MXPA96006165A - Procedure for removing disposal materials containing phosphorus, alendronate and sussubproduct - Google Patents

Abstract

The present invention relates to a process characterized in that it comprises the steps of: a) contacting an aqueous medium composed of omega-amino-amino-alkylidene salts of C2-C6-1-hydroxy-1,1-bisphosphonic acid, methanesulfonic acid, phosphorous acid and phosphoric acid, with a calcium chloride compound in an amount of 2-10 parts by weight of calcium chloride, taken as the anhydrous salt, to 100 parts by volume of the medium, b) contacting said solution from the step (a) ) calcium oxide in an amount sufficient to produce the precipitation of calcium / phosphorus-containing salts formed in step (a); c) contacting said mixture of step (b) with hydrochloric acid to adjust the pH of the aqueous portion of mixing at about 6-8 to produce the precipitation of calcium / phosphorus-containing salts; d) separating said precipitated mixture of calcium / phosphorus-containing salts from the aqueous medium

Description

, PROCEDURE TO REMOVE DISPOSAL MATERIALS CONTAINING PHOSPHORUS. RLENDRQNRTQ AND ITS SUBPRODUCTS BACKGROUND OF THE INVENTION 1- FIELD OF THE INVENTION This invention relates to a process for the treatment of phosphorus-containing materials, POx, alendronate and its byproducts from raw mother liquors of the bisphosphonate synthesis process using a CaClz / CaO precipitation / neatization process. 2. - BRIEF DESCRIPTION OF THE DESCRIPTIONS IN THE TECHNICAL The + nh? Dra + o of tpsodium of 4 ~ arn? No-l ~ * "" ÍdrOx? But? Leno-l? B? Són? Co, and alendronate-sodium, is a promising new agent to combat bone resorption in bone diseases including osteoporosis, particularly in postmenopausal women. The composition, utility and method of preparation are described in the U.S. patents. 4,922,007 and 5,019,551, both assigned to Merck a Co., Inc. Large-scale procedures as described in the above-mentioned countries to produce alendronat or-sodium generate large volumes of soluble phosphorus-containing materials JX) including sodium salts of phosphates, phosphites and pyrophosphate as waste. In general, the waste water treatment processing facilities (IRWTP) can handle on a total daily basis of approximately 1-10 ppm (g / l) of waste. However, the alendronate procedure can generate as many as 500 mg of phosphorus as P0X per liter of waste per day greatly exceeding the permissible limit? many geographic regions for processing wastewater and discharging effluent. A general approach to dealing with this problem has involved passing the waste stream to an acclimated sludge culture to biodegrade P0X waste and rnetansulonic acid (MSA) materials. However, this method suffers from the low amount of POx / MSfi that can process an activated sludge on a base "'' 'T.aria For example, of the waste load of 454 kg of biological oxygen demand material (BOD), the sludge can generally only handle 2.27 - 4.54 kg / day of phosphorus co or a food supplement What is desired in the art is a process for recovering and reusing, without a process, phosphorus-containing materials from wastewater, in an environmentally safe, efficient and cost-effective manner.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 illustrates a flowchart of an overall bisphosphonate process for the manufacture of alendronate-sodium. Figure 2 illustrates the step of calcium precipitation / phosphorus removal.

BRIEF DESCRIPTION PE LR INVENTION It has been found that residual materials containing phosphorus, POx, in aqueous raw mother liquors of the sodium bisphosphonate-alendronate process can be efficiently removed by a precipitation method involving the addition of calcium chloride, after the addition of lime. , followed by neutralization and filtration. The cake of "The P0 containing substance", which also contains alendronate from residual waste and byproducts of alendronate, can be disposed of by environmentally acceptable methods, eg, landfills, incineration or recirculation of phosphorus as fertilizer. process comprising the steps of: a) Contacting an aqueous medium, around pH 4-8, eg, solution, composed of salts, e.g., sodium, potassium, calcium, omega acid arnino alkylidene of Ca-Cβ-1-hydroxyl -1, 1-bisphosphonic acid, methanesulphonic acid, phosphorous acid and phosphoric acid, with calcium chloride compound in an amount of 2-10 parts by weight of calcium chloride , taken as the anhydrous salt, at 100 parts by volume of the medium, at about room temperature, b) putting said step means a) with calcium oxide in an amount sufficient to increase the pH to approximately 10- 12 to produce precipitation of salts and contain calcium / phosphorus, c) contacting said mixture from step b) with acid, hydrochloric acid, phosphoric acid, to adjust the pH of the aqueous portion of the mixture to about 6-8 to produce a substantially incomplete precipitation of salts containing calcium / forum. d) separating said precipitated mixture in calcium / phosphorus-containing salts from the aqueous medium.

