DE202023106581U1 - Crystalline methanol hydrate of calcium D-pantothenate and calcium D-pantothenate - Google Patents

Abstract

A crystalline methanol hydrate of calcium D-pantothenate, characterized in that the production process comprises the following steps: A mixed solution containing calcium D-pantothenate is prepared at 40°C-45°C by mixing and dissolving the calcium D-pantothenate -Solution obtained in methanol; This calcium D-pantothenate mixed solution undergoes an initial cooling process to reduce the temperature of the calcium D-pantothenate mixed solution to 25°C~15°C within 0.5h. After adding the crystal seeds, the initial temperature maintenance is carried out, and then a second cooling process is carried out to reduce the temperature of the calcium D-pantothenate mixed solution to 5°C to 0°C in ≥4 h, and then the second maintenance of the temperature was carried out to obtain the crystalline methanol hydrate of calcium D-pantothenate.

Description

Relevant subject area

The present invention relates to the field of pharmaceutical compounds and in particular to crystalline methanol hydrate of calcium D-pantothenate and calcium D-pantothenate obtained by a new manufacturing process.

Technical background

Calcium D-pantothenate, with the chemical name Calcium D-N-(2,4-dihydroxy-3,3-dimethylbutyryl)-β-aminopropionate, has a relative molecular weight of 476.54 and releases calcium and pantothenic acid in the human body. Pantothenic acid is a precursor substance of coenzyme A, which is converted into coenzyme A and produces physiological effects and participates in the metabolism of carbohydrates, fats and proteins, and is a micro-substance indispensable for maintaining the normal physiological function of the human and animal body. It is often used to prevent and treat pantothenic acid deficiency as well as to treat contact dermatitis and acute and chronic eczema.

Calcium D-pantothenate is often produced by microbial enzymatic fermentation, which first produces a fermentation broth containing calcium D-pantothenate, which contains a large number of unknown impurities. EP1918383A1 uses a semi-continuous fermentation process that reduces the amount of pantothenic acid-related metabolites, such as 3-(2-hydroxy-3-methyl-butyrylamino)-propionic acid. In contrast, conventional purification methods yield the crystalline calcium D-pantothenate with low purity and low bulk density, which limits the subsequent application of calcium D-pantothenate.

Therefore, the state of the art still needs to be improved.

Content of the invention

On this basis, the present invention provides the crystalline methanol hydrate of calcium D-pantothenate and calcium D-pantothenate obtained by a new production process of the crystalline methanol hydrate of calcium D-pantothenate. The manufacturing process of crystalline methanol hydrate of calcium D-pantothenate enables the production of bulk crystal of calcium D-pantothenate, improves the purity and bulk density of the produced crystalline methanol hydrate of calcium D-pantothenate.

• Erstens stellt die vorliegende Erfindung ein kristallines Methanolhydrat von Calcium-D-Pantothenat bereit, dass durch ein neues Herstellungsverfahren hergestellt wird und dadurch gekennzeichnet ist, dass das Herstellungsverfahren die folgenden Schritte umfasst:
  • Eine Mischlösung enthaltend Calcium-D-Pantothenat wird bei 40°C~45°C durch Mischen und Auflösen der Calcium-D-Pantothenat-Lösung in Methanol gewonnen;
  • Diese Calcium-D-Pantothenat-Mischlösung wird einem erstmaligen Abkühlungsprozess unterzogen, um die Temperatur der Calcium-D-Pantothenat-Mischlösung innerhalb von 0,5 h auf 25°C bis 15°C zu reduzieren. Nach der Zugabe der Kristallkeime wird die erstmalige Aufrechterhaltung der Temperatur durchgeführt, und dann wird ein zweiter Abkühlungsprozess durchgeführt, um die Temperatur der Calcium-D-Pantothenat-Mischlösung in ≥4 h auf 5°C bis 0°C zu reduzieren, und dann wird die zweite Aufrechterhaltung der Temperatur durchgeführt, um das kristalline Methanolhydrat von Calcium-D-Pantothenat zu erhalten.

The technical solutions of this invention to solve the above technical problems are as follows:

• First, the present invention provides a crystalline methanol hydrate of calcium D-pantothenate produced by a new manufacturing process and characterized in that the manufacturing process includes the following steps:
  • A mixed solution containing calcium D-pantothenate is obtained at 40°C~45°C by mixing and dissolving the calcium D-pantothenate solution in methanol;
  • This calcium D-pantothenate mixed solution undergoes an initial cooling process to reduce the temperature of the calcium D-pantothenate mixed solution to 25°C to 15°C within 0.5 h. After adding the crystal seeds, the initial temperature maintenance is carried out, and then a second cooling process is carried out to reduce the temperature of the calcium D-pantothenate mixed solution to 5°C to 0°C in ≥4 h, and then the second maintenance of the temperature was carried out to obtain the crystalline methanol hydrate of calcium D-pantothenate.

1. (a) Bei dem zweiten Abkühlungsprozess wird die Temperatur der Calcium-D-Pantothenat-Mischlösung in 4 bis 8 Stunden auf 5 bis 0°C gesenkt;
2. (b) Bei dem zweiten Abkühlungsprozess handelt es sich um einen gleichmäßigen Abkühlungsprozess.

