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Details for Patent: 4,639,338

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Details for Patent: 4,639,338

Title: Preparation of crystalline disodium 3-amino-1-hydroxypropane-1,1-diphosphonate pentahydrate
Abstract:The invention relates to a novel crystal modification, containing water of crystallization, of disodium 3-amino-1-hydroxypropane-1,1-diphosphonate of the formula ##STR1## and to a process for the manufacture thereof. This modification is suitable for the oral treatment of disorders of the calcium and phosphate metabolism and associated diseases in warm-blooded animals.
Inventor(s): Stahl; Peter H. (Freiburg i/Br., DE), Schmitz; Beat (Allschwil, CH)
Assignee: Ciba-Geigy Corporation (Ardsley, NY) Henkel Kommanditgesellschaft auf Aktien (Dusseldorf-Holthausen, DE)
Filing Date:Jul 29, 1985
Application Number:06/759,985
Claims:1. Process for the manufacture of disodium 3-amino-1-hydroxypropane-1,1-diphosphonate in a crystalline form that contains water of crystallisation, characterised in that disodium 3-amino-1-hydroxypropane-1,1-diphosphonate is caused to crystallise from a water-containing solution or that a solid form of disodium 3-amino-1-hydroxypropane-1,1-diphosphonate containing relatively little water is treated with water, and in each case the product is isolated and dried at normal or slightly elevated temperature.

2. Process according to claim 1, characterised in that an approximately 10% to approximately 55% aqueous solution of disodium 3-amino-1-hydroxypropane-1,1-diphosphonate is concentrated at from approximately 70.degree. C. to approximately 80.degree. C. to the saturation concentration of disodium 3-amino-1-hydroxypropane-1,1-diphosphonate and crystallisation is effected by cooling slowly to approximately from 0.degree. C. to 5.degree. C., or in that an approximately 35% to approximately 45% aqueous solution of disodium 3-amino-1-hydroxypropane-1,1-diphosphonate is cooled from an initial temperature of from approximately 70.degree. C. to approximately 80.degree. C. until the start of crystal formation, but to not less than 55.degree. C., and crystallisation is effected by cooling slowly to from approximately 20.degree. C. to approximately 25.degree. C., adding approximately from 35 to 45% by volume (based on the total amount of water) of ethanol and cooling slowly to from approximately 0.degree. C. to approximately 5.degree. C.

3. Process according to claim 1, characterised in that a crystalline form of disodium 3-amino-1-hydroxypropane-1,1-diphosphonate that contains relatively little water is treated with at least that amount of water that is required for the formation of the novel crystal modification containing water of crystallisation and at most that amount of water that corresponds to the reciprocal value, reduced by 1, of the saturation concentration of disodium 3-amino-1-hydroxypropane-1,1-diphosphonate.

4. Process according to claim 3 characterised in that stirring is carried out with approximately from 2 to 3 times the amount by weight of water.

5. Process according to claim 1, characterised in that drying is carried out at from approximately 18.degree. C. to approximately 25.degree. C. or at from approximately 35.degree. C. to approximately 40.degree. C.

6. Process according to claim 1, characterised in that drying is effected under reduced pressure.

7. Process according to claim 1, characterised in that moist air having a relative humidity of from approximately 90% to approximately 99% is allowed to act on a crystalline form of disodium 3-amino-1-hydroxypropane-1,1-diphosphonate that contains relatively little water, at from approximately 20.degree. C. to approximately 25.degree.0 C., until there is a weight increase of at least approximately 32.2% by weight (taking into consideration the initial water content), and the atmospheric humidity is then gradually reduced to from approximately 35% to approximately 80%.

8. Process according to claim 1, characterised in that as the solid form of disodium 3-amino-1-hydroxypropane-1,1-diphosphonate that contains relatively little water there is used substantially anhydrous disodium 3-amino-1-hydroxypropane-1,1-diphosphonate.

9. Process according to claim 1, characterised in that as the solid form of disodium 3-amino-1-hydroxypropane-1,1-diphosphonate that contains relatively little water there is used disodium 3-amino-1-hydroxypropane-1,1-diphosphonate having a water content of approximately 5 to 10% by weight, determined by removing by heating at approximately 180.degree. C.

10. Process for the manufacture of disodium 3-amino-1-hydroxypropane-1,1-diphosphonate in a crystalline form that contains water of crystallisation by reacting 3-amino-1-hydroxypropane-1,1-diphosphonic acid with a basic sodium salt suitable for the partial neutralisation thereof, characterised in that 3-amino-1-Hydroxypropane-1,1-diphosphonic acid in a water-containing suspension and/or solution is reacted with the requisite amount of aqueous sodium hydroxide solution, the resulting disodium 3-amino-1-hydroxypropane-1,1-diphosphonate is caused to crystallise from an at least saturated water-containing solution in the form of the novel form containing water of crystallisation, and the product is isolated and dried at normal or slightly elevated temperature, wherein the reaction conditions are so selected that neutralisation takes place at from approximately 35.degree. C. to approximately 85.degree. C., initial crystal formation takes place at at least 50.degree. C. and crystal growth takes place predominantly at from approximately 50.degree. C. to approximately 0.degree. C.

11. Process according to claim 10, characterised in that a suspension of 10 parts by weight of 3-amino-1-hydroxypropane-1,1-diphosphonic acid in approximately from 18 to 23 parts by volume of water is neutralised at from approximately 65.degree. C. to approximately 85.degree. C. with that amount of approximately 30% aqueous sodium hydroxide solution that is required for the formation of disodium 3-amino-1-hydroxypropane-1,1-diphosphonate, that is to say approximately from 8.5 to 8.7, parts by volume, the resulting solution is allowed to cool to from approximately 70.degree. C. to approximately 55.degree. C. and, when crystal formation has begun or been initiated, then cooled slowly to approximately from 20.degree. C. to 25.degree. C., approximately from 7 to 12 parts by volume of ethanol are added and the whole is cooled slowly to approximately from 5.degree. C. to 0.degree. C. and stirred at this temperature for approximately from 1 to 15 hours, and the product is isolated by filtering with suction or centrifuging, washed in portions with a total of approximately 7.5 to 12.5 parts by volume of approximately 40 to 60% aqueous ethanol or that a suspension of 10 parts by weight of 3-amino-1-hydroxypropane-1,1-diphosphonic acid in approximately from 25 to 37.5 parts by volume of water is neutralised at an initial temperature of approximately 35.degree. C. with that amount of approximately 30% aqueous sodium hydroxide solution that is required for the formation of disodium 3-amino-1-hydroxypropane-1,1-diphosphonate, that is to say approximately from 8.5 to 8.7 parts by volume, the rate of addition thereof being so adjusted that the temperature rises to approximately from 50.degree. C. to 55.degree. C. and, when crystallisation has begun or been initiated, the whole is allowed to cool slowly to from approximately 18.degree. C. to approximately 25.degree. C., and the product is isolated by filtering with suction, washed in portions with a total of approximately from 15 to 25 parts by volume of from approximately 50 to 75% aqueous ethanol, and in either case subsequently dried under from approximately 5 to approximately 25 mbar at from approximately 35.degree. C. to approximately 40.degree. C. until the weight is constant.
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