BRIEF DESCRIPTION OF THE INVENTION AND PREFERRED MODALITY The chemistry of the global alendronate sodium procedure as shown in the following scheme includes 3 steps: a bisphosphonation reaction, a controlled aqueous extinction in terms of pH and a crude hydrolysis / crystallization step. The procedure can be carried out either as an intermittent or continuous procedure using normal appliances. The scheme is illustrated below: SCHEME pyrophosphanate y- ACIDO GAMA-AMINOBUTIRICO PW 295. PM 103.1 + HCl (g) + OLIGOMERS STEP 2 : SODIUM PIROPHOSPHANATE PIROFOSFANATO PM 295 PW 295 0 SODIUM ALENDRONATE. » PYROPHOSPHATE OF SODIUM TFIHIDRATE PM 325.1 In the bisphosphonation reaction (see EU patent No. 4,922,007), gamma aminobutyric acid (GABA) is reacted with phosphorus chloride (PC13) and phosphorous acid (HaP0) in neonic acid (MSA) as solvent. under reflux temperature, v.yr., B0-100 ° C, for about 0.5 to 3 hours. The reaction can generally be carried out at atmospheric pressure. As seen in the previous scheme, the initial product in the reaction is ¿and of os fato (PP) and nitrimeric alendronate precursors (not shown). The reaction mixture is then quenched in water under pH control using aqueous caustic soda at a pH maintained from about 4 to 7. Then, the pH is adjusted to 4-5, e.g., 4.3-4.7 and warmed or pressure, e.g., 1 to 10 atmospheres, a useful scale being 1-4 atmospheres, at a temperature of about 100 to 150 ° C for about "" at 30 hours to substantially convert pyrophosphate and multimeric precursors to alendronate-sodium. The small residual fraction that is not converted to alendronate-sod or is called "alendronate byproducts". The crude crystallization is carried out by cooling the hydrolysis mixture to about 10-60 ° C, e.g., 50 ° C and adjusting the pH to about 4-5, a useful scale being 4.2-4.7, by addition of aqueous caustic soda or hydrochloric acid, producing alendronate-sodium tphidratado) crystalline which is filtered, collected, purified and processed.

The overall process flow diagram for the manufacture of alendronate-sodium is shown in figure 1. As can be seen, the limitation of gravel is prepared from the mixture of GABA, USA and HaP03 and fed to the reaction vessel of bis phonation together with PC13 to form pyro osphate (PP). After the bisphosphonation step, the reaction mixture is reacted with caustic soda in a pH passage under controlled pH conditions of pH 4 to 7 to form sodium pyrophosphate (other pyrophosphates are not shown ) and then heated under elevated pressure and temperature in a subsequent hydrolysis step to form alendronate-sodium. The hydrolysis mixture is cooled to a pH of 4 to 5 and the alendronate monosodium trihydrate is allowed to precipitate as a mass of crude crystallization. Alendronate-sodium crystallized in crude oil is filtered, The humid surface is then washed with a minimum amount of cold demystified water (DM) separated from the raw mother liquors and then subjected to a pure crystallization step from water. The pure crystallized alendronate-sodium which is of pharmaceutically acceptable quality is collected and milled to produce alendronate-pure sodium, in bulk, ground, which can then be processed for formulation of pharmaceutical doses. The gaseous side products of the Phosphonation step, which subsequently contain HCl, PCla and vapor, of the extinction steps and in crude oil containing minimum amounts of dimethyl disulphide (DMDS) are passed to a This scrubber contains water, caustic soda and sodium hypochlo- prate to produce a wastewater stream that contains predominantly a mixture of NaaHPOa, N sjHPO-v NaaP03, Na3P04 and sodium chloride that can be discharged to a waste water installation under controlled conditions. The raw mother liquors (L) can be passed over a bed of activated carbon to remove disulfide from dirnet., DMDS and the filtrate are collected in a tank for precipitation of PO ^ / lendronate. The P0. " it can be partially or totally removed by the C Cls? / C O precipitation procedure here. The crude mother liquors are first passed over a bed of activated charcoal to remove di ethyl disul urate (JMDC) and then passed to a precipitation tank for CaCla / CaO co adjustment or shown in figure 2. The novel aspect of this invention involves a new form for the processing / reuse / disposal of the raw mother liquors produced. The raw mother liquors (L) contain approximately 5-10% by weight of phosphate and phosphite as P0", 22-25% of MSA, 5% NaCl, 1-2% of GABA, 0.5-1% of alendronate and byproducts and 60-65% water In the initial step, the CaCl compound is added in an amount of from about 2 to 10% by weight by volume of mother liquor and generally 2-4% by weight, or by anhydrous CaClz. CaCl2 is generally used for convenience as the hexahydrate, although the anhydrous form, which is expensive, can also be used. The purpose of first adding each in the procedure is to increase the ionic strength of the liquid medium and separate the calcium / phosphorus salts subsequently formed. Then, CaO (lime) is added in a sufficient quantity, usually 3-7% by weight / ol, and generally around 5% w / v to dissolve in the mother liquors and to produce a pH about 10-12 to facilitate subsequent precipitation to the P0 species ?. Next, the mixture is neutralized by the addition of e.g. hydrochloric acid to reduce the pH to about 6-8, e.g., 7. The resulting suspension is left for about 2-4 hours to ensure a maximum possible precipitation of all PO ^ species in mother liquors. Eliminating the addition of CaCla- from the neutralization step, all results in the recovery of reduced POx. Repairs of P0? of about 90-95 +% are achieved by this described method of the invention. However, using the CaO step only gives approximately 60% recovery. In addition, using the addition of CaCla / CaO without the neutralization step yields 8% recovery.