In some embodiments, the second cooling process satisfies at least one of conditions (a) - (b):

1. (a) In the second cooling process, the temperature of the calcium-D-pantothenate mixed solution is reduced to 5 to 0 ° C in 4 to 8 hours;
2. (b) The second cooling process is a uniform cooling process.

• (c) Die Dauer der ersten Aufrechterhaltung der Temperatur beträgt 1 h bis 4 h;
• (d) Die Dauer der zweiten Aufrechterhaltung der Temperatur beträgt 1 h bis 4 h.

In some embodiments, maintaining the temperature of the process for producing the crystalline methanol hydrate of calcium D-pantothenate satisfies at least one of conditions (c) - (d):

• (c) The duration of the initial temperature maintenance is 1 h to 4 h;
• (d) The duration of the second temperature maintenance is 1 h to 4 h.

• Eine Fermentationsbrühe, die Ammonium-D-Pantothenat enthält, wird durch Fermentation von Glukose in Escherichia coli unter Verwendung von Glukose als Ausgangsmaterial hergestellt;

In some embodiments, the preparation of the calcium D-pantothenate solution includes the following steps:

• A fermentation broth containing ammonium D-pantothenate is prepared by fermentation of glucose in Escherichia coli using glucose as a starting material;

The fermentation broth containing ammonium D-pantothenate is pretreated to obtain a pretreatment solution containing ammonium D-pantothenate, and then the pretreatment solution is neutralized with calcium hydroxide to obtain a pretreatment solution of the calcium D-pantothenate;

The calcium D-pantothenate pretreatment solution is concentrated to obtain the calcium D-pantothenate solution.

In some embodiments, the pretreatment is performed sequentially using the ion exchange membrane and the ion exchange resin;

The ion exchange membrane is ceramic membrane and organic polymer membrane;

The ion exchange resin is a cation exchange resin.

In some embodiments, the content (% dry matter) of calcium D-pantothenate in the calcium D-pantothenate pretreatment solution is 60% to 80%.

1. (e) Die Konzentrationstemperatursbehandlung beträgt 30°C bis 50°C;
2. (f) Der Druck der Konzentrationsbehandlung beträgt 4000 Pa bis 10000 Pa;
3. (g) Der Gehalt an Calcium-D-Pantothenat in der Calcium-D-Pantothenat-Lösung beträgt 45 Gew.-% bis 55 Gew.-%.

In some embodiments, the concentration treatment step satisfies at least one of conditions (e) - (g):

1. (e) The concentration temperature treatment is 30°C to 50°C;
2. (f) The pressure of the concentration treatment is 4000 Pa to 10000 Pa;
3. (g) The content of calcium D-pantothenate in the calcium D-pantothenate solution is 45% by weight to 55% by weight.

In some embodiments, the mass-volume ratio of calcium D-pantothenate to the methanol in the calcium D-pantothenate solution is 1 g: (5 - 9) mL.

In some embodiments, the seed crystal is a calcium D-pantothenate tetramethanol compound, the crystal seed having a mass of 0.05% to 1% of the calcium D-pantothenate content in the calcium D-pantothenate solution.

Secondly, the present patent application provides a calcium D-pantothenate obtained by a new production process using the crystalline methanol hydrate of calcium D-pantothenate, that by the above-described production process of the crystalline methanol hydrate of calcium D-pantothenate are produced, and in which this crystalline methanol hydrate of calcium D-pantothenate is used to produce the calcium D-pantothenate.

• Bei dem oben beschriebenen Herstellungsverfahren des kristallinen Methanolhydrats von Calcium-D-Pantothenat wird die Calcium-D-Pantothenat-Lösung in Methanol umkristallisiert. Durch die Steuerung des Abkühlungsprozesses mit zwei spezifischen Abkühlungsbehandlungen nimmt die Löslichkeit von Calcium-D-Pantothenat mit der Abnahme der Temperatur ab, wobei die Lösung übersättigt wird und anfällig für Kristallisationen und Ausfällungen ist. Dabei werden die Kristallkerne durch die Initiierung der Kristallkeime zur Kristallbildung angeregt. Durch die Steuerung der Zeit und der Temperatur jeder Abkühlungsbehandlung zur Kontrolle der Abkühlungsgeschwindigkeit werden nicht-hygroskopische Massenkristalle des kristallinen Methanolhydrats von Calcium-D-Pantothenat erhalten, die eine höhere Schüttdichte und Reinheit aufwiesen und für spätere Anwendungen günstig sind.

Compared with the conventional technology, the crystalline methanol hydrate of calcium D-pantothenate obtained by the new manufacturing method of the present patent application has the following beneficial effects:

• In the production process of the crystalline methanol hydrate of calcium D-pantothenate described above, the calcium D-pantothenate solution is recrystallized in methanol. By controlling the cooling process with two specific cooling treatments, the solubility of calcium D-pantothenate decreases with the decrease in temperature, causing the solution to become supersaturated and is susceptible to crystallization and precipitation. The crystal nuclei are stimulated to form crystals through the initiation of the crystal nuclei. By controlling the time and temperature of each cooling treatment to control the cooling rate, non-hygroscopic bulk crystals of the crystalline methanol hydrate of calcium D-pantothenate are obtained, which had higher bulk density and purity and are favorable for later applications.

