Method for preparing crystals of tromethamine or hydrochloride thereof

Abstract

The present invention relates to a method for preparing crystals of tromethamine or hydrochloride thereof, and crystals of tromethamine or hydrochloride thereof prepared using the preparation method. By lowering the temperature and maintaining same at a constant temperature, large crystal particles of tromethamine or hydrochloride thereof can be obtained uniformly and with high purity.

Description

Method for preparing tromethamine or its hydrochloride crystals

[0001] The present invention relates to a method for producing tromethamine or a hydrochloride crystal thereof and to tromethamine or a hydrochloride crystal thereof produced by such method.

[0002]

[0003] Pharmaceutical raw materials must satisfy a purity of 99.9% or higher and be managed to maintain consistent quality. Among separation and purification technologies, cold crystallization is a separation method that utilizes differences in solubility according to temperature, obtaining crystals by controlling the saturation state of the solution. The state of a solution is divided into three regions: stable, metastable, and unstable. The stable region refers to a state where more solute can dissolve in the solvent, representing the state of the solution prior to reaching saturation. The metastable region is a supersaturated state where new crystal nuclei do not spontaneously precipitate. When the degree of supersaturation increases beyond the metastable region, crystal nuclei are spontaneously generated while existing crystals grow; this region is called the unstable region. If the crystallization process is operated in the unstable region, the formation of new nuclei and crystal growth occur simultaneously, making it very difficult to control the particle size distribution of the final product. Therefore, to achieve a uniform particle size distribution, appropriate crystallization conditions tailored to the raw material are required to separate the formation and growth of nuclei.

[0004] Meanwhile, tromethamine is widely used in the pharmaceutical and cosmetics industries as it serves as a flavoring agent, acidity regulator, thickener, solvent, and pH buffer. Research is continuously being conducted on processes to produce uniform crystals by controlling particle size with the high purity of tromethamine.

[0005]

[0006] The present invention is intended to solve the above-mentioned problems,

[0007] The present invention aims to provide a method for cooling crystallization of tromethamine or its hydrochloride crystals to improve purity and have a uniform particle size by lowering and maintaining the temperature of the tromethamine or its hydrochloride solution at a constant level.

[0008]

[0009] The present invention comprises the step (S1) of cooling a tromethamine or a hydrochloride solution thereof at a rate of 0.05 to 10.0 ℃ / min at a temperature corresponding to an unsaturated state of the tromethamine or hydrochloride solution concentration;

[0010] A step (S2) of maintaining a tromethamine or hydrochloride solution thereof at a temperature corresponding to a supersaturation of 102–140% for a certain period of time;

[0011] Step (S3) of cooling again at a rate of 0.01~5.0℃ / min; and

[0012] A method for manufacturing a crystal of tromethamine or its hydrochloride, comprising the step (S4) of maintaining at the termination temperature of the above S3 step for 10 to 300 minutes.

[0013] The present invention also provides tromethamine crystals produced by the above manufacturing method.

[0014]

[0015] The crystallization method according to the present invention can suppress the generation of microcrystals and improve mother liquor separation, thereby reducing the mother liquor attached to the crystals, which improves purity and reduces the time required for separation, thereby improving productivity. In addition, crystals having a larger particle size can be obtained uniformly.

[0016]

[0017] Figure 1 shows a temperature control graph over time of Example 1 of the present invention.

[0018] Figure 2 shows a graph of temperature control over time of Comparative Example 1 of the present invention.

[0019] Figure 3 shows an optical microscope image of Example 1 according to the present Experimental Example 1.

[0020] Figure 4 shows an optical microscope image of Comparative Example 1 according to Experimental Example 1.

[0021] Figure 5 shows an optical microscope image of Comparative Example 2 according to Experimental Example 1.

[0022]

[0023] The present invention will be described below with reference to the attached drawings.

[0024] Meanwhile, each description and embodiment disclosed herein may be applied to each other description and embodiment. That is, all combinations of the various elements disclosed herein fall within the scope of the present invention. Furthermore, the scope of the present invention is not to be limited by the specific descriptions provided below.

[0025] When a part is said to "include" a certain component, this means that, unless specifically stated otherwise, it does not exclude other components but rather allows for the inclusion of additional components.

[0026] The present invention comprises the step (S1) of cooling a tromethamine or a hydrochloride solution thereof at a rate of 0.05 to 10.0 ℃ / min at a temperature corresponding to an unsaturated state of the tromethamine or hydrochloride solution concentration;

[0027] Step (S2) of maintaining the solution of tromethamine or its hydrochloride solution at a temperature corresponding to a supersaturation of 102–140% for a certain period of time; and

[0028] Step (S3) of cooling again at a rate of 0.01~5.0℃ / min; and

[0029] A method for preparing a crystal of tromethamine or its hydrochloride, comprising the step (S4) of maintaining at the termination temperature of step S3 for 10 to 300 minutes.

