B1 (enrdf_load_stackoverflow)
GB (1) GB1261872A (enrdf_load_stackoverflow)
LU (1) LU60789A1 (enrdf_load_stackoverflow)
NL (1) NL149812B (enrdf_load_stackoverflow)
PH (1) PH9528A (enrdf_load_stackoverflow)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4789666A (en) * 1985-07-05 1988-12-06 Bioresearch Spa Cytidine-diphosphocholine salts, particularly suitable for oral use
US5109126A (en) * 1988-12-06 1992-04-28 Worcester Foundation For Experimental Biology 5'[2'(3')-O-(2,4,6-trinitrophenyl) pyprimidine nucleoside]diphosphate 1-glycosides
US5215973A (en) * 1991-03-07 1993-06-01 Magis Farmaceutici S.P.A. Optically active and racemic hydrated diacetylesters of α-glycero-phosphoryl-choline
US6057301A (en) * 1997-12-24 2000-05-02 Interneuron Pharmaceuticals, Inc. Hyperhydrated citicoline, process and use
CN103509073A (zh) * 2013-08-29 2014-01-15 洪军 一种胞磷胆碱钠化合物
WO2018066690A1 (ja) * 2016-10-06 2018-04-12 協和発酵バイオ株式会社 シチジンジリン酸コリンの結晶及びその製造方法
RU2800932C2 (ru) * 2016-10-06 2023-08-01 Киова Хакко Био Ко., Лтд. Кристалл цитидиндифосфатхолина и способ его получения

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1207106B (it) * 1980-04-18 1989-05-17 Made Italiana Srl Ora Searle I Preparazione farmaceutica contenente citidin disfofocolina assorbibile per via orale

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3300479A (en) * 1965-08-05 1967-01-24 Upjohn Co Deazapurine riboside cyclic 3', 5'-phosphates and process therefor
US3317512A (en) * 1965-06-01 1967-05-02 Upjohn Co 5', 5'-dinucleoside phosphates
US3454559A (en) * 1963-08-30 1969-07-08 Ajinomoto Kk Preparation of guanosine and intermediates obtained thereby
US3471471A (en) * 1965-09-21 1969-10-07 Univ Sydney Adenosine derivatives and therapeutic preparations containing same
US3507854A (en) * 1964-04-08 1970-04-21 Sankyo Co Process for preparing thiamine derivatives

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3454559A (en) * 1963-08-30 1969-07-08 Ajinomoto Kk Preparation of guanosine and intermediates obtained thereby
US3507854A (en) * 1964-04-08 1970-04-21 Sankyo Co Process for preparing thiamine derivatives
US3317512A (en) * 1965-06-01 1967-05-02 Upjohn Co 5', 5'-dinucleoside phosphates
US3300479A (en) * 1965-08-05 1967-01-24 Upjohn Co Deazapurine riboside cyclic 3', 5'-phosphates and process therefor
US3471471A (en) * 1965-09-21 1969-10-07 Univ Sydney Adenosine derivatives and therapeutic preparations containing same

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4789666A (en) * 1985-07-05 1988-12-06 Bioresearch Spa Cytidine-diphosphocholine salts, particularly suitable for oral use
US5109126A (en) * 1988-12-06 1992-04-28 Worcester Foundation For Experimental Biology 5'[2'(3')-O-(2,4,6-trinitrophenyl) pyprimidine nucleoside]diphosphate 1-glycosides
US5215973A (en) * 1991-03-07 1993-06-01 Magis Farmaceutici S.P.A. Optically active and racemic hydrated diacetylesters of α-glycero-phosphoryl-choline
US6057301A (en) * 1997-12-24 2000-05-02 Interneuron Pharmaceuticals, Inc. Hyperhydrated citicoline, process and use
CN103509073A (zh) * 2013-08-29 2014-01-15 洪军 一种胞磷胆碱钠化合物
CN103509073B (zh) * 2013-08-29 2016-01-06 洪军 一种胞磷胆碱钠化合物
WO2018066690A1 (ja) * 2016-10-06 2018-04-12 協和発酵バイオ株式会社 シチジンジリン酸コリンの結晶及びその製造方法
CN109790197A (zh) * 2016-10-06 2019-05-21 协和发酵生化株式会社 胞苷二磷酸胆碱的晶体及其制造方法
JPWO2018066690A1 (ja) * 2016-10-06 2019-07-25 協和発酵バイオ株式会社 シチジンジリン酸コリンの結晶及びその製造方法
AU2017341136B2 (en) * 2016-10-06 2021-07-08 Kyowa Hakko Bio Co., Ltd. Crystal of cytidine diphosphate choline and production method thereof
US11186605B2 (en) * 2016-10-06 2021-11-30 Kyowa Hakko Bio Co., Ltd. Crystal of cytidine diphosphate choline and production method thereof
RU2800932C2 (ru) * 2016-10-06 2023-08-01 Киова Хакко Био Ко., Лтд. Кристалл цитидиндифосфатхолина и способ его получения

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DE2019308C3 (de) 1981-04-09
BE749332A (fr) 1970-10-22
CH542858A (de) 1973-11-30
FR2042370A1 (enrdf_load_stackoverflow) 1971-02-12
NL7005785A (enrdf_load_stackoverflow) 1970-10-27
PH9528A (en) 1976-01-09
NL149812B (nl) 1976-06-15
CH542857A (de) 1973-10-15
FR2042370B1 (enrdf_load_stackoverflow) 1974-08-09
DE2019308B2 (enrdf_load_stackoverflow) 1980-08-21
CA954510A (en) 1974-09-10
LU60789A1 (enrdf_load_stackoverflow) 1970-06-29
DE2019308A1 (de) 1971-05-13
GB1261872A (en) 1972-01-26

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