Brief description of the drawings

• shows a micrograph of the crystalline calcium D-pantothenate tetramethanol monohydrate compound from Example 1;

Embodiment

The manufacturing process of the present patent application is described in more detail below in connection with certain exemplary embodiments. The present patent application may be implemented in many different forms and is not limited to the embodiments described herein. Instead, these embodiments are provided to provide a more thorough and comprehensive understanding of the disclosure of the present patent application.

In the description of the present patent application, the terms "first" and "second" are used for descriptive purposes only and are not to be understood as an indication or indication of relative importance, nor as an indication of the number of technical features specified. Therefore, a feature containing the words “first” or “second” may clearly or implicitly contain one or more such features.

Unless otherwise defined, all technical and scientific terms used herein have the same meanings as generally understood by those skilled in the art within the scope of the present patent application. Terms used herein in the specification of the present patent application are intended only to describe certain embodiments and are not intended to limit the present patent application. The term “and/or” as used herein includes any and all combinations of one or more of the relevant items listed.

The terms "include", "comprise" or any other variation thereof are intended to cover a non-exclusive inclusion such that a process, procedure, article or equipment that includes a number of elements, not only those elements, but also includes other elements not clearly listed or inherent in such process, procedure, article or device. Without further limitation, the fact that an element is described by the statement “include a......” does not preclude the possibility of another identical element in the process, method, article or device containing that element contains, is present. The indefinite articles “a kind of” and “a” preceding the elements or components of the present patent application are not restrictive with respect to the quantitative requirements (i.e., number of occurrences) of the elements or components. Thus, "a kind of" or "a" is understood to mean one or at least one, and elements or components in the singular also include plural forms, unless it is clearly stated that the specified Number only refers to the singular. “Plurality” means at least two, e.g. two, three, etc., unless clearly and specifically qualified.

It should be noted that if a range of values is specified here, this range is considered continuous and the minimum and maximum values of the range, any value between the minimum and maximum values, and a range divided by any two values between the minimum and maximum values Maximum value is determined, includes.

1. (1) Die Ammonium-D-Pantothenat enthaltende Fermentationsbrühe wird vorbehandelt, um eine Ammonium-D-Pantothenat enthaltende Vorbehandlungslösung zu erhalten, und dann wird die Vorbehandlungslösung mit Calciumhydroxid neutralisiert, um eine Vorbehandlungslösung des Calcium-D-Pantothenats zu erhalten.
2. (2) Die Vorbehandlungslösung des Calcium-D-Pantothenats aus (1) wird konzentriert, um die Calcium-D-Pantothenat-Lösung zu erhalten.
3. (3) Die Calcium-D-Pantothenat enthaltende Mischlösung wird bei 40°C-45°C durch Mischen und Auflösen der Calcium-D-Pantothenat-Lösung aus (2) in Methanol gewonnen.
4. (4) Diese Calcium-D-Pantothenat-Mischlösung aus (3) wird einem erstmaligen Abkühlungsprozess unterzogen, um die Temperatur der Calcium-D-Pantothenat-Mischlösung innerhalb von 0,5 h auf 25°C-15°C zu reduzieren. Nach der Zugabe der Kristallkeime wird die erstmalige Aufrechterhaltung der Temperatur durchgeführt, und dann wird ein zweiter Abkühlungsprozess durchgeführt, um die Temperatur der Calcium-D-Pantothenat-Mischlösung in ≥4 h auf 5°C-0°C zu reduzieren, und dann wird die zweite Aufrechterhaltung der Temperatur durchgeführt, um das kristalline Methanolhydrat von Calcium-D-Pantothenat zu erhalten.

An embodiment of the present patent application provides a methanol hydrate crystal of calcium D-pantothenate obtained by a novel preparation process comprising steps (1) - (4).

1. (1) The fermentation broth containing ammonium D-pantothenate is pretreated to obtain a pretreatment solution containing ammonium D-pantothenate, and then the pretreatment solution is neutralized with calcium hydroxide to obtain a pretreatment solution of the calcium D-pantothenate.
2. (2) The calcium D-pantothenate pretreatment solution from (1) is concentrated to obtain the calcium D-pantothenate solution.
3. (3) The mixed solution containing calcium D-pantothenate is obtained at 40°C-45°C by mixing and dissolving the calcium D-pantothenate solution from (2) in methanol.
4. (4) This calcium D-pantothenate mixed solution from (3) is subjected to an initial cooling process to reduce the temperature of the calcium D-pantothenate mixed solution to 25°C-15°C within 0.5 h. After adding the crystal seeds, the initial temperature maintenance is carried out, and then a second cooling process is carried out to reduce the temperature of the calcium D-pantothenate mixed solution to 5°C-0°C in ≥4 h, and then the second maintenance of the temperature was carried out to obtain the crystalline methanol hydrate of calcium D-pantothenate.

Conventionally, there are three methods for synthesizing D-pantothenic acid or its salt: the chemical synthesis method, the enzymatic and the biological fermentation method. However, the chemical synthesis method has many limitations, for example, hydrogen cyanide and sodium cyanide cause serious environmental pollution and danger to humans, so the enzymatic and biological fermentation method is often used to produce calcium D-pantothenate in practice. However, in the microbial enzymatic fermentation method, the fermentation broth containing ammonium D-pantothenate is first obtained, which contains a large number of unknown impurities. EP1918383A1 uses a semi-continuous fermentation process that reduces the amount of pantothenic acid-related metabolites, such as 3-(2-hydroxy-3-methyl-butyrylamino)-propionic acid. In contrast, conventional purification methods yield the crystalline calcium D-pantothenate with low purity and low bulk density, which limits the subsequent application of calcium D-pantothenate.