[0030] In the present invention, tromethamine is Tris(hydroxymethyl)aminomethane or 2-amino-2-hydroxymethyl-1,3-propanediol, and is also referred to as “Tris” or “Tris amino”. Tromethamine is mainly used as a pH adjuster or buffer in the cosmetics and pharmaceutical fields, and can be usefully used as a fragrance to impart scent to cosmetics.

[0031] In the present invention, the hydrochloride of tromethamine may mean “Tris-HCl”.

[0032] In the present invention, “%” means mass%.

[0033] In the present invention, in step S1, which is the first cooling step of tromethamine, the tromethamine or its hydrochloride solution may be obtained by dissolving tromethamine or its hydrochloride in a solvent. The solvent may be water, methanol, ethanol, alcohols having 1 to 5 carbon atoms such as 1,3-propanol and butanol, isopropyl alcohol (IPA), or a combination thereof. Additionally, the tromethamine or its hydrochloride solution may contain by-products that may occur during the synthesis of tromethamine or its hydrochloride, such as methylated tromethamine (methylated TRIS), serinol (SERINOL), methylated serinol, or oxazolidine. Tromethamine or its hydrochloride may be contained in an amount of less than about 30 wt% of the total solute including the by-products in the solution.

[0034] In the present invention, in step S1, “the temperature at which the concentration of the tromethamine or its hydrochloride solution is in an unsaturated state” can be any temperature at which the solution is in an unsaturated state, and the temperature range may vary depending on the amount of solute or the type of solvent.

[0035] In the present invention, the cooling rate of step S1 may be 0.05 to 10.0 ℃ / min, preferably 0.1℃ / min or more, 0.2 ℃ / min or more, or 0.3℃ / min or more, and 8 ℃ / min or less, 5 ℃ / min or less, 4℃ / min or less, or 3 ℃ / min or less. If the cooling rate is slower than the above, it may be difficult to form supersaturation.

[0036] In the present invention, the cooling time of step S1 is the time taken to reach the end temperature of the first cooling step below by cooling at the cooling rate from a temperature (temperature before cooling) where the concentration of the tromethamine or its hydrochloride solution is in an unsaturated state, and the cooling time may be set according to the temperature before cooling, the cooling rate, and the end temperature. Specifically, it may be 10 minutes to 3000 minutes, and more specifically, 10 minutes or more, 20 minutes or more, 30 minutes or more, or 40 minutes or more, and 2000 minutes or less, 1000 minutes or less, 500 minutes or less, or 150 minutes or less.

[0037] In the present invention, the end temperature of the first cooling step according to step S1 may be a temperature corresponding to a supersaturation of 102 to 140% of tromethamine or a hydrochloride solution thereof, and the end temperature of the first cooling step may be the same as the temperature maintained at a constant level in step S2 below.

[0038] The cooling step, which is the S1 step of the present invention, may represent a process in which the solubility of tromethamine or its hydrochloride decreases as the temperature decreases, and changes from an unsaturated state through a saturated state to a supersaturated state (particularly, a metastable region) to prepare for crystal nucleation.

[0039] In the present invention, the degree of supersaturation refers to the amount dissolved in excess of the saturation state of tromethamine or its hydrochloride. For example, if the degree of supersaturation is 10%, it may mean a state in which tromethamine or its hydrochloride is dissolved in excess of 10% by weight in a saturated solution. Accordingly, a degree of supersaturation of 102 to 140% may mean a state in which 102 to 140% by weight is dissolved in excess relative to the weight of tromethamine or its hydrochloride in a saturated solution of tromethamine or its hydrochloride.

[0040] If the degree of supersaturation is too small compared to the above range, additional nucleation may occur during cooling to the S3 stage, and if the degree of supersaturation is too large compared to the above range, too many crystal nuclei may be generated at once, which may result in a smaller crystal grain size.

[0041] The concentration of the tromethamine or its hydrochloride solution at the start of the S2 stage may be the same as the initial concentration before cooling in the S1 stage, and if the temperature of the solution is maintained for a certain period of time according to the S2 stage, the concentration remains constant until nucleation is induced and the concentration decreases to a saturated state, so that the concentration of the solution at the end of the S2 stage may correspond to the concentration at which tromethamine or its hydrochloride becomes saturated at that temperature.

