Triethylenetetramine tetrahydrochloride, and composition

Abstract

To provide a triethylenetetramine tetrahydrochloride crystal.SOLUTION: The present invention includes a step of adding a poor solvent into an aqueous solution of triethylenetetramine tetrahydrochloride at a feeding temperature and stirring to precipitate crystals, wherein the feeding temperature ranges from 50°C to 75°C and the poor solvent is an alcohol solvent. The present invention also provides a novel triethylenetetramine tetrahydrochloride. The crystal thereof has an XRPD pattern with peaks at 2θ of 21.9, 24.8, 25.2, 28.0 and 35.6±0.1°. Compositions prepared using the triethylenetetramine tetrahydrochloride of the present invention have the advantage of storage stability.SELECTED DRAWING: Figure 3

Description

[Technical field]

[0001] The present invention relates to the field of triethylenetetramine tetrahydrochloride, in particular to the synthesis and application of triethylenetetramine tetrahydrochloride. [Background technology]

[0002] Triethylenetetramine (TETA), also known as trientine, has the structure of formula 1, which uses the four nitrogen atoms in its structure to chelate copper and help flush excess copper from the body, and is therefore often used to treat Wilson's disease. Currently, triethylenetetramine is primarily used in treatment and research in the form of its hydrochloride, which is also divided into triethylenetetramine dihydrochloride (TETA·2HCl) and triethylenetetramine tetrahydrochloride (TETA·4HCl).

[0003] [ka]

[0004] China Patent Registration No. CN102924289B discloses a method for the synthesis of TETA·2HCl, but also teaches that the stability of TETA·2HCl is poorer than that of TETA·4HCl. Taiwan Patent Publication No. 202002956A discloses TETA·4HCl Form B crystalline form and its preparation method. Taiwan Patent Publication No. 202002956A teaches that the crystalline form of TETA·4HCl prepared by the method described in WO 2006 / 027705 is Form A, and also shows that tablets made with TETA·4HCl Form A show fading of the pieces after storage at 40°C and 75% humidity for 6 months, whereas tablets made with TETA·4HCl Form B show less tendency to fading over time, indicating that tablets made with TETA·4HCl Form B have better stability. However, the method disclosed in Taiwan Patent Publication No. 202002956A involves crystal precipitation at low temperatures and requires the addition of seed crystals to promote the formation of TETA·4HCl Form B, which makes the procedure complicated and inconvenient. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Chinese Patent No. 102924289 [Patent Document 2] Taiwan Patent Publication No. 202002956 [Patent Document 3] International Publication No. 2006 / 027705 Summary of the Invention [Problem to be solved by the invention]

[0006] Based on the above, it can be seen that the stability and preparation method of TETA·4HCl in the prior art still have deficiencies and need to be improved. [Means for solving the problem]

[0007] In view of the above, an object of the present invention is to provide a method for producing triethylenetetramine tetrahydrochloride crystals, the method comprising step 1 of adding a poor solvent to an aqueous solution of triethylenetetramine tetrahydrochloride at a supply temperature and stirring to precipitate crystals, wherein the supply temperature is 50°C to 75°C and the poor solvent is an alcohol solvent.

[0008] To achieve the above object of the invention, the alcohol solvent includes methanol (MeOH) or ethanol (Ethanol), preferably methanol.

[0009] In order to achieve the above object of the invention, the stirring is carried out under a time condition and a stirring temperature, where the time condition is at least 1 hour, and the stirring temperature is 5°C to 25°C, preferably 15±5°C.

[0010] To achieve the above object of the invention, step 1 further comprises drying the crystals such that the loss on drying of the crystals is less than 1%.

[0011] In order to achieve the above object of the invention, the method further includes, before step 1, a preliminary step 1 of mixing an aqueous solution of triethylenetetramine dihydrochloride with an acidic solution to obtain a reaction solution and carrying out an acidification reaction (Acidification), and a preliminary step 2 of adding an alcohol poor solvent and stirring to precipitate a crude product of triethylenetetramine tetrahydrochloride.

[0012] In order to achieve the above object of the invention, the pH value of the reaction solution is below 2.0.

