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    • 专利摘要:
    abstract patent of invention: "preparation of gadobutrol of high purity". the present invention relates to a process for producing the high purity gadobutrol in a purity (according to hplc) greater than 99.7 or 99.8 or 99.9% and the use for the preparation of a pharmaceutical formulation for parenteral administration. the process is carried out using specifically controlled crystallization conditions. the most recent developments in the field of gadolinium-containing mr contrast agents (ep 0448191 b1, ca ca 1341176, ep 0643705 b1, ep 0986548 b1, ep 0596586 b1) include the mrt gadobutrol (gadovist (r) 1.0) contrast agent which was approved for a relatively long time in europe and more recently also in the us under the name gadavist (r).
    公开号:BR112013027028B1
    申请号:R112013027028-4
    申请日:2012-04-17
    公开日:2020-08-11
    发明作者:Johannes Platzek；Wilhelm Trentmann
    申请人:Bayer Intellectual Property Gmbh；
    IPC主号:
    专利说明:

    [0001] The present invention relates to a process of preparing gadobutrol in high purity, gadobutrol in a purity greater than 99.7 or 99.8 or 99.9% and the use for the preparation of a pharmaceutical formulation for parenteral application.
    [0002] The most recent developments in the field of gadolinium containing MR contrast agents (EP 0448191 B1, US 5,980,864, EP 0643705 B1, EP 0986548 B1, EP 0596586 B1) include the MRT contrast agent gadobutrol (Gadovist® 1.0) which was approved for a relatively long time in Europe and more recently also in the USA under the name Gadavist®.
    [0003] The action of the contrast is based on gadobutrol, a nonionic complex consisting of gadolinium (III) and the macrocyclic ligand dihydroxy hydroxymethyl propiltetraazo cyclododecane triacetic (butrol), which leads among other things in clinically dosages recommended for shorter relaxation times of water protons in tissues,

    [0004] Due to their importance for diagnostic imaging, particularly as MRI diagnosis, metal complexes, particularly the gadolinium complex N- (1-hydroxymethyl-2,3-dihydroxypropyl) -1,4,7-triscarboxymethyl -1,4,7,10-tetraazocyclododecane "gadobutrol" (DE 4009119) can be prepared by several routes. Despite the progress made in comparison to the original processes, there is still a need for synthesis that is more environmentally friendly and cost-effective, and is suitable for implementation especially on an industrial scale. In particular, there is a high demand for high product productivity and high quality. In recent years, there has been a trend to replace some or all open-chain contrast agents with cyclic contrast agents. Here, there is a requirement for the production of particularly pure products, which additionally must also be profitable. In general, these are requirements that are mutually exclusive, as high quality products are expensive to produce due to specific purification measures. For optimum quality control, it is necessary to have available a highly reliable method of analytical determination that allows the detection and quantification of all the less relevant components present.
    [0005] Consequently, there is a need for an economically favorable process for the production of gadobutrol, and also for an analytical method that allows the selective detection and quantification of minimum quantities of less relevant components (production monitoring).
    [0006] Very important aspects in the preparation of gadobutrol are quality and production costs of the final product. Due to regulatory requirements, high quality standards have to be adjusted. Of interest in this context are the purity and content of the active compound. Linked to purity, it is particularly the spectrum of by-products having to be monitored. The less relevant components have to be toxicologically qualified and evaluated. Consequently, they are listed in specifications and the maximum occurrence in the product is defined. For product safety reasons and for the sake of the patient, the by-product spectrum and / or the presence of individual contaminants is kept as low as possible.
    [0007] In this context, the polymorphism of the active compound is of importance, since this is closely related to solubility in water and the storage period. Consequently, it is desirable for the process according to the invention to produce the polymorphic form having a better solubility in water and is the most stable through storage.
    [0008] The prior art describes a highly profitable preparation of gadobutrol starting from the cyclene (1,4,7,10-tetraazocyclododecane) of formula 1, which is known in the literature (DE19608307

    [0009] The prior art very close (Inorg. Chem. 1997, 36, 6086-6093 and DE 19724186 A, DE19608307 A) and EP 1343770 B1 describe processes where the butrol binder is isolated as a lithium complex and further converted into the product Final.
    [00010] It is an objective of the present invention to provide a process that allows gadobutrol to be produced in high yield and highest purity (in accordance with the specification).
    [00011] This objective is achieved by the invention, a process of producing gadobutrol with high purity (= the gadolinium complex of N- (1-hydroxymethyl-2,3-dihydroxypropyl) -1,4,7- triscarboxymethyl- 1,4,7,10-tetra-azocyclododecane) which comprises the reaction of the starting material cyclene (1,4,7,10-tetra-azocyclododecane) with 4,4-dimethyl- 3,5,8 -trioxobicyclo [5.1,0] octane and lithium chloride in alcohol at elevated temperatures, alkylation with sodium monochloroacetate in alkaline medium, working under acidic conditions, removing salts and adding gadolinium oxide, then adjusting the pH with lithium hydroxide at a slightly basic neutral value, concentration of the solution and addition of alcohol, then heating under reflux and, after cooling, isolation and drying of the crude product, dissolution of the crude product in water and purification in exchange resin ionic, then treatment with activated carbon followed by sterile filtration, then boiling under reflux, cooling and isolation ning and drying the product.