[0042] In Step S2, “maintaining” means maintaining the termination temperature from Step S1 and leaving it as is for a certain period without any other processing.

[0043] In step S2, the time maintained at a constant level is not significantly limited, but may be 10 to 300 minutes. Specifically, it may be 10 to 250 minutes, or 50 to 250 minutes. Maintaining the temperature at a constant level in step S2 can induce the formation of tromethamine or its hydrochloride as crystal nuclei to the extent of supersaturation by maintaining the degree of supersaturation at a constant level. In conventional cooling crystallization methods, the slower the cooling rate, the larger the particle size of the crystal can be; however, in the case of the present invention, crystals with large particle size and a uniform particle size distribution can be produced even with a shorter crystallization process time.

[0044] After maintaining a constant temperature for a certain period of time, crystals can be visually confirmed, and since the crystal formation reaction is an exothermic reaction, a rise in temperature can be observed. After the rise in temperature is observed, the process can proceed to the next cooling step, step S3, after 10 to 120 minutes.

[0045] By cooling according to step S1, tromethamine or its hydrochloride can be induced from an unsaturated state through a saturated state to a supersaturated state, and into a metastable region where no crystals are formed even in the supersaturated state. Subsequently, according to step S2, it can be saturated from the supersaturated state; specifically, it can be saturated as nuclei are formed, passing through an unstable region that generates crystal nuclei from the supersaturated state of the metastable region. By controlling the amount of such nucleation, the particle size of the final obtained tromethamine or its hydrochloride crystals can be controlled.

[0046] In the present invention, according to step S3, which is a step of cooling again, crystal nuclei can be grown while lowering the temperature at a constant rate.

[0047] In step S3, the cooling start temperature can be the same as the holding temperature in step S2.

[0048] In step S3, the cooling rate may be 0.01 to 5.0℃ / min, preferably 0.01℃ / min or more, 0.05℃ / min or more, 2.0℃ / min or less, 1.5℃ / min or less, 1.0℃ / min or less, or 0.5℃ / min or less. If the cooling rate is too slow compared to the above rate, productivity may decrease, and if the cooling rate is too fast compared to the above rate, there is a possibility that crystals may unintentionally adhere to the wall of the crystallizer.

[0049] In step S3, the cooling termination temperature is not significantly limited as long as it is higher than the freezing point of the solution, but it can be controlled to a temperature corresponding to a saturated concentration in which the weight ratio of dissolved tromethamine or its hydrochloride relative to the solution containing tromethamine or its hydrochloride is 0.5 to 50%.

[0050] Specifically, it may be 0 to 20°C, and more specifically, 5 to 15°C.

[0051] The manufacturing method of the present invention may include a step (S4) of maintaining at the termination temperature of step S3 for 10 to 300 minutes after step S3. Through step S4, crystals may be generated to the maximum extent to obtain the maximum yield.

[0052] According to the manufacturing method of the present invention, when cooling a tromethamine solution, the temperature is lowered until it reaches a temperature indicating a supersaturated state, at which point it is maintained for a certain period of time to induce crystal nucleation, and then cooled again to grow uniformly formed crystal nuclei (Example 1).

[0053] If the manufacturing method of the present invention is used, and the process is cooled uniformly to the same final temperature for the same duration (Comparative Example 1), new crystal nuclei of tromethamine are formed throughout the cooling time, and the growth time of each crystal nucleus varies significantly, resulting in the formation of many crystals with non-uniform particle sizes, and the crystal size may decrease as the number of crystal nuclei increases relative to the same amount of tromethamine.

[0054] In addition, in the case of the seed addition technique that provides crystal nuclei from the outside (Comparative Example 2), the average particle size of the tromethamine crystals was smaller, and the crystals clumped together. The seed addition technique also has the disadvantage that the user must directly add seeds with a constant particle size to the reactor during the crystallization operation.

[0055] However, in the case of the crystallization method according to the present invention, stable crystallization process operation with a high particle size and narrow particle size distribution was possible by simply setting the temperature, even when the user was not present at the site.

[0056] In the present invention, steps S1 to S4 can be crystallized using a crystallizer. Specifically, crystallization can be achieved by controlling the cooling rate within the crystallizer using a single crystallizer. For example, the cooling rate of the crystallizer can be controlled by varying the temperature or speed of the refrigerant entering the outer jacket or inner coil of the crystallizer, and the temperature inside the reactor can be maintained evenly using a stirrer. Conditions such as the temperature, cooling rate, and time of the crystallizer are as described above.