[0013] To achieve the above object of the invention, the alcohol anti-solvent in preliminary step 2 comprises methanol or ethanol, and the alcohol solvent is preferably methanol.

[0014] In order to achieve the above object of the invention, the stirring in the preliminary step 2 is carried out under temperature and time conditions, where the temperature condition is 15°C to 35°C, preferably 25±5°C, and the time condition is at least 2 hours.

[0015] In order to achieve the above object of the invention, the preliminary step 2 further includes drying the crude product of triethylenetetramine tetrahydrochloride, so that the loss on drying of the crude product of triethylenetetramine tetrahydrochloride is less than 10%.

[0016] Another object of the present invention is to provide triethylenetetramine tetrahydrochloride, wherein a crystalline triethylenetetramine tetrahydrochloride has an XRPD pattern with peaks at 21.9, 24.8, 25.2, 28.0 and 35.6±0.1 degrees 2θ.

[0017] Another object of the present invention is to provide a pharmaceutical composition, which contains the triethylenetetramine tetrahydrochloride crystals produced by the above-mentioned production method or the above-mentioned triethylenetetramine tetrahydrochloride.

[0018] To achieve the above objectives of the invention, the pharmaceutical composition may further comprise a pharma- ceutically acceptable carrier.

[0019] To achieve the above object of the invention, the carrier includes a solubilizer, diluent, lubricant, binder, depolymerizing agent, foaming mixture, dye, sweetener, wetting agent, or other non-toxic and pharmacologically inactive substance used in pharmaceutical preparations.

[0020] To achieve the above object of the invention, the dissolving agent includes cyclodextrin or modified cyclodextrin, the diluent includes lactose, dextrose, sucrose, cellulose, corn starch or potato starch, the lubricant includes silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate or polyethylene glycol, the binder includes starch, tragacanth, gelatin, syrup, gum arabic, sorbitol, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone, the depolymerizing agent includes starch, alginic acid, alginate or sodium starch glycolate, and the wetting agent includes lecithin, polysorbate or lauryl sulfate.

[0021] To achieve the above objectives of the invention, the dosage form of the pharmaceutical composition includes solution, emulsion, suspension, powder, tablet, pill, troche or capsule.

[0022] Yet another object of the present invention is to provide a use of triethylenetetramine tetrahydrochloride crystals produced by the above-mentioned production method or the above-mentioned triethylenetetramine tetrahydrochloride in the manufacture of a pharmaceutical composition for preventing or treating Wilson's disease. Effect of the Invention

[0023] In summary, the present invention provides TETA·4HCl of crystalline form N and a preparation method thereof. The TETA·4HCl provided by the present invention has the advantages of easier preparation and higher yield. Furthermore, tests have shown that the TETA·4HCl of crystalline form N and its composition provided by the present invention have excellent stability and moisture absorption resistance, which can improve the storage shortcomings of TETA·4HCl and tablets in the prior art. [Brief description of the drawings]

[0024] [Figure 1] 1 is a flowchart for preparing crude TETA·4HCl product of the present invention. [Diagram 2] 1 is a flowchart for preparing the TETA·4HCl crystals of the present invention. [Diagram 3] FIG. 2 is an XRPD analysis diagram of TETA·4HCl according to one embodiment of the present invention. [Figure 4] FIG. 2 is a graph showing the results of a hygroscopicity test for the TETA·4HCl tablet of the present invention. [Diagram 5] FIG. 2 is an XRPD analysis diagram of TETA·4HCl according to one embodiment of the present invention. [Figure 6] FIG. 2 is an XRPD analysis of a comparative example of one embodiment of the present invention. [Figure 7] 1 shows the results of comparing the stability of the TETA·4HCl of the present invention with that of a comparative example after storage for one month. [Figure 8] 1 shows the results of comparing the stability of the TETA·4HCl of the present invention with that of a comparative example after storage for one month. [Figure 9] 1 shows the results of comparing the stability of the TETA·4HCl of the present invention with that of a comparative example after storage for three months. [Figure 10] 1 shows the results of comparing the stability of the TETA·4HCl of the present invention with that of a comparative example after storage for three months. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] All technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art unless otherwise defined.