    [00012] This is particularly a process where the starting material cyclene (1,4,7,10-tetra-azocyclododecane) is reacted with 4,4-dimethyl-3,5,8-trioxobicyclo [5.1,0] octane and lithium chloride in isopropanol at high temperatures, then distilled in water and alkylated with sodium monochloroacetate in an alkaline medium, worked under hydrochloric conditions, the salts are removed by the addition of methanol and the crude binder is reacted with the oxide of gadolinium in water at elevated temperatures, the pH is then adjusted with lithium hydroxide from 7.1 to 7.4, the solution is concentrated and the ethanol is added in such an amount that a water content of 7 to 17%, preferably from 8.0 to 9.0%, are reached, the mixture is then heated under reflux for at least 60 minutes and the crude product is, after cooling, isolated and dried, preferably dried at 46 to 48 ° C, the crude product is then dissolved in water and purified in an ion exchange resin cascade, where the solution is passed through through the acidic ion exchange resin and then through the basic, the purified solution, having a conductivity <40 pS / cm, is then concentrated, treated with activated carbon, subjected to sterile filtration and, by the exact addition of ethanol, is adjusted to a water content in the range of 7 to 17%, preferably approximately 11%, then boiled under reflux and cooled, and the product is isolated and dried.
    [00013] This is a particular process where the starting material cyclene (1,4,7,10-tetra-azocyclododecane) is reacted with 4,4-dimethyl-3,5,8-trioxobicyclo [5.1,0 ] octane and lithium chloride in isopropanol at elevated temperatures, then distilled in water and alkylated with sodium monochloroacetate in an alkaline medium and worked under hydrochloric conditions, the salts are removed by the addition of methanol and the crude binder is reacted with gadolinium in water at elevated temperatures, the pH is then adjusted with lithium hydroxide from 7.1 to 7.4, the solution is concentrated and the ethanol is added in such an amount that a water content of particularly preferably 8.5% is reached, the mixture is then heated under reflux for at least 60 minutes and the crude product is, after cooling, isolated and dried at 46 to 48 ° C, the crude product is then dissolved in water and purified in a cascade of ion exchange resin, where the solution is first passed through the exchange resin acidic ion and then through the basic, the purified solution, having a conductivity <20 pS / cm, is then concentrated, treated with activated carbon, then subjected to sterile filtration and, by the exact addition of ethanol during the period of 120 minutes, adjusted to a water content of 10 to 12%, preferably 11%, then boiled under reflux and cooled, and the product is isolated and dried, preferably dried at 53 to 55 ° C.
    [00014] For ion exchange resin cascades, the following ion exchange resins are used in the process:
    [00015] Suitable ion exchange resins are the usual commercial ion exchange resins.
    [00016] Advantageously, the acidic ion exchange resin used is Amberlite IRC 50, and the basic ion exchange resin used is IRA 67. After this purification by a cascade of ion exchange resin, where the solution is first passed through the resin of acidic ion exchange and then through the basic, the solution thus purified, having a conductivity <20 pS / cm, is then concentrated, treated with activated carbon, such as Norit SX Plus activated carbon, then subjected to sterile filtration and, by the exact addition of ethanol over the period of 120 minutes, adjusted to a water content of preferably 11%, then boiled under reflux and cooled, and the product is isolated and dried at 53 to 55 ° C.
    [00017] A detailed description of the new process according to the invention is given in detail: • After complexing the butrol binder, present in the aqueous solution, with gadolinium oxide (120 minutes, 90 ° C) and adjusting the pH with the lithium hydroxide monohydrate at pH 7.1 to 7.4, the mixture is substantially concentrated under reduced pressure. Ethanol is added to the remaining solution. Here, it is ensured that the final water content reached is 7.0 to 9.5%, preferably from 8.0 to 9.0%, and particularly preferably 8.5% (this is achieved by the new addition of ethanol or alternatively water). The mixture is heated under reflux (60 minutes), and stirring is continued at a jacket temperature of 100 ° C for 480 minutes. The mixture is cooled to 20 ° C. The crude product is isolated using a centrifuge or pressure nutsch filter, and the filtered cake is washed with ethanol and then dried at 58 ° C (jacket) under reduced pressure until an internal temperature of 48 ° C is reached. • The crude product (gadobutrol, crude) is dissolved in water. The new purification is carried out via a cascade of ion exchange resin in the following way: the aqueous solution is initially added to the acidic ion exchange resin AMBERLITE IRC 50. The eluate is then added directly to the basic ion exchange resin IRA 67. The eluate is pumped back over the acidic ion exchange resin etc. The solution is recycled until the conductivity of the solution has reached a value <20 pS / cm. In the thin layer evaporator, the solution is then carefully and gently concentrated to 50 mbar. The ion exchange resin treatment provides a product that is already of very high quality. The analysis shows that very few quantities of the following components are still present: See Figure 14, formula III.
    [00018] Due to its negative charge, Gd-DOTA is completely adsorbed on anionic ion exchange resin. Gd-DO3A is an electrically neutral compound and is therefore not absorbed into the ion exchange resin. In contrast to two other impurities (di-TOBO ligands and butrol ligands), Gd-DO3A has a more lipophilic nature. However, surprisingly, the analysis detects the di-TOBO diastereoisomeric ligands (the potential Gd complexes, which are not very stable, can lose the gadolinium in the cationic ion exchange resin). In addition, the occurrence of the free butrol ligand is observed (here, too, the acidic ion exchange resin can remove Gd from the complex). For the person skilled in the art, the occurrence of di-TOBO ligands and butrol ligand after this purification step is surprising, since it would be expected that potentially substances containing amine and acid groups are quantitatively absorbed by the ion exchange resin.