Accordingly, the technicians engaged in the study of the present patent application have a large number of analyzes and researches on the mechanism and synthesis process of calcium D-pantothenate produced by enzyme and biofermentation processes in many years of practical production and research carried out. After mastering the main mechanism and impurity properties of calcium D-pantothenate produced by enzyme and biofermentation processes, they have creatively proposed the production process of the crystalline methanol hydrate of calcium D-pantothenate in this present patent application: The Calcium-D -Pantothenate solution is recrystallized in methanol. By controlling the cooling process with two specific cooling treatments, the solubility of calcium D-pantothenate decreases with the decrease in temperature, making the solution supersaturated and susceptible to crystallization and precipitation. The crystal nuclei are stimulated to form crystals through the initiation of the crystal nuclei. By controlling the time and temperature of each cooling treatment to control the cooling rate, non-hygroscopic bulk crystals of the crystalline methanol hydrate of calcium D-pantothenate are obtained, which had higher bulk density and purity and are favorable for later applications.

In some embodiments, fermentation broth containing ammonium D-pantothenate mentioned in step (1) is prepared by fermenting glucose in Escherichia coli using glucose as starting material.

In some embodiments, the ratio of the fermentation broth containing ammonium D-pantothenate mentioned in step (1) to calcium hydroxide: 1000mL: 10.88 to 11.34 g.

In some embodiments, the pretreatment mentioned in step (1) is carried out sequentially with an ion exchange membrane and an ion exchange resin.

Specifically, the ion exchange membrane is ceramic membrane and organic polymer membrane manufactured by Shanghai Saiao.

Specifically, the ion exchange resin is cation exchange resin manufactured by Purolite.

The fermentation broth containing calcium D-pantothenate undergoes a purification pretreatment that allows some of the impurities to be screened out for subsequent steps.

In some embodiments, the content (% dry matter) of calcium D-pantothenate in the calcium D-pantothenate pretreatment solution mentioned in step (1) is 60% to 80%.

Specifically, the content (% dry matter) of calcium D-pantothenate in the pretreatment solution of calcium D-pantothenate mentioned in step (1) can be 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79% and 80%.

The content (% dry matter) is the mass content of calcium D-pantothenate in the solid raw material after deducting the moisture and the remaining solvent in the raw material.

In some embodiments, the concentration step mentioned in step (2) is: Concentrate at 30 ° C to 50 ° C and a pressure of 4000 Pa to 10000 Pa to a calcium D-pantothenate solution with a calcium D-pantothenate content of 45% to 55%.

Specifically, the temperature of the concentration step mentioned in step (2) may be 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39° C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C or 49°C, 50°C.

Specifically, the pressure of the concentration step mentioned in step (2) may be 4000 Pa, 4500 Pa, 5000 Pa, 5500 Pa, 6000 Pa, 6500 Pa, 7000 Pa, 7500 Pa, 8000 Pa, 8500 Pa, 9000 Pa, 9500 Pa or 10000 Pa be.

Specifically, in some embodiments, the calcium D-pantothenate content of the calcium D-pantothenate solution can be 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54% or be 55%.

It is believed that the crystallization efficiency can be improved by concentrating the pretreatment solution of calcium D-pantothenate and removing part of the solvent.

In some embodiments, the mass to volume ratio of calcium D-pantothenate to methanol in the calcium D-pantothenate solution mentioned in step (3) is 1g: 5 to 9 mL.

Specifically, the mass-volume ratio of calcium D-pantothenate to methanol in the calcium D-pantothenate solution mentioned in step (3) can be 1g:5mL, 1g:6mL, 1g:7mL, 1g:8mL or 1g:9mL.

In some embodiments, after the addition of methanol in step (3), the solution is transferred to a crystallizer and stirred.

In some embodiments, the stirring speed in step (3) is 50 rpm - 200 rpm.

The aforementioned crystallizer may be a crystallizer commonly used in the art, for example a cooling crystallizer.

In some embodiments, the temperature of the calcium D-pantothenate mixed solution before the first cooling process is 40°C to 45°C.

It can be assumed that in step (3) at 40 ° C to 45 ° C by mixing and dissolving the calcium D-pantothenate solution in the methanol, the resulting calcium D-pantothenate mixed solution also reaches the corresponding temperature.

In some embodiments, the temperature in the first cooling process may be 25°C, 24°C, 23°C, 22°C, 21°C, 20°C, 19°C, 18°C, 17°C, 16°C or 15°C; the duration of the first cooling process can be 0.5 h, 0.4 h, 0.3 h, 0.2 h or 0.1 h; and the temperature in the second cooling process can be reduced to 5°C, 4°C, 3°C, 2°C, 1°C or 0°C.

During the crystallization process, as the temperature decreases, the solubility of the crystalline methanol hydrate of calcium D-pantothenate in methanol decreases, causing the solution to become supersaturated and susceptible to crystallization and precipitation. The solubility properties of the crystalline methanol hydrate of calcium D-pantothenate in methanol are significantly different from those of the major impurities, allowing purification of the resulting calcium D-pantothenate.

If the cooling rate of the second cooling process is too fast, the crystalline calcium D-pantothenate will not be completely formed, resulting in the crystalline calcium D-pantothenate not being able to be precipitated or the crystalline calcium D-pantothenate not being completely precipitated can and more impurities Y are included in it.