[0057] The particle size of the final obtained tromethamine crystal of the present invention may be 200 to 2000 μm. More specifically, it may be 200 to 1500 μm, 300 to 1500 μm, or 400 to 1000 μm.

[0058] In the present invention, the "particle diameter" is the average particle diameter, for example, the median particle diameter (D 50 It can mean ).

[0059] In the present invention, "D" indicating the particle size 10 ", "D 50 ", "D 90 " is the particle size value of the volumetric cumulative distribution of the crystal measured using the laser diffraction method. Specifically, “D 10 ” is the particle size when the volume accumulation is 10%, and "D 50 " is the particle size when the volume accumulation is 50%, and "D 90 is the particle size when the volume accumulation is 90%.

[0060] In the present invention, the purity of the tromethamine crystals produced according to the present invention may be 99.0% or higher.

[0061] In the present invention, the SPAN (particle size distribution width) according to the following mathematical formula 1 of the tromethamine crystals prepared according to the present invention may be 0.5 or more and 1.8 or less. Specifically, it may be 1.8 or less, 1.7 or less, or 1.5 or less, and may be 0.5 or more and 0.6 or more.

[0062]

[0063] [Mathematical Formula 1]

[0064] SPAN(Particle Size Distribution Width)=(D 90 -D 10 ) / D 50

[0065]

[0066] The present invention also provides tromethamine crystals produced by the above manufacturing method.

[0067] The particle size distribution width of the tromethamine crystals produced according to the present invention may be 1.8 or less, 1.7 or less, or 1.5 or less according to the above mathematical formula 1, and may be 0.5 or more, or 0.6 or more.

[0068] D, corresponding to the numerator of the particle size distribution width formula 90 -D 10 The smaller this is, the more D corresponding to the denominator 50 It can be seen that the larger this value, the more uniform the particle size distribution of the crystals produced.

[0069] The purity of the tromethamine crystals produced according to the present invention may be 99.0% or higher.

[0070] Average particle size (D) of tromethamine crystals produced according to the present invention 50 ) can be 200 to 2000 μm. More specifically, it can be 200 to 1500 μm, 300 to 1500 μm, or 400 to 1000 μm.

[0071] Tromethamine crystals produced according to the present invention may be manufactured by applying the contents of the manufacturing method of the present invention as is.

[0072]

[0073] Hereinafter, preferred embodiments and experimental examples are presented to aid in understanding the present invention. However, the following embodiments and experimental examples are provided merely to facilitate a better understanding of the present invention, and the scope of the present invention is not limited by the following embodiments and experimental examples.

[0074]

[0075] Preparation of Example 1 (cooling crystallization method according to the present invention)

[0076] Tromethamine was dissolved in distilled water at a concentration of approximately 50% at a temperature of 60°C. After confirming that all the solute had dissolved, the tromethamine solution was cooled to 42°C at a rate of 0.2°C / min. Subsequently, the solution was maintained at 42°C for a certain period of time until the concentration reached saturation. Once the concentration of the solution reached saturation, it was cooled again to the target termination temperature of 10°C at a rate of 0.2°C / min.

[0077]

[0078] Preparation of Comparative Example 1 (linear cooling method)

[0079] Tromethamine was dissolved in distilled water at a concentration of approximately 50% at a temperature of 60°C. After confirming that all the solute had dissolved, the tromethamine solution was cooled to the target termination temperature of 10°C at a rate of 0.15°C / min.

[0080]

[0081] Preparation of Comparative Example 2 (seed addition method)

[0082] Tromethamine was dissolved in distilled water at a concentration of approximately 50% at a temperature of 60°C. After confirming that all the solute had dissolved, the tromethamine solution was cooled to 42°C at a rate of 0.2°C / min. Subsequently, tromethamine seeds were added at 42°C, and the solution was cooled again to the target termination temperature of 10°C at a rate of 0.2°C / min.

[0083]

[0084] Experimental Example 1. Particle Size and Purity Analysis

[0085] The particle diameters of the particles according to Example 1, Comparative Examples 1 and 2 were measured using a particle size analyzer (PSA), and the particle size distribution width was calculated according to the following mathematical formula 1, and the results are shown in Table 1.

[0086] In addition, its appearance was examined using an optical microscope and is shown in Figures 3 to 5.