    [00019] Since the 3 by-products mentioned are the critical impurities that in all cases must be kept as low as possible, a new purification step is necessary. Here, the conditions have to be chosen in such a way that the maximum yield with the optimum quality is reached.
    [00020] By adding water, the concentrated fraction containing the ion exchange purification product is adjusted to a concentration of 19.1 to 20.9% (w / w). This is followed by treatment with activated carbon, the goal of which is the greatest possible reduction in the product's endodoxin value (preparation for parenteral administration). At this end point, the product is stirred with NORIT SX plus (conductivity 20 pS) at 20 ° C for 60 minutes and then separated from the carbon by filtration, and the filtrate is filtered through a sterile filter plug and concentrated gently under reduced pressure ( jacket temperature up to 80 ° C). The jacket temperature is lowered to 75 ° C and a first partial amount of ethanol is added, a second partial amount of ethanol is then added over the period of 120 minutes in such a way that the (internal) temperature does not fall below 72 ° Ç. The water content of the solution is determined according to the Karl-Fischer method. The value should be 10.0 to 12.0, preferably 10.5 to 11.5%, particularly preferably 11%. If the desired value is not reached, it can be precisely adjusted by adding water or ethanol again. The mixture is then boiled under reflux for 120 minutes. The mixture is allowed to cool to 20 ° C and the product is isolated using a centrifuge or a nutsch pressure filter, the filtered cake being washed with ethanol.
    [00021] The drying of pure gadobutrol is carried out under reduced pressure at an internal temperature> 53 ° C and a jacket temperature of 55 ° C. The final product is placed in aluminum-coated PE bags. By the appropriate selection of drying parameters, it is possible to reduce the residual amount of ethanol to <202 ppm.
    [00022] The invention also relates to gadobutrol of a purity (according to HPLC) greater than 99.7 or 99.8 or 99.9% and to gadobutrol of a purity greater than 99.7 or 99.8 or 99 , 9%, comprising less than 0.01% gadolinium III ions, having a residual ethanol solvent content of less than 200 ppm and comprising the butrol binder (= N- (1-hydroxymethyl-2,3-di -hydroxypropyl) -1,4,7- triscarboxymethyl-1,4,7,10-tetra-azocyclododecane) in a proportion of less than 0.03%.
    [00023] One requirement is to keep the content of the free complex builder (butrol ligand, formula 3) as low as possible.
    [00024] During the preparation of the pharmaceutical composition GADO-VIST® a small excess of complex builder (of the order of approximately 0.1%) in the form of the calcium / butrol complex (Inorg. Chem. 1997, 36, 6086-6093) is added to the formulation. Calcobutrol is an additive in pharmaceutical gadobutrol formulations and has the task of preventing a release of free gadolinium in the formulation (solutions) (see EP 0 270483 B2).

    [00025] This approach ensures maximum stability of aqueous solutions and allows storage for a relatively long period of time. The problem encountered during the storage of contrast agents comprising gadolinium in aqueous solution is the transchelation of gadolinium in the complex with metal ions in the glass of the flasks (eg Zn, Cr, etc.), which also form stable complexes and would result in formation of toxic free gadolinium ions. If no excess of the complex builder is added to the formulation, free gadolinium is formed. In contrast, the thermodynamically less stable calcium complex of the butrol ligand readily exchanges calcium. As calcium is a naturally occurring element in the body, it is toxicologically acceptable and thus ensures the patient's absolute safety (the formation of free gadolinium can be excluded with absolute certainty).
    [00026] The excess of the complex builder (in the form of the calcium complex) in the formulation is limited by a very narrow specification (from 0.08 to 0.14%), and the use of gadobutrol with high purity in which the proportion of the butrol ligand is as low as possible is, therefore, a pre-condition otherwise the excess of the total complex builder would be> 0.14 mol% (sum of calcium / butrol complex and butrol ligand). This takes batches "out of specification", that is, batches that do not fit the specification, in pharmaceutical production, which would result in considerable economic losses. This represented a serious problem in the initial preparation of gadobutrol and there was, therefore, an urgent need to control this less relevant component (butrol binder) by a stable production process and by a sensitive analytical method.
    [00027] An essential prerequisite for the preparation of gadobutrol with high purity is a special analytical method that allows the detection and quantification of main products and by-products (impurity). For a long time, the main problem specifically in the gadobutrol analysis was this quantification of the proportion of the free butrol ligand. Detection that was already by a non-selective titration method (see examples), di-TOBO ligands (see formula scheme below) were also measured and the totalization was shown. All gadobutrol batches prepared according to the prior art were characterized by this "totalization method". As for the critical limit described above based on the content of the free complex builder (butrol ligand), this was an absolutely unsatisfactory situation, which had to be resolved. In addition to the objective of providing an excellent preparation process that provides a product of excellent quality, it is thus another objective to provide an analytical process for selective monitoring of the main impurity that allows the determination of the butrol binder and di-TOBO binder content with a accuracy <0.01%. Only by combining the preparation and analysis process, it is possible to produce gadobutrol> 99.7% (=> 99.9% a spot / peak quality).