Specifically, the impurity Y is 3-(2-hydroxy-3-methyl-butyrylamino)-propionic acid.

In some embodiments, the seed crystal added in step (4) is a calcium D-pantothenate tetramethanol compound, and the mass of the seed crystals is 0.05% to 1% of the calcium D-pantothenate content in the calcium D Pantothenate solution.

Specifically, the mass of the crystal seeds is 0.05% to 1% of the calcium D-pantothenate content in the calcium D-pantothenate solution, which is 0.05%, 0.06%, 0.07%, 0.08 %, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9 % or 1%.

It is an effective method to induce the formation of crystal nucleus by adding crystal seed. Calcium D-pantothenate has a high degree of selectivity in the crystallization process. When similar molecules with a similar structure to calcium D-pantothenate are added, further crystallization and precipitation is encouraged while maintaining the temperature.

In addition, the addition of the calcium D-pantothenate methanol compound is regulated so that its concentration in the solution is appropriate to precipitate crystalline methanol hydrate of calcium D-pantothenate with higher purity, eliminating the problem of lower purity due to too rapid Precipitation of the crystals is avoided.

In some embodiments, the first maintenance of the temperature in step (4): maintaining the temperature for 1 h ~ 4 h at 15°C to 25°C.

The temperature in the first maintenance of the temperature can be 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C or 25 °C; and the duration can be 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours or 4 hours.

In some embodiments, the second temperature maintenance in step (4): maintaining the temperature for 1 h to 4 h at 15°C to 25°C. The temperature in the second temperature maintenance may be 0°C, 1°C, 2°C, 3°C, 4°C or 5°C; and the duration can be 1h, 1.5h, 2h, 2.5h, 3h, 3.5h or 4h.

This production process of the crystalline methanol hydrate of calcium D-pantothenate ensures sufficient precipitation of the crystals with as few impurities as possible and obtains crystals with a specific shape: non-hygroscopic bulk crystals. In addition, this manufacturing process simultaneously improves the purity of the product and its bulk density, and it is simple and efficient, favoring large-scale production.

• Das kristalline Methanolhydrat von Calcium-D-Pantothenat wird nach dem oben beschriebenen Herstellungsverfahren des kristallinen Methanolhydrats von Calcium-D-Pantothenat hergestellt; das kristalline Methanolhydrat von Calcium-D-Pantothenat wird zur Herstellung von Calcium-D-Pantothenat verwendet.

The present patent application also provides a new manufacturing process for obtaining calcium D-pantothenate, the process comprising the following steps:

• The crystalline methanol hydrate of calcium D-pantothenate is prepared according to the production method of the crystalline methanol hydrate of calcium D-pantothenate described above; The crystalline methanol hydrate of calcium D-pantothenate is used to produce calcium D-pantothenate.

In some embodiments, the crystalline methanol hydrates of calcium D-pantothenate described above are dissolved, demethanolized, concentrated, spray dried, and packaged to obtain a calcium D-pantothenate product.

The present patent application is described below in connection with certain embodiments, but the present patent application is not limited to the following embodiments, and it is understood that the appended claim summarizes the scope of the present patent application and those skilled in the art from the conception The present patent application should be aware that certain changes are made The various embodiments of the present claim are covered by the spirit and scope of the claim of the present patent application.

Examples of embodiments

The present patent application is explained in more detail below in connection with the exemplary embodiments, but the scope of protection of the present patent application is not limited to the scope described in the exemplary embodiments.

Example 1

1. The preparation of a calcium D-pantothenate solution

(1) Pretreatment: After purification and pretreatment of the fermentation broth containing ammonium D-pantothenate using an ion exchange membrane and an ion exchange resin, it is reacted with calcium hydroxide in the ratio of 1000mL:11.34g to make 1500g pretreatment solution of calcium D-pantothenate. To obtain pantothenate solution.

Wherein the fermentation broth containing ammonium D-pantothenate is prepared by aerobic fermentation by Escherichia coli using glucose as a starting material.

(2) Concentration: The pretreatment solution of calcium D-pantothenate is evaporated and concentrated using the 2L rotary evaporator to obtain calcium D-pantothenate solution with a mass concentration of about 50%. The content (% dry matter) of the calcium D-pantothenate solution obtained under different concentration conditions was different, as shown in Table 1. Table 1 Ongoing No. Concentration temperature (°C) concentration pressure (Pa) Mass concentration (% by weight) Content (% dry matter) 1 40 5000 50.02% 70.12% 2 50 4000 50.21% 75.55% 3 45 5000 49.96% 70.52% 4 40 6000 50.25% 75.83%

2. Crystallization

(1) Dissolution: 180.15 g of calcium D-pantothenate solution with a mass concentration of 50.02% by weight are mixed with 720 ml of methanol with a volume fraction of 99% to produce 748.95 g of aqueous calcium D-pantothenate. Pantothenate-methanol solution is obtained and transferred to a crystallizer for stirring at a stirring speed of 30 rpm, and the temperature of the aqueous calcium D-pantothenate-methanol solution is 40 ° C.