[0087]

[0088] [Mathematical Formula 1]

[0089] SPAN(Particle Size Distribution Width)=(D 90 -D 10 ) / D 50

[0090]

[0091] Example 1 Comparative Example 1 Comparative Example 2D 10 378 μm 97 μm 119 μm D 50 668 μm277 μm270 μmD 901145 μm 1423 μm 669 μm SPAN (Particle Size Distribution Width) 1.1 4.8 2.0 Purity > 99.0% 98.4% 98.0%

[0092]

[0093] Example 1, prepared by the method according to the present invention, has a crystal particle size (particle size D 50 The particle size corresponding to the particle size was 668 µm, which is larger than that of Comparative Example 1 (277 µm) which was linearly cooled and Comparative Example 2 (270 µm) which had seeds added during manufacturing, allowing for the production of crystal particles with a larger size. In addition, the SPAN (particle size distribution width) of Example 1 was 1.1, which is lower than that of Comparative Example 1 (4.8) and Comparative Example 2 (2.0), indicating a narrow particle size distribution and the production of uniform particles; as a result, Example 1 was obtained with higher purity than Comparative Examples 1 and 2. Accordingly, it can be seen that large-sized tromethamine crystal particles can be obtained with uniformity and high purity using the method according to the present invention.

[0094]

[0095] The crystallization method according to the present invention can suppress the generation of microcrystals and improve mother liquor separation, thereby reducing the mother liquor attached to the crystals, which improves purity and reduces the time required for separation, thereby improving productivity. In addition, crystals having a larger particle size can be obtained uniformly.

Claims

1. A step (S1) of cooling a tromethamine or a hydrochloride solution thereof at a rate of 0.05 to 10.0 ℃ / min at a temperature corresponding to an unsaturated state of the tromethamine or hydrochloride solution concentration; Step (S2) of maintaining a tromethamine or a hydrochloride solution thereof at a temperature corresponding to a supersaturation of 102–140% for a certain period of time; Step (S3) of cooling again at a rate of 0.01~5.0℃ / min; and A method for preparing a crystal of tromethamine or its hydrochloride, comprising the step (S4) of maintaining at the termination temperature of the above S3 step for 10 to 300 minutes.

2. In Paragraph 1, A method for preparing crystals of tromethamine or its hydrochloride, wherein in step S1, the solvent of the solution of tromethamine or its hydrochloride is water, an alcohol having 1 to 5 carbon atoms, isopropyl alcohol (IPA), or a combination thereof.

3. In Paragraph 1, A method for manufacturing tromethamine or its hydrochloride crystals, wherein the cooling termination temperature of the cooling step according to step S1 is a temperature corresponding to a supersaturation of 102~140% of step S2.

4. In Paragraph 1, A method for preparing tromethamine or its hydrochloride crystals, wherein the cooling time in step S1 is 10 minutes to 3000 minutes.

5. In Paragraph 1, A method for manufacturing tromethamine or its hydrochloride crystals, wherein the time in step S2 is 10 to 300 minutes.

6. In Paragraph 1, A method for preparing crystals of tromethamine or its hydrochloride, wherein the cooling termination temperature in step S3 is a temperature corresponding to a saturation concentration in which the weight ratio of dissolved tromethamine or its hydrochloride relative to a solution containing tromethamine or its hydrochloride is 0.5 to 50%.

7. In Paragraph 1, According to step S1, tromethamine or a solution of its hydrochloride progresses from an unsaturated state through a saturated state to a supersaturated state, and A method for preparing tromethamine or its hydrochloride crystals in which a solution of tromethamine or its hydrochloride becomes saturated from a supersaturated state according to step S2.

8. In Paragraph 1, Average particle size of manufactured tromethamine crystals (D 50 A method for preparing tromethamine or its hydrochloride crystals having a diameter of 200 to 2000 μm.

9. In Paragraph 1, A method for manufacturing tromethamine or its hydrochloride crystals, wherein the SPAN (particle size distribution width) according to the following mathematical formula 1 of the manufactured tromethamine crystals is 0.5 or more and 1.8 or less. [Mathematical Formula 1] SPAN(Particle Size Distribution Width)=(D 90 -D 10 ) / D 50 10. In Paragraph 1, A method for manufacturing tromethamine or its hydrochloride crystals, wherein the purity of the manufactured tromethamine crystals is 99.0% or higher.

11. Tromethamine or a hydrochloride crystal thereof produced by the manufacturing method according to paragraph 1.

12. In Paragraph 11, Average particle size (D 50 Tromethamine or its hydrochloride crystals having a particle size of 200 to 2000 μm and a purity of 99.0% or higher.

13. In Paragraph 11, Tromethamine or its hydrochloride crystal having a SPAN (particle size distribution width) of 0.5 or more and 1.8 or less according to the following mathematical formula 1. [Mathematical Formula 1] SPAN(Particle Size Distribution Width)=(D 90 -D 10 ) / D 50

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