    [00028] The new process according to the invention allows, by combining specifically controlled crystallization conditions, together with a highly selective analytical method, to detect <0.01% by-products, and thus provide very good control over the purity of the gadobutrol active compound, and keep the level of impurities as low as possible.
    [00029] The preparation scheme below serves to illustrate the source of the main gadobutrol impurity: See Figure 12, Formula II
    [00030] Starting with cyclene (1,4,7,10-tetra-azocyclododecane), which is known in the literature, in a first stage in which the bicyclotrioxaoctane ring (TOBO) is fused as described in EP 0986548 B1 ( Schering AG) (opening the epoxide with lithium chloride in isopropanol under reflux leads to N- (6-hydroxy-2,2-dimethyl-1,3-dioxepanyl-5) - 1,4,7 complex, 10-tetra-azocyclododecane / LiCl). In addition to the desired mono-substituted compound, two new compounds are obtained as by-products. These are the double alkylated products (Di-TOBO = 1,7- and 1,4-bis (N- (6-hydroxy-2,2-dimethyl-1,3-dioxepan-5yl) -complex1,4,7 , 10- tetraazacyclododecan / LiCI), which are also obtained in the form of Li complexes (4 diastereoisomers of substituted compounds 1,4- and 1,7- in racemic form, that is, a total of 8 species). After the reaction, the products are not isolated but the mixture is directly further processed.The crude product from this reaction step still comprises the unreacted residual cyclene (1) which is transferred to the next step (by distillation, the isopropanol solvent is replaced with the water).
    [00031] In the next step, using the sodium salt of chloroacetic acid, the products are alkylated under controlled basic conditions to provide the corresponding acetic acids (butrol step). It is important to keep the pH> 12 always. In this process step, the impurity contained in the main product is also alkylated, giving a characteristic impurity spectrum at this stage. In addition to the diastereoisomeric ligands di-TOBO, DOTA and DO3A (by incomplete alkylation) are formed from cyclene. After acid work with hydrochloric acid, the salts (mainly NaCl) are filtered out after the addition of methanol and the butrol binder is prepared as an aqueous solution for complexing with gadolinium oxide.
    [00032] Complexation with gadolinium oxide in water gives a corresponding crude product which, as a main component, essentially comprises gadobutrol. However, the by-products described above are also complexing binders by gadolinium, and they provide the corresponding Gd complexes (4 diastereoisomeric complexes of Gd-di-TOBO, Gd-DOTA, Gd-DO3A).
    [00033] In these terms, the process is analogous to the prior art procedure. The prior art describes the use of ethanol for crystallization of raw and pure gadobutrol, and aqueous ethanol is also mentioned.
    [00034] Surprisingly, it has now been found that, by properly selecting the crystallization parameters in both the raw and pure stages of gadobutrol, it is possible to achieve excellent yields and superior product qualities.
    [00035] What is new is the specific procedure described below that allows the preparation of gadobutrol with high purity having purity (according to HPLC)> 99.7 or 99.8 or 99.9% in 4 process steps:

    [00036] An important factor in the new process according to the invention is, surprisingly, the exact adjustment of a certain water content in the crystallization of both the raw product and the pure product. Surprisingly, the limits are very narrow and provide optimal results only in this range. Surprisingly, by selecting a specific water content, it is possible to reduce the amount of both, the lipophilic impurity (eg DO3A) and also the strongly hydrophilic impurity (di-TOBO ligands, butrol ligand), with an optimum total yield of gadobutrol. For the person skilled in the art, this was not obvious, and was therefore surprising to everyone.
    [00037] The total yields obtained in the new process according to the invention (starting with the cyclene) are excellent and are shown in the table below:

    [00038] In combination with very high purity, such a high total yield leads to a significant economic improvement in the production process.
    [00039] The schematic representation below summarizes how the total yield and purity are related to the water content in the final crystallization (the principle also applies to the first crystallization):
    [00040] See Figure 4: Yield, purity and water content after final crystallization.
    [00041] With increasing water content (left side), a reduction in yield and at the same time an increase in lipophilic impurity are observed. With reduced water content (right side), the yield increases; however, at the same time the proportion of hydrophilic impurities increases. Consequently, it was very surprising that such a high total yield (compared to the prior art) could be achieved combined with excellent quality.
    [00042] A new important point of the process according to the invention is based on the fact that practically only one major polymorph is obtained in the preparation (a second unwanted polymorph is also observed, but only in insignificant quantities). The physical properties are of great interest and very important because they are related to the stability in storage and the solubility of the product. With a long shelf life, it is possible to produce stocks of the product that can then be used to produce the pharmaceutical preparation, in this case GADOVIST®, on request. This allows for optimal flexibility in the preparation process.
    [00043] It is found that 2 polymorphs are present in the form of monohydrates (water content 3 to 3.5%):
    [00044] Monohydrate I and monohydrate II (see examples at the end).
    [00045] It has been found that when a very high purity, preferably> 99.7 or 99.8 or 99.9%, is achieved, what is present is substantially the polymorph I. This is important since this polymorph also has more favorable properties compared to polymorph II, particularly regarding the solubility of polymorphs in water. The best solubility of polymorph I ensures optimal preparation of pharmaceutical formulations (solutions for parenteral administration in water). Of special interest here is the 1 molar solution of GADOVIST® which is specifically based on the high solubility of gadobutrol. The better the solubility of the material in pharmaceutical production, the better and more reproducible the process. This ensures high security and reproducibility in the preparation.