(2) Crystallization: The aqueous calcium D-pantothenate-methanol solution is cooled to 20 °C for 15 min for the first time, and 0.09 g of calcium D-pantothenate-tetramethanol monohydrate compound is then added to it carry out the first maintenance of the temperature for 1 h. After the end of the first maintenance of the temperature, a second cooling to 2 ° C is carried out for 4.5 h. After the end of the second cooling, a second maintenance of the temperature is carried out for 3 h. After the end of second temperature maintenance, filtration and drying are carried out to obtain the crystalline calcium D-pantothenate tetramethanol monohydrate compound.

Example 2

The manufacturing process of the calcium D-pantothenate product of Embodiment 2 is basically the same as that of Embodiment 1, except that the steps of crystallization treatment are different as follows:

2. Crystallization

(1) Dissolution: 180.15 g of calcium D-pantothenate solution with a mass concentration of 50.02% by weight are mixed with 450 ml of methanol with a volume fraction of 99% to produce 535.65 g of aqueous calcium D-pantothenate. Pantothenate-methanol solution is obtained and transferred to a crystallizer for stirring at a stirring speed of 30 rpm, and the temperature of the aqueous calcium D-pantothenate-methanol solution is 40 ° C.

(2) Crystallization: The aqueous calcium D-pantothenate-methanol solution is cooled to 15°C for 15 minutes for the first time, and 0.045 g of the calcium D-pantothenate-tetramethanol monohydrate compound is then added to the first maintain the temperature for 1 h. After the end of the first maintenance of the temperature, a second cooling to 0 ° C is carried out for 4 h, and after the end of the second cooling, the second maintenance of the temperature is carried out for 2 h. After the end of second temperature maintenance, filtration and drying are carried out to obtain the crystalline methanol hydrate of calcium D-pantothenate.

Example 3

The manufacturing process of the calcium D-pantothenate product of Embodiment 3 is basically the same as that of Embodiment 1, except that the steps of crystallization treatment are different as follows:

2. Crystallization

(1) Dissolution: 180.15 g of calcium D-pantothenate solution with a mass concentration of 50.02% by weight are mixed with 540 ml of methanol with a volume fraction of 99% to produce 606.75 g of aqueous calcium D-pantothenate. Pantothenate-methanol solution is obtained and transferred to a crystallizer for stirring at a stirring speed of 30 rpm, and the temperature of the aqueous calcium D-pantothenate-methanol solution is 40 ° C.

(2) Crystallization: The aqueous calcium D-pantothenate methanol solution is cooled to 18 °C for 15 min for the first time, and 0.18 g of calcium D-pantothenate tetramethanol monohydrate compound is then added to carry out the first maintenance of the temperature for 1.5 h. After the end of the first maintenance of the temperature, a second cooling to 1 ° C is carried out for 5 h, and after the end of the second cooling a second maintenance of the temperature is carried out for 2.5 h. After the end of second temperature maintenance, filtration and drying are carried out to obtain the crystalline calcium D-pantothenate tetramethanol monohydrate compound.

Example 4

The manufacturing process of the calcium D-pantothenate product of Embodiment 4 is basically the same as that of Embodiment 1, except that the steps of crystallization treatment are different as follows:

2. Crystallization

(1) Dissolution: 180.15 g of calcium D-pantothenate solution with a mass concentration of 50.02% by weight are mixed with 630 ml of methanol with a volume fraction of 99% to produce 677.85 g of aqueous calcium D-pantothenate. Pantothenate-methanol solution is obtained and transferred to a crystallizer for stirring at a stirring speed of 30 rpm, and the temperature of the aqueous calcium D-pantothenate-methanol solution is 40 ° C.

(2) Crystallization: The aqueous calcium D-pantothenate-methanol solution is cooled to 21 °C for 20 min for the first time, and 0.36 g of calcium D-pantothenate tetramethanol monohydrate is then added to maintain the first time Temperature to be carried out for 2 hours. After the end of the first maintenance of the temperature, a second cooling to 3 ° C is carried out for 5 h, and after the end of the second cooling the second maintenance of the temperature is carried out for 3 h. After the end of second temperature maintenance, filtration and drying are carried out to obtain the crystalline calcium D-pantothenate tetramethanol monohydrate compound.

Example 5-6

Examples 5 to 6 are essentially identical to Example 1 and differ only in that the test parameters in Table 2 are different. Specific established test parameters for each embodiment are shown in Table 2, where: Calcium D-pantothenate content: volume of organic solvent (g:mL) is denoted as M:V and the content of the crystal seed is the mass of the crystal seed as a percentage of the Calcium D-pantothenate is in the calcium D-pantothenate solution. Table 2 Examples of implementation M:V (g:m L) Temperature of the first cooling (°C) Crystal seed content (%) Duration of the first maintenance of the temperature (h) Duration of the second cooling (h) Temperature of the second cooling (°C) Duration of the second maintenance of the temperature (h) Example 1 1:8 20 0.09 1 4.5 2 3 Example 2 1:5 15 0.05 1 4 0 2 Example 3 1:6 18 0.2 1.5 5 1 2.5 Example 4 1:7 21 0.4 2 6 3 3 Example 5 1:8 23 0.6 2.5 7 4 3.5 Execute 1:9 25 0.8 3 8th 5 4 example 6

Comparative example 1

Comparative Example 1 is essentially the same as Example 1, with the difference that no membrane and resin pretreatment is used in step (1) in the preparation of the calcium D-pantothenate solution.

The remaining steps are the same as in Embodiment 1.