An additional advantage of this P0 removal methodology? is that residual alendronate-sodium, being the active drug ingredient, as well as alendronate byproducts, are also selectively and quantitatively removed from the P0 filter cake? After precipitation of CaO, the suspension is filtered and washed with water, a useful form being de-mineralized (DM) water. The filtered products are cyclized to the wastewater treatment plant, or to solvent recovery, or if they are sufficiently low in P0 ?, at one step of bacterial biodegradation for treatment with M fl before moving to WUTP. A step of microbial biodegradation involving an acclimated sludge culture can be used to biodegrade MSA, in which higher concentrations of M ñ, in waste water are fed to the sludge while maintaining the pH, ^ D, hydraulic residence time and mud density within optimized processing limits. The filter cake of PO *. precipitated, containing predominantly CaHPO-3, CaHPOA and alendronate calcium, can be dried and used in landfill, incinerated or recirculated to a fertilizer plant for the extraction of usable phosphorus. At moderate production levels, this procedure can be carried out intermittently. However, the PO reduction procedure "can also be done in < , Continuous ration at full production scale. The P0 removal efficiencies in the procedure are the function of the reagents used and the pH.

An alternative reagent useful in the precipitation of P0"is A1 (0H) 3, but this only adds a new cation to an already complex waste stream. Also, it was found that l *** is less effective than Ca ** in the removal of P0 «from this current. The recovery procedure of PO? described can also be used in other bisphosphonation processes wherein the appropriate amino acid starting material can be used to produce the following omega amino alkylidene acids of CSZ-CA-I, 1-bisphosphonic acids: 2-amino-1-amino acid Hydro-oxyisob? tiiiden-l, 1-bisphosphonic acid, 3-amino-l-hydroxy-propylidene-1, 1-bisphosphonic acid, 5-arnino-l-hydroxy? entiidene-1,1-bisphosphonic acid and 6-amino acid -l-hydroxyhexylidene-1,1-bisphosphonic acid. The term "omega amino" is used herein to indicate the presence of an amino group on the terminal carbon of the alkylidene chain at the other end of the bisphosphonate carbon atom. The following examples are illustrative for carrying out the invention as contemplated by the inventors.

Neutralization of CaCl ^ / CaO ñ 1 liter of crude ML of alendronate sodium treated i .. < ) carbon (to remove DMD?) (pH -4.5) at room temperature (20-25 ° C), add 70 g of calcium chloride (CaCla) and stir for 15 minutes (pH -4 .T = 20 ~ 25 ° C). Then, 50 g of lime (CaO) are added and mixed rapidly for 30 minutes (pH 12). The pH and temperature generally increase to approximately 12 and -45 ° C, respectively. Concentrated HCl (36%) is then added to adjust the pH of the mixture to about 7. Several additions of HCl may be required to stabilize the pH at 7. Approximately 75 L of 36% HCl are required. The neutralization is complete when the pH stabilizes at about 7 for at least 10 minutes. The increase in temperature is generally minimal (<5 ° C). The mixture is allowed to stir for 5 minutes, then it is filtered using Whatman # 4 filter paper in a funnel of The filter cake is washed with 2-5 volumes of demineralized water to remove the residual MSA from the NaCl filter cake.The washes are combined with the filtrate for the recovery of MSA. Total filtration is generally about 1 <1. The filtered product can be treated by means of an activated sludge system, described above.The CaPOx cake is saved for final disposal. 96-98% The overall procedure for the removal of P0? Is written as: ML crude + 70 g / l CaCl2 (mixing) + 50 g / L lime (mixing) + pH adjustment using HCl at -7, followed by filtration and washing with demineralized water. Repeating the above procedure in the absence of the addition of CaCla and the neutralization steps only result in a recovery of P0? of approximately 60%. Repeating the above procedure in the absence of the final pH neutralization rate only results in a recovery of P0? of approximately 88%.