    [00046] Solubilities of polymorphs I and II in water.
    [00047] The table below shows the solubility of the two polymorphs I and II of gadobutrol at 20 ° C in water.

    [00048] The values determined for gadobutrol solubility show that it is soluble in water in almost any reason. Surprisingly, polymorph I monohydrate I is more soluble than monohydrate II. This is favorable in relation to the formulation preparation process, but has no effect on the safety of the preparation (in the case of polymorph II, longer agitation is required / in general, batches comprising a proportion of polymorph II are not used because of a standardized preparation process).
    [00049] Stability in storage.
    [00050] The three batches of monohydrate I and one batch of monohydrate II were kept under ICH conditions. Both forms remained unchanged for 6 months at 40 ° C / 75% relative humidity and for 36 months at 25 ° C / 60% relative humidity and 30 ° C / 75% relative humidity. No de-composition products were observed, and no other parameters of the specification have been substantially modified. In storage, the batches maintained their solid state.
    [00051] Behavior of monohydrates during the preparation of the pharmaceutical composition.
    [00052] The differences between the two monohydrates I and II were observed during the dissolution of the active compound. In general, the time required to put monohydrate I in solution is 45 minutes at 40 to 50 ° C. During this time, monohydrate II was not completely dissolved. For dissolution, significantly longer periods of time were required.
    [00053] Analytical characterization of gadobutrol.
    [00054] As already mentioned, the main problem in the analysis was the analysis of the differentiation and the quantification of the butrol ligand and the di-TOBO ligand. Surprisingly, conditions were found that allowed the determination of this main impurity with an analytical accuracy <0.01%, which represents a major break in the entire production chain. With this process, for the first time, it was possible to differentiate the crystallization processes in relation to their efficiency and productivity. The tables below show the essential parameters of this method (see also the examples). HPLC conditions Column length: 250 mm Bore diameter: 4.6 mm Stationary fasel: Luna Fenil-Hexil 3 pm Column temperature: 50 ° C Self-sampling temperature: 10 ° C Flow rate: 1.0 mL / min Detector Corona: 100 pa UV detector: 195 nm Flow rate: 1.0 mL / min Gradient parameters: Mobile phase A: 0.0025% strong formic acid + 0.5% mobile aceton itri la Mobile phase B: acetonitrile.

    [00055] The quality of the gadobutrol batches prepared by the new process according to the invention for specific crystallization can be summarized as follows:

    [00056] The process according to the invention allows the profitable production of gadobutrol in individual batches on a 100 kilogram scale. Here, selecting the crystallization parameters, it was possible to achieve the optimal yield combined with an optimum purity. Due to the high purity, it is possible to produce polymorph I in a reproducible way, which means firstly great flexibility in relation to the storage of the active compound and secondly a good dissolution rate in the production of the pharmaceutical formulation.
    [00057] The invention further comprises the use of gadobutrol with high purity to produce a pharmaceutical formulation for parenteral administration. The conditions of such preparation are known to the prior art and are familiar to the person skilled in the art (EP 0448191 B1, Patent CA 1341176, EP 0643705 B1, EP 0986548 B1, EP 0596586 B1).
    [00058] The invention is illustrated by the examples below, where the following analytical methods were used:
    [00059] Methods: 1) Methods used to determine purity:
    [00060] The method described below was used first and also served to determine the purity of the preparation processes described in the prior art. I .1. Method: non-selective photometric titration of free complex builders.
    [00061] Principle of the method:
    [00062] The active compound is quantified by titration. The change in color is monitored photometrically.
    [00063] Reagents: 1N sodium hydroxide solution 1% hydrochloric acid [m / V] Water Rg 0688, indicator / buffer solution III 0.00025N gadolinium sulfate standard solution 0.00025M standard edetate solution sodium
    [00064] Test procedure:
    [00065] For laboratories comprising automated analysis equipment, the work procedure below does not apply; is replaced by the corresponding laboratory work procedure.
    [00066] Test solution:
    [00067] In a 50 ml beaker, 0.2250 to 0.2750 g of the test substance, m, is dissolved in a 50 ml beaker in 5.0 ml_ of gadolinium sulfate solution, V [1] , The solution is then heated in a boiling water bath for 15 minutes. After cooling, 10.0 ml of indicator Rg 0688 / buffer solution III is added, and the pH is adjusted to 5.0 using 1% hydrochloric acid [w / v] or 1N sodium hydroxide solution. The pH is potentiometrically measured using a glass electrode combination.
    [00068] Practice:
    [00069] With magnetic stirring, the sodium edetate solution, V [2], is titrated in the test solution until the electronically determined end point is reached. The color change from violet-red via yellow-orange to yellow is monitored photometrically. The evaluation is carried out by plotting the curve or using the instrument's software. The equivalence point is determined by extending the starting line and the tangent of the turn; the titration volume read corresponds to the standard solution, V [2], consumed.
    [00070] Test conditions:
    [00071] Instrument: for example Titroprocessor 682, from Metrohm.
    [00072] Photometer: for example 662 fiber optic photometer.
    [00073] Wavelength: 570 nm.
    [00074] Initial transmission value: 15%.
    [00075] Burette: for example Dosimat 665; 10 ml_ accuracy of 0.005 ml_.
    [00076] Titration rate: high.
    [00077] Agitator: intense agitation.