Comparative example 2

Comparative Example 2 is essentially the same as Example 1, with the difference that in step (2) during crystallization, after adding the crystal seeds, the solution is cooled to 0 ° C for 3 hours in order to carry out the crystallization.

The remaining steps are the same as in Embodiment 1.

2. Crystallization

(1) Dissolution: 180.15 g of calcium D-pantothenate solution with a mass concentration of 50.02% by weight are mixed with 720 ml of methanol with a volume fraction of 99% to produce 748.95 g of aqueous calcium D-pantothenate. Pantothenate-methanol solution is obtained and stirred at a stirring speed of 30 Rpm transferred into a crystallizer, and the temperature of the aqueous calcium D-pantothenate methanol solution is 40 ° C.

(2) Crystallization: The aqueous calcium D-pantothenate-methanol solution is cooled to 20 °C for 15 min for the first time, and 0.09 g of calcium D-pantothenate-tetramethanol monohydrate is added to it for the first maintenance the temperature for 1 hour. After the end of the first maintenance of the temperature, a second cooling to 2 ° C is carried out for 3 h, and after the end of the cooling, the second maintenance of the temperature is carried out for 3 h. After the end of second temperature maintenance, filtration and drying are carried out to obtain the crystalline calcium D-pantothenate tetramethanol monohydrate compound.

Comparative example 3

Comparative Example 3 is essentially the same as Example 1, with the difference that the aqueous calcium D-pantothenate methanol solution in step (2) is cooled to 20 ° C for 60 minutes during crystallization.

The remaining steps are the same as in Embodiment 1.

Comparative example 4

Comparative Example 4 is essentially the same as Example 1, with the difference that the aqueous calcium D-pantothenate methanol solution in step (2) is cooled to 30 ° C in the first 15 minutes during crystallization.

The remaining steps are the same as in Embodiment 1.

Testing:

1. 1. Observations were made on the crystalline calcium D-pantothenate tetramethanol monohydrate compounds prepared in the exemplary embodiments and in the corresponding comparative examples.
2. 2. The content (% dry matter) of the calcium D-pantothenate solution (starting material for crystallization) and the crystalline calcium D-pantothenate tetramethanol monohydrate compounds produced in the exemplary embodiments and in the corresponding comparative examples was determined with reference to liquid chromatography the “GB/T 7299-2006 Calcium D-Pantothenate” was tested.
3. 3. The impurity Y of the calcium D-pantothenate solution (starting material for crystallization) and the crystalline calcium D-pantothenate tetramethanol monohydrate compounds produced in the exemplary embodiments and in the corresponding comparative examples was tested. Conditions for liquid chromatography: mobile phase: 1.36 g aqueous potassium dihydrogen phosphate solution: acetonitrile = 99:1 (V/V); Chromatography column: SBAQ C18 150*4.6 mm, 5 µm; Detection wavelength: 200 nm; Temperature: 35°C; Flow rate: 1.2ml/min; Running time: 20 min.
4. 4. The bulk density of the crystalline calcium D-pantothenate tetramethanol monohydrate compounds produced in the exemplary embodiments and in the corresponding comparative examples was tested. 20 g of the sample was weighed and slowly poured into a 100 mL graduated cylinder tilted at 45 degrees. The volume V ml occupied by the sample was read. 20 g/V ml would be the bulk density of the measured sample.
5. 5. The hygroscopicity of the crystalline calcium D-pantothenate tetramethanol monohydrate compounds produced in the exemplary embodiments and in the corresponding comparative examples was tested. 1 g of crystalline calcium pantothenate was precisely weighed and then expanded in a weighing flask and left to rest in a constant temperature and humidity machine at 40°C and 75% RH for 24 h to observe weight gain.

Table 3 shows the specific test results. Table 3 Before crystallization After crystallization Content (% dry matter) of starting material for crystallization Contaminant content Y % Content (% dry matter) of crystalline products Contaminant content Y % Morphology of the crystalline products Bulk density (g/ml) Hygroscopicity Example 1 70.12% 3.20% 95.23% 0.25% mass crystallization 0.63 0.51% Execution example 2 75.55% 3.15% 97.10% 0.15% mass crystallization 0.65 0.63% Example 3 70.52% 6.10% 96.01% 0.38% mass crystallization 0.61 0.55% Example 4 75.83% 6.08% 96.50% 0.45% mass crystallization 0.67 0.49% Example 5 60% 3.15% 96.50% 0.50% mass crystallization 0.58 0.70% Example 6 65% 3.00% 96.80% 0.40% mass crystallization 0.64 0.48% Comparison example 1 1 70.12% 3.20 percent 90.23% 2.03% mass crystallization 0.42 1.53% Comparison example 1 2 70.12% 3.20% 90.30% 2.10% mass crystallization 0.58 0.65% Comparison example 1 3 70% 3.11% 95.33% 0.82% Needle-shaped 0.30 1.00% Comparison example 1 4 75% 3.15% 95.80% 0.93% Needle-shaped 0.31 0.98%

shows a micrograph of the crystalline calcium D-pantothenate tetramethanol monohydrate compound. From the figures shown above and the test results in the table, it can be seen that the purity and bulk density of the crystalline products of the comparative example are lower than those of the embodiment, and the content of impurity Y is higher than that of the embodiment. It can therefore be seen that non-hygroscopic bulk crystals of calcium D-pantothenate tetramethanol monohydrate produced with the technical solution of the present patent application can have a higher bulk density and a high purity.