[0026] As used in the specification and claims, the singular terms "a," "one," and "the" may refer to plural referents unless specifically stated otherwise.

[0027] As used herein, "or", "and" and "and" all refer to "and / or" unless otherwise specified. Furthermore, the terms "comprise" and "include" are open-ended conjunctions. The preceding paragraphs are for systematic reference only and should not be construed as limitations on the subject matter of the present invention.

[0028] The terms "treat," "treat," and similar terms refer to methods of slowing, ameliorating, alleviating, or reversing a diagnosable disease from which a patient suffers and associated symptoms caused by that disease, as well as methods of preventing the disease or any symptoms associated therewith.

[0029] The term "pharmaceutical acceptable" means that a substance or composition must be compatible with the other ingredients of the pharmaceutical formulation and not exacerbate the patient's condition.

[0030] The term "pharmaceutically acceptable carrier" includes one or more components selected from the group consisting of solvents, emulsifiers, suspending agents, disintegrating agents, binders, excipients, stabilizers, chelating agents, diluents, gelling agents, preservatives, lubricants, surfactants, and other similar carriers or carriers applicable to the present invention.

[0031] The term "pharmaceutically acceptable excipient" includes, but is not limited to, at least one of a polymer, a resin, a plasticizer, a filler, a lubricant, a diluent, a binder, a disintegrant, a solvent, a co-solvent, a surfactant, a preservative, a sweetener, a flavoring agent, a pharmaceutical grade dye or pigment, and a thickener.

[0032] The term "effective amount" refers to the dose required to produce or elicit the expected biological response, and not the amount required to produce a cure. Those skilled in the art will appreciate that the effective amount of a pharmaceutical composition may vary depending on factors such as the desired biological endpoint, the bioactive agent being delivered, the composition of the encapsulating matrix, the target tissue, and the like.

[0033] The term "pharmaceutical composition" refers to a solid or liquid composition of a form, concentration and purity suitable for administration to a patient and capable of inducing a desired physiological change after administration, and the pharmaceutical composition is sterile or non-pyrogenic.

[0034] The term "feed" refers to the addition of material to a reactor during a production process.

[0035] The term "in-process control (IPC)" refers to the monitoring and process adjustments carried out during the production process.

[0036] The term "anti-solvent" refers to a solvent used to reduce the solubility of a solute.

[0037] The term "acidification" refers to a reaction caused by the addition of a sufficient amount of acid to a solid or liquid to make it acidic.

[0038] The term "crystal precipitation" or "crystallization" refers to the formation of crystals by supersaturation of a solute in a solution.

[0039] The term "Crystal Wash" refers to washing the product obtained during the production process with a specific solvent.

[0040] The term "loss on drying (LOD)" refers to the weight loss after a product is dried to a certain weight.

[0041] The term "Re-crystallization" refers to redissolving a substance or crystal in a solvent and then recrystallizing from the solution.

[0042] In some cases, the production method provided by the present invention can first prepare TETA·2HCl into a crude TETA·4HCl product (crude trientine tetrahydrochloride), and then prepare the crude TETA·4HCl product into the TETA·4HCl provided by the present invention.

[0043] Preparation of crude TETA·4HCl (Crude trientine tetrahydrochloride)

[0044] For example, in one embodiment of the present invention, the preparation of crude TETA·4HCl is as follows: TETA·2HCl is mixed with pure water to dissolve, an acidic solution is added to carry out acidification, a poor solvent is then added and stirring is continued to cause crystallization, and then the reaction suspension is filtered, the crystals are washed, and the product is dried to obtain crude TETA·4HCl.

[0045] Here, the anti-solvent may be any solvent in which TETA·4HCl is substantially insoluble, including but not limited to ethanol or methanol, with methanol being optimal, and the acidic solution may be any solution commonly used in acidification reactions, preferably hydrochloric acid, more preferably 35% or more hydrochloric acid.