REFERENCES Baker, S.C., Kelly, D.P. and Murrell, 3.C. , "Microbial Degradation of Methanesulphonic acid: 0 Missing Link in the Biogeochernical S? Lfur Cycle". Nature, 350-527-8, 1991. Ruth, 3., "Odor Thresholds and Irritation Levéis of Several Chemical Substances: 0 Review", ñm. Ind. Hyg. fissoc. 3., 47, 142-150, 1986. Patent of E.U.P. 4,938,846 to Comstock, and others, (assigned to flTOCHEM North America, Inc.) Patent of E.U.fi. No. 4,922,007 to Kieczykowski, et al. (Assigned to Merck 8 Co., Inc.). Patent of E.U.H. No. 4,450,047 (assigned to Elf-Otochern). Patent of E.U.ñ. No. 5,019,651 (assigned to Merck to C., Inc.). Venkataranani, E.S., Vaidya, F., Olsen, U. and Uittner, S., "Créate Dr? Gs, Not Uaste - Case Histories of One Conpany's Successes," Chemtech, p. 674, November 1992. Uierenga, D.E. and Eaton, C.R., "The Dr? g Develop in and fl approach Process," p. 10 in "New Drug fipprovals in 1992" presented by the Pharnaceutical Man? fact? rers Ossociation (Association of Pharmaceutical Manufacturers), January 1992.

Claims (10)

NOVELTY PE R INVENTION CLAIMS

1. - A process comprising the steps of: a) contacting an aqueous medium composed of omega-to-alkyl-alkylidene salts of Ca-Cs-l-l-hydroxy-1, b-phosphonic acid, net acids, co, phosphorous acid and phosphoric acid, with a calcium chloride tax in an amount of 2-10 parts by weight of calcium chloride, taken as the anhydrous salt, to 100 parts by volume of the medium; b) contacting said solution of step (a) with calcium oxide in an amount sufficient to produce precipitation of salts containing calcium / phosphorus; c) contacting said mixture of step (b) with acid to adjust the pH of the aqueous portion of the mixture to about 6-8 to produce precipitation of salts that - calcium / phosphorus; d) separating said precipitation mixture of calcium / phosphorus-containing salts from the aqueous medium.

2. A process according to claim 1, further characterized in that said acid omega arrimo alq? Ilideno of Cß-Cs-1, 1-b? Sfosfómco is selected from acid 4-am? No-lh? Drox? But l ? den-1, l? b? phosphon? co, 2-ammo-1-hydrox acid? ? sobut? l? den-l, 1-b? sfosfóm co, 3-apuno-l-hidroxi pro? l? den-1, 1-b? sfosfóm co, acid 5-arn? no-lh? drox? pent? i? den-1, 1-b? syphosphon co and acid 6-arnmo-l- Y? rox? hex? l? den ~ l, 1-b? sphosphon? co.

3. A process according to claim 2, further characterized in that said omega-arnino alkylidene acid of C_t -CA-1, b-phosphon? Co is 4-amino-l-hydroxybutyl acid. l? den-1, 1-b? phosphon? co.

4. A process according to claim 1, further characterized in that said salts of omega-amino-alkylaidene acid of Ca-C-1, 1-hydroxyl-1, -phosphonic, methane-1-phonic acid , phosphorous and phosphoric acids are sodium salts.

5. A method according to claim 1, further characterized in that said calcium chloride compound is the hexahydrate form.

6. A process according to claim 1, further characterized in that said calcium chloride in step (a) is present in an amount of 2 to 7%? * "» Weight / volume of the mother liquor.

Process according to claim 1, further characterized in that said pH in step (d) of about 10-12

8. A process according to claim 1, further characterized in that step (e) the acid added is acid hydrochloric 9.- A precipitated mixture of salts containing calcium / phosphorus produced by the process of claim 1.

10. - The precipitated mixture of claim 9 which contains alendronate ..