The various technical features of the embodiments described above can be combined arbitrarily, and all possible combinations of the various technical features of the embodiments described above will not be described for reasons of brevity of description; However, as long as there are no inconsistencies in the combinations of these technical features, they should be considered within the scope of the present specification as recorded herein.

The embodiments described above express only some embodiments of the present patent application, which are described in more specific and detailed terms, but are not to be construed as limiting the scope of the present patent application. It should be noted that a person skilled in the art may make several modifications and improvements without departing from the spirit of the present patent application, all of which fall within the scope of the present patent application. The scope of protection of the present patent application is therefore determined by the appended claim.

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Cited patent literature

• EP 1918383 A1 [0003, 0027]

Claims (10)

A crystalline methanol hydrate of calcium D-pantothenate, characterized in that the production process comprises the following steps: A mixed solution containing calcium D-pantothenate is prepared at 40°C-45°C by mixing and dissolving the calcium D-pantothenate solution obtained in methanol; This calcium D-pantothenate mixed solution undergoes an initial cooling process to reduce the temperature of the calcium D-pantothenate mixed solution to 25°C~15°C within 0.5h. After adding the crystal seeds, the initial temperature maintenance is carried out, and then a second cooling process is carried out to reduce the temperature of the calcium D-pantothenate mixed solution to 5°C to 0°C in ≥4 h, and then the second maintenance of the temperature was carried out to obtain the crystalline methanol hydrate of calcium D-pantothenate. The crystalline methanol hydrate of calcium D-pantothenate Claim 1 , characterized in that the second cooling process fulfills at least one of the conditions (a) to (b): (a) In the second cooling process, the temperature of the calcium-D-pantothenate mixed solution is reduced to 5 to 0 ° C in 4 to 8 hours lowered; (b) The second cooling process is a uniform cooling process. The crystalline methanol hydrate of calcium D-pantothenate Claim 1 or 2 , characterized in that the maintenance of the temperature of the process for producing the crystalline methanol hydrate of calcium D-pantothenate satisfies at least one of the conditions (c) - (d): (c) The duration of the first maintenance of the temperature is 1 h to 4 H; (d) The duration of the second temperature maintenance is 1 h to 4 h. The crystalline methanol hydrate of calcium D-pantothenate Claim 1 or 2 , characterized in that the preparation of the calcium D-pantothenate solution comprises the following steps: A fermentation broth containing ammonium D-pantothenate is prepared by fermentation of glucose in Escherichia coli using glucose as a starting material; The fermentation broth containing ammonium D-pantothenate is pretreated to obtain a pretreatment solution containing ammonium D-pantothenate, and then the pretreatment solution is neutralized with calcium hydroxide to obtain a pretreatment solution of calcium D-pantothenate; The calcium D-pantothenate pretreatment solution is concentrated to obtain the calcium D-pantothenate solution. The crystalline methanol hydrate of calcium D-pantothenate Claim 4 , characterized in that the pretreatment is carried out sequentially using the ion exchange membrane and the ion exchange resin; The ion exchange membrane is ceramic membrane and organic polymer membrane; The ion exchange resin is a cation exchange resin; The content (% dry matter) of calcium D-pantothenate in the pretreatment solution of calcium D-pantothenate is 60% to 80%. The crystalline methanol hydrate of calcium D-pantothenate Claim 4 , characterized in that the concentration treatment step satisfies at least one of conditions (e)-(g): (e) the concentration temperature treatment is 30°C to 50°C; (f) The pressure of the concentration treatment is 4000 Pa to 10000 Pa; (g) The content of calcium D-pantothenate in the calcium D-pantothenate solution is 45% by weight to 55% by weight. The crystalline methanol hydrate of calcium D-pantothenate Claim 1 or 2 , characterized in that the mass-volume ratio of calcium D-pantothenate to the methanol in the calcium D-pantothenate solution is 1 g: (5-9) mL. The crystalline methanol hydrate of calcium D-pantothenate Claim 4 , characterized in that the crystal seed is a calcium D-pantothenate tetramethanol compound, the crystal seeds having a mass of 0.05% to 1% of the calcium D-pantothenate content in the calcium D-pantothenate solution . The crystalline methanol hydrate of calcium D-pantothenate Claim 1 , characterized in that the crystalline methanol hydrate of calcium D-pantothenate is the bulk crystal having a bulk density of 0.63 g/ml and a hygroscopicity of 0.51%; or a bulk density of 0.63 g/ml and a hygroscopicity of 0.51%; or a bulk density of 0.65 g/ml and a hygroscopicity of 0.63%; or a bulk density of 0.61 g/ml and a hygroscopicity of 0.55%; or a bulk density of 0.67 g/ml and a hygroscopicity of 0.49%; or a bulk density of 0.58 g/ml and a hygroscopicity of 0.70%; or has a bulk density of 0.64 g/ml and a hygroscopicity of 0.48%. A calcium D-pantothenate, characterized in that the production process comprises the following steps: The crystalline methanol hydrate of calcium D-pantothenate is produced according to the production process of the crystalline methanol hydrate of calcium D-pantothenate according to one of the processes Claims 1 until 9 manufactured; Calcium D-Pantothenate is prepared using crystalline methanol hydrate of Calcium D-Pantothenate.