[0046] In order to obtain a better preparation effect, the weight ratio of TETA·2HCl to pure water is 0.5:1-1:1, preferably 1:1, the temperature of the acidification reaction is 10℃-40℃, preferably 20±10℃, the pH value of the reaction solution of the acidification reaction is below 2.0, the temperature of the addition of anti-solvent is 10℃-40℃, preferably 20±10℃, the weight ratio of anti-solvent to TETA·2HCl is 2:1-6:1, preferably 4:1, the temperature of crystallization is 15℃-35℃, preferably 25±5℃, the continuous stirring time is at least 2 hours, and the loss on drying (LOD) of the product is less than 10%, preferably less than 5.0%.

[0047] Preparation of TETA·4HCl crystals (trientine tetrahydrochloride)

[0048] In one embodiment of the present invention, the TETA·4HCl crystals provided by the present invention are prepared by mixing and dissolving the crude TETA·4HCl product with pure water, adding a poor solvent, and continuing to stir to cause recrystallization to precipitate crystals. Thereafter, the reaction suspension is filtered, the crystals are washed, and the product is dried to obtain the TETA·4HCl crystals provided by the present invention.

[0049] Here, the anti-solvent may be any solvent in which TETA·4HCl is substantially insoluble, including but not limited to ethanol or methanol, with methanol being most preferred.

[0050] In order to obtain a better preparation effect, the weight ratio of the TETA·4HCl crude product to pure water is 1:1-1:2, preferably 1:1.2; the mixed dissolution temperature of the product and pure water is 15°C-35°C, preferably 25±5°C; the weight ratio of the TETA·4HCl crude product to anti-solvent is 1:2-1:6, preferably 1:4; the supply temperature of the anti-solvent is 50°C-75°C, preferably 60±5°C; the continuous stirring temperature is 5°C-25°C, preferably 15±5°C; the continuous stirring time is at least 1 hour; and the loss on drying (LOD) of the product is less than 1%, preferably less than 0.6%.

[0051] For the pharmaceutical composition provided by the present invention, the active ingredient or composition provided herein can be combined with at least one pharma- ceutically acceptable carrier (vehicle) to prepare a suitable dosage form for the composition of the present invention using techniques well known to those skilled in the art. Dosage forms include, but are not limited to, solutions, emulsions, suspensions, powders, tablets, pills, troches, or capsules and other similar dosage forms or dosage forms applicable to the present invention.

[0052] Furthermore, suitable routes of administration of the pharmaceutical compositions according to the present invention include, but are not limited to, oral administration, injection, mucosal administration, topical transdermal administration, and other similar routes of administration or routes of administration applicable to the present invention, among which the best route of administration is oral administration.

[0053] Those skilled in the art can prepare the TETA·4HCl provided by the present invention and at least one pharma- ceutically acceptable carrier into a suitable dosage form according to conventional techniques. For example, in one embodiment of the present invention, the pharmaceutical composition is an oral dosage form, which can be prepared according to process steps including step 1 of milling or granulating the TETA·4HCl crystals provided by the present invention, if necessary, and step 2 of combining the TETA·4HCl crystals with a pharma- ceutically acceptable carrier to form a mixture.

[0054] If the oral dosage form is a tablet, step 2 may be followed by step 3 of compressing the mixture to form a tablet, and optionally sugar-coating or film-coating the tablet, step 4. If the oral dosage form is a capsule or powder, step 2 may be followed by encapsulating the mixture. The process steps may further include other basic pharmaceutical steps, including but not limited to milling, granulation, sugar-coating or film-coating.

[0055] Pharmaceutically acceptable carriers include, but are not limited to, solubilizers, diluents, lubricants, binders, depolymerization agents, effervescent mixtures, dyes, sweeteners, wetting agents, or other non-toxic, pharmacologically inactive substances used in pharmaceutical preparations. Solubilizers include, but are not limited to, cyclodextrins or modified cyclodextrins. Diluents include, but are not limited to, lactose, dextrose, sucrose, cellulose, corn starch, or potato starch. Lubricants include, but are not limited to, silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, or polyethylene glycol. Binders include, but are not limited to, starch, tragacanth, gelatin, syrup, gum arabic, sorbitol, methylcellulose, carboxymethylcellulose, or polyvinylpyrrolidone. Depolymerization agents include, but are not limited to, starch, alginic acid, alginates, or sodium starch glycolate. Wetting agents include, but are not limited to, lecithin, polysorbate, or lauryl sulfate.