    [00078] Calculations:
    [00079] Free complex trainer in%, calculated as butrol (ZK 00150307), calculated for anhydrous substance and without solvent
    V [1] = consumption of gadolinium sulfate solution in mL VI [2] = consumption of sodium edetate standard solution in mL T [1] = title of gadolinium sulfate solution T [2] = title of solution sodium edetate m = heavy test substance, in gm = heavy test substance, in g W = test method water measurement result in% LM = test method ethanol measurement result in% 450.49 = mass molar value of ZK 00150307 in g / mol
    [00080] 1 mL of the sodium edetate standard solution corresponds to 450.49 mg of ZK 00150307. 2) New selective method for determining butrol and di-TOBO binders.
    [00081] In the context of the development of the new preparation process according to the invention for gadobutrol, a very specific HPLC method of differentiating the butrol ligand from another impurity (for example: the di-TOBO ligand) was developed:
    [00082] Method parameters: HPLC conditions Column length: 250 mm Bore diameter: 4.6 mm Stationary phase 1: Luna Fenil-Hexil 3 pm Column temperature: 50 ° C Autosampler temperature: 10 ° C Flow rate : 1.0mL / min Crown detector: 100 pA UV detector: 195 nm Flow rate: 1.0 mL / min
    [00083] Gradient parameters: Mobile phase A: 0.0025% strong formic acid + 0.5% acetonitrile Mobile phase B: acetonitrile

    [00084] Mobile phase A: 50 pl of strong formic acid 50% in 995 g of water + 5 ml_ of ACN pipette using a transfer pipette Formic acid quality: for HPLC or LC-MS Acetonitrile quality: Hyper grade
    [00085] Test solution: in 10 ml bottles, the samples are dissolved in the mobile phase A, and the bottle filled to the mark. Injection volume: 20 pl Notes: heavy: 25.0 mg / 10 ml_
    [00086] Samples must be filled into polypropylene bottles.
    [00087] The table below shows the retention times for gadobutrol and the main relevant impurities:
    [00088] Retention times and relative retention times.

    [00089] The synthesis of Gd-di-TOBO (No. 1b, the counterion used was acetate instead of chloride):
    [00090] For a method of unambiguous determination of the gadolinium complex of the di-TOBO ligand, this was specially prepared (EP 0985548 B1, Example 1). However, it was found in the investigations that there is no Gd complex of the di-TOBO ligand present in the final product (the complex is not sufficiently stable and probably decomposes in acidic ion exchange resin) See Figure 13, Formula III See Figure 5 spectra MS Example 1 Preparation of gadobutrol (G- complex of N- (1-hydroxymethyl-2,3-dihydroxypropyl) -1,4,7-triscarboxymethyl-1,4,7,10-tetraazocyclododecane)
    [00091] Similar to Example 1 and Example 5 the open publication EP 0986548 B1, starting with cyclene, the gadobutrol, crude is prepared in a pot reaction and then purified on ion exchange resins and finally converted by crystallization in gadobutrol, pure. A. Preparation of crude gadobutrol
    [00092] 160 kilograms of cyclene (1,4,7,10-tetra-azocyclodecane), 154 kilograms of 4,4-dimethyl-3,5,8-trioxobicyclo [5.1,0] octane and 34.7 kilograms of lithium chloride are initially loaded in 325 kilograms of isopropanol and heated under reflux for 1320 minutes.
    [00093] 1250 L of water are added, and the mixture is distilled until an internal temperature of 78 ° C is reached. The mixture is then made up with 805 L of water, and 375 kg of sodium monochloroacetate are added at 35 ° C, followed by 120 kg of resistance to 50% aqueous sodium hydroxide solution. The mixture is heated to an internal temperature of 65 ° C, and new 85 kilograms of 50% resistance to aqueous sodium hydroxide solution is added. If the pH drops below 12, it is readjusted with 10 kilograms of the strong 50% aqueous sodium hydroxide solution (gradual). The mixture is stirred at an internal temperature of 65 ° C for 90 minutes. After cooling to 50 ° C, 240 kilograms of 36% aqueous hydrochloric acid are added in such a way that the pH is now 3.1 to 4.9 (if appropriate, additional hydrochloric acid has to be added; it is important that the target pH is reached). At a jacket temperature of 95 ° C and under reduced pressure, the solvent (isopropanol / water mixture) is then distilled out of a total of 1200 kg.
    [00094] At 40 ° C, 2554 kilograms of methanol are added and the pH is adjusted to 1.4 or less (1.1 to 1.3, favorable condition 1.2) by using 282 kilograms of aqueous hydrochloric acid at 36%. The mixture is stirred at 40 ° C for 35 minutes. The mixture is then cooled to 20 ° C and the precipitated sodium chloride (NaCI) is separated from the use of a centrifuge or a pressure nutsche filter (the filtered cake is washed with methanol as the product is in the solution). 996 (this is still being examined) I from the water are added, and the methanol is substantially distilled from at a jacket temperature of 90 ° C (250 mbar), with the water, the mixture is concentrated to a mass of 966 kilograms, and an additional 1200 L of water are then added. 155 kilograms of gadolinium oxide are added to this solution, and the mixture is heated at 95 ° C for 120 minutes. The mixture is allowed to cool to 50 ° C and adjusted to pH 7.1 to 7.4 lithium hydroxide monohydrate using (approximately 85 kg of lithium hydroxide monohydrate is required). At a jacket temperature of 120 ° C and under reduced pressure, 895 kilograms of water are then distilled from. The mixture is allowed to cool to 73 ° C, 5286 kg of alcohol (MEK = denatured methyl ethyl ketone) is added and the water content is checked using the Karl-Fischer method. The water content is adjusted to 8.5%. (If the value is less than 7.0, an appropriately calculated amount of water is added. If the value is greater than 9.5%, an appropriate amount of ethanol is added. For the process, it is important that the value is in the range of 7.0 to 9.5).
    [00095] The mixture is then heated under reflux (78 ° C) for 60 minutes. Consequently, spontaneous crystallization occurs. The mixture is stirred at a jacket temperature of 100 ° C for 480 minutes and then allowed to cool to 20 ° C.
    [00096] The product is isolated using a centrifuge or nutsche pressure, the filtered cake being washed twice with ethanol. In a paddle dryer, the crude product is dried at a jacket temperature of 58 ° C for 90 minutes under reduced pressure (until a pressure <62 mbar and a temperature> 46 ° C is reached) or washed with ethanol three times and dried at <34 ° C. The product is then dried at an internal temperature of 48 ° C for 60 minutes. The crude product is cooled to 20 ° C and placed in reservoirs. This gives 540 kilograms of colorless crystalline powder (yield> 96%).
    [00097] B. Purification with crude gadobutrol ion exchange resin.
    [00098] Part of the batch prepared above is purified as follows:
    [00099] 120 kilograms of gadobutrol, the crude is dissolved in 1200 kilograms of water and initially pumped over a column containing the acidic ion exchange resin (AMBERLITE IRC 50). The eluate is pumped directly over a basic ion exchanger column (IRA 67) and the eluate is then pumped back over the acidic ion exchange resin (and so on). The solution is re-circulated until a conductivity limit value <20 pS / cm is reached.
    [000100] The solution is transferred to a thin layer evaporator and carefully concentrated to 50 mbar (89 kilograms in approximately 585 I of water, yield 74.1%).
    [000101] C. Final crystallization of crude gadobutrol.
    [000102] 16 kilograms of activated carbon NORIT SX PLUS are added to 324 kilograms of crude gadobutrol (19.1 to 20.9% strong solution in water) (conductivity 20 knots), and the mixture is stirred at 20 ° C for 60 minutes. The activated carbon is filtered off and washed twice with water. The filtrate solution containing the product is then filtered through a sterile filter plug and concentrated at a jacket temperature of 80 ° C under reduced pressure (the amount of the distillate approximately 1600 I). The jacket temperature is then raised to 75 ° C and, in a first step, 100 kilograms of alcohol are measured in, the jacket temperature is then raised to 98 ° C (> 75 ° C internal temperature), and a further 1360 kg of alcohol are added in such a way that the internal temperature does not fall below 72 ° C (total time of the exact addition approximately 120 minutes). At this point, the water content of the solution is determined according to the Karl-Fischer method. Ideally, the value should be 10 to 12%. If the value is higher or lower, it is adjusted to 11% exactly by adding water or alcohol (in small portions). Once the desired water content is reached, the mixture is heated under reflux for 120 minutes. The mixture is allowed to cool to 20 ° C, the product is isolated using a centrifuge or nutsche pressure and the filtered cake is washed with ethanol. The product is then dried under reduced pressure (jacket temperature 55 ° C) until an internal temperature> 53 ° C is reached. The product is then placed in aluminum-coated PE bags.
    [000103] Yield: 314 kg (96.9% of theory) of a colorless crystalline powder, polymorph I. Water content (Karl-Fischer): 3.1% Amount of residual ethanol solvent: <200 ppm Content: 100 , 4% (compared to external reference) HPLC (100% method):> 99.7% (99.8 or 99.9%) Gd3 + free <0.01% Butrol binder: <0.03% Binder di-TOBO usually <0.03% Gd-DO3A: undetectable <0.03% Endotoxin: <0.5 EU Unspecified impurity: <0.03%
    [000104] The table below shows the analytical data of 6 lots taken during the course of gadobutrol production and produced by the process described above:
    Example 2:
    [000105] Characterization of polymorphs I and II. 1. X-ray diffraction.
    [000106] The graphic illustrations below show the X-ray diffraction spectra of the two polymorphs compared to the amorphous material.
    [000107] Method:
    [000108] X-ray powder diffraction (XRPD).
    [000109] The measurement was carried out in transmission mode using the STOE STADI P Powder Diffractometer. Detector: linear position sensitive detector radiation: Germanio-monochromatized CuKcd radiation (À = 1.5406 A) Mode: transmission Variation range: 3rd <20 <40 ° or 3rd <20 <35 ° Step: 0.5 ° or 1.0 ° Time measurement: t> 60 s / step Sample preparation: thin layer
    [000110] See Figure 6 X-ray diffractogram of the polymorph monohydrate I (above) compared to the calculated theoretical diffractogram of the monohydrate (below).
    [000111] See Figure 7, X-ray diffractogram of polymorph II monohydrate II.
    [000112] See Fig.8, X-ray diffractogram of amorphous gadobutrol. 2. IR spectra:
    [000113] See Figure 9, IR spectrum of monohydrate I (nujol preparation).
    [000114] See Figure 10, IR spectrum of monohydrate II (nujol preparation).