[0056] The pharmaceutical composition comprises up to 85 weight percent (wt%) TETA·4HCl, for example, in one embodiment of the invention, the pharmaceutical composition comprises 50 weight percent (wt%) TETA·4HCl. The pharmaceutical composition is preferably sterile and pyrogen-free.

[0057] All materials utilized in the present invention are commercially available and readily available unless otherwise specified.

[0058] The novel technical features of the present invention, including specific features, are disclosed in the scope of the patent application, and in order to better understand the technical features of the present invention, the preferred embodiments of the present invention will be described in detail in conjunction with the present specification, the embodiments based on the principles of the present invention, and the accompanying drawings.

[0059] The present invention will be described with reference to the following examples, but the present invention is not limited to these examples. EXAMPLES

[0060] Example 1. Synthesis of TETA·4HCl

[0061] Preparation of crude TETA·4HCl (Crude trientine tetrahydrochloride)

[0062] As shown in the flow chart of Figure 1, 10 kg of triethylenetetramine dihydrochloride (TETA·2HCl) and 10 kg of purified water (PW) were placed in a reaction tank and dissolved at 25±5°C. The temperature of the reaction tank was set to 15±5°C, and then 9.45-9.9 kg of hydrochloric acid (35% or more) was added to the reaction tank at a temperature of 20±10°C, and acidification reaction (Acidification) was performed at a temperature of 20±10°C, and the pH value of the reaction solution was controlled to 2.0 or less. Next, the temperature of the reaction tank was set to 15±5°C, and 40 kg of methanol (MeOH) was added at an internal temperature of 20±10°C to precipitate crystals (Crystallization). Next, the temperature of the reaction tank was controlled to 25±5°C and stirred for at least 2 hours. After that, the suspension in the reaction tank was filtered, and the crystals were washed twice with 25 kg of methanol each time. Finally, the product was dried until the loss on drying (LOD) was <5% to obtain the crude TETA·4HCl product.

[0063] Preparation of TETA·4HCl (trientine tetrahydrochloride)

[0064] As shown in the flow chart in Figure 2, the crude TETA·4HCl obtained in the previous step and 1.2 times its weight of pure water were put into a reactor and dissolved at 25±5°C. Then, methanol 4 times the weight of the crude TETA·4HCl was added at a feed temperature of 60±5°C, and then the temperature of the reactor was lowered. The temperature of the reactor was set at 15±5°C, and after the internal temperature dropped to 15±5°C, stirring was continued at this temperature for at least 1 hour to precipitate crystals by re-crystallization. After that, the suspension in the reactor was filtered, and the crystals were washed twice with methanol, 2.5 times the weight of the crude TETA·4HCl each time. Finally, the product was dried to obtain TETA·4HCl with an LOD of less than 0.6%.

[0065] Example 2. Analysis of the Crystalline Form of TETA·4HCl

[0066] The TETA·4HCl prepared by the method described in Example 1 was analyzed by X-ray powder diffraction (XRPD), and the results are shown in Figure 3. The crystals of TETA·4HCl provided by the present invention have an XRPD pattern with peaks at 2θ of 21.9, 24.8, 25.2, 28.0, and 35.6±0.1°, and are designated as Form N.

[0067] Example 3, Stability Test 1

[0068] Chromatographic purity was confirmed using thin-layer chromatography (TLC) according to the method disclosed in the United States Pharmacopeia (USP), and the impurities contained in the TETA·4HCl synthesized in Example 1 were analyzed after storage at different temperatures (25°C to 40°C) and different humidities (60%RH to 75%RH) for one month. The results are shown in Table 1. No impurities were detected after storage of TETA·4HCl for one month at different temperatures and humidities, proving that the TETA·4HCl provided by the present invention has good stability.

[0069] [Table 1]

[0070] Example 4, Stability Test 2

[0071] The TETA·4HCl prepared by the method described in Example 1 was compressed into tablets, and the tablets were stored under environmental conditions of 25°C, 60% RH or 40°C, 75% RH for 3 months, and their content and impurities were analyzed.