    [000115] Figure 11, IP spectrum of amorphous material (nujol preparation). 3. Differential thermal analysis (DTA) and thermogravimetry (TG).
    [000116] Method:
    [000117] Simultaneous DTA / TG measurements are recorded on a Seteram DSC 111. Heating rates: 5 K / min Temperature range: 25 ° C to 250 ° C (partial up to 500 ° C) Purge gas: dry nitrogen Support sample: aluminum crucibles See Figure 1, DTA / TG traces of monohydrate I See Figure 2, DTA / TG traces of monohydrate II See Figure 3, DTA / TG traces of amorphous phase Description of the figures and Formula. Figure 1 - DTA / TG traces of monohydrate I Figure 2 - DTA / TG traces of monohydrate II Figure 3 - DTA / TG traces of amorphous phase Figure 4 - Yield, purity and water content after final crystallization Figure 5 - MS spectra Figure 6 - Polymorph monohydrate X-ray diffractogram (above) compared to the calculated theoretical diffractogram of monohydrate (below) Figure 7 - Polymorph II monohydrate II X-ray diffractogram Figure 8 - Amorphous X-ray diffractogram gadobutrol Figure 9 - JR spectrum of monohydrate, (preparation nnjol) Figure 11 - JR spectrum of amorphous material (preparation nnjol) Figure 12 - Formula I Figure 13 - Formula II Figure 14 - Formula III
    权利要求:
    Claims (4)
    [0001]
    1. Process for the production of gadobutrol with high purity (= the gadolinium complex of N- (1-hydroxymethyl-2,3-dihydroxypropyl) -1,4,7-triscarboxymethyl-1,4,7,10-tetra -azocyclododecane), characterized by the fact that: the starting material cyclene (1,4,7,10-tetra-azocyclodecane) is reacted with 4,4-dimethyl-3,5,8-trioxobicyclo [5.1 , 0] octane and lithium chloride in isopropanol at elevated temperatures, then distilled in water and alkylated with sodium monochloroacetate in alkaline medium, worked under hydrochloric conditions, the salts are removed by the addition of methanol and the binder crude is reacted with gadolinium oxide in water at elevated temperatures, the pH is then adjusted with lithium hydroxide from 7.1 to 7.4, the solution is concentrated and the ethanol is added in such an amount that a water content from 7.0 to 9.5% is reached, the mixture is then heated under reflux for at least 60 minutes and the crude product is, after cooling, isolated and dried at 46 to 48 ° C, the product crude pipeline is then dissolved in water and purified in a cascade of ion exchange resin, where the solution is first passed through the acidic ion exchange resin and then through the basic, the purified solution, having a conductivity <20 pS / cm, it is then concentrated, treated with activated carbon, subjected to sterile filtration and, by the exact addition of ethanol, adjusted to a water content in the range of 10 to 12%, then boiled under reflux and cooled, and the product is isolated and dry between 53 and 55 ° C.
    [0002]
    2. Process according to claim 1, characterized by the fact that the starting material cyclene (1,4,7,10-tetra-azocyclododecane) is reacted with 4,4-dimethyl-3,5,8 - trioxobicyclo [5.1,0] octane and LiCI in isopropanol at elevated temperatures, then distilled in water and alkylated with sodium monochloroacetate in an alkaline medium and worked under hydrochloric conditions, the salts are removed by adding the methanol and the crude binder is reacted with gadolinium oxide in water at elevated temperatures, the pH is then adjusted with lithium hydroxide from 7.1 to 7.4, the solution is concentrated and the ethanol is added in such an amount that a water content of preferably 8.5% is reached, the mixture is then heated under reflux for at least 60 minutes and the crude product is, after cooling, isolated and dried at 46 to 48 ° C, the crude product is dissolved in water and purified in an ion exchange resin cascade, where the solution is first passed through the t acidic ion wheel, the purified solution having a conductivity <20 pS / cm, is concentrated, treated with activated carbon, then subjected to sterile filtration and, by the exact addition of ethanol during the period of 120 minutes, adjusted to a water content in the range of 10 to 12%, then boiled under reflux and cooled, and the product is isolated and dried at 53 to 55 ° C.
    [0003]
    3. Process according to claim 1 or 2, characterized by the fact that the obtained Gadobutrol has a purity (according to HPLC) greater than 99.7%, comprising less than 0.01% of gadolinium-free ions (III), comprising a residual content of the ethanol solvent less than 200 ppm and comprising a proportion of the butrol binder (= N- (1-hydroxymethyl-2,3-dihydroxypropyl) -1,4,7-triscarboxymethyl- 1,4,7,10-tetra-azocyclododecane) less than 0.03%.
    [0004]
    4. Process according to claim 3, characterized by the fact that the obtained Gadobutrol has a water content of 3.0 to 3.5%.
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    AU2012244791B2|2017-04-27|
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    IL228885D0|2013-12-31|
    BR112013027028A2|2016-12-27|
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    MY163709A|2017-10-13|
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    EP2896405A1|2015-07-22|
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    CU24439B1|2019-09-04|
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    MX362133B|2019-01-07|
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    法律状态:
    2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-03-19| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2020-01-28| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-06-16| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2020-08-11| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 17/04/2012, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    DE102011100128|2011-04-21|
    DE102011100128.3|2011-04-21|
    PCT/EP2012/057013|WO2012143355A1|2011-04-21|2012-04-17|Preparation of high-purity gadobutrol|
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