[0072] The results are shown in Table 2. After the tablets were stored for 3 months, no obvious decomposition of TETA·4HCl was observed, and all impurities were the same as the initial measurement results and lower than the quantification limit of the analysis.

[0073] [Table 2]

[0074] Example 5, Hygroscopicity Test

[0075] The tablets described in Example 4 were stored for one month under environmental conditions of 25°C and 75% RH, and then their hygroscopicity was tested, using commercially available trientine hydrochloride tablets (Cuprior®, TETA·4HCl form B tablets) and commercially available TETA·2HCl capsules as comparative examples. The results are shown in Figure 4. The tablets prepared from the TETA·4HCl crystals of the present invention did not show obvious weight gain due to hygroscopicity, while the weight gain of the commercially available TETA·2HCl capsules due to hygroscopicity was more than 75% of the original weight, which demonstrated that the tablets prepared from the TETA·4HCl crystals of the present invention had better hygroscopicity resistance.

[0076] Example 6. Yield Analysis and Stability Comparison

[0077] Crystalline form N of TETA·4HCl was prepared according to the preparation method described in Example 1, and form B of TETA·4HCl was prepared as a comparative example by the method disclosed in Taiwan Patent Publication No. 202002956A.

[0078] The XRPD analysis results are shown in Figures 5 and 6. Figure 5 shows the XRPD pattern of the TETA·4HCl crystals of the present invention, and Figure 6 shows the XRPD pattern of the comparative example, which shows that the comparative example is Form B as described in Taiwan Patent Publication No. 202002956A. The yield results are shown in Table 3. The TETA·4HCl (crystal form N) prepared according to the preparation method provided by the present invention has an unexpectedly high yield (77.1%-86.6%), and the method provided by the present invention has the advantage that it is not necessary to precipitate crystals at a low temperature in the preparation procedure, and TETA·4HCl can be obtained without using seed crystals.

[0079] [Table 3]

[0080] Furthermore, the TETA·4HCl of the present invention and the comparative example were stored at different temperatures (25°C to 40°C) and different humidities (60%RH to 75%RH) for one or three months, and then the chromatographic purity was confirmed using thin layer chromatography according to the method disclosed in the United States Pharmacopeia. The comparative stability results are shown in Figures 7 to 10. The TETA·4HCl of the present invention has the same stability as the comparative example.

[0081] To sum up the above results, it can be seen that the preparation method provided by the present invention not only has the advantage of simpler preparation procedure, but also can obtain TETA·4HCl in high yield. Furthermore, the TETA·4HCl synthesized by the preparation method provided by the present invention belongs to crystal form N, and the TETA·4HCl and its composition provided by the present invention have excellent stability and moisture absorption resistance, which can improve the stability problems existing in the prior art.

[0082] With respect to the contents disclosed in the preferred embodiments of this specification, those skilled in the art can clearly understand that the above-mentioned embodiments are merely examples, and those skilled in the art can implement the present invention through many transformations and substitutions without departing from the technical features of the present invention. According to the embodiments of this specification, the present invention can be modified in various ways without hindering its implementation. The claims provided herein define the scope of the present invention, which covers the above-mentioned methods and structures and their equivalent inventions.

[0083] The many features mentioned above fully meet the statutory patent requirements of novelty and inventiveness, therefore, we urge your Office to submit the application in accordance with the law and approve the invention patent application to encourage invention.

Claims

1. Triethylenetetramine tetrahydrochloride, the crystals having an XRPD pattern with peaks at 21.9, 24.8, 25.2, 28.0 and 35.6±0.1 degrees 2θ.

2. A pharmaceutical composition comprising the triethylenetetramine tetrahydrochloride or a crystal thereof according to claim 1.

3. The pharmaceutical composition of claim 2 , further comprising a pharma- ceutically acceptable carrier.

4. 4. The pharmaceutical composition of claim 3, wherein the carrier comprises a solubilizer, diluent, lubricant, binder, depolymerizing agent, foaming mixture, dye, sweetener, wetting agent, or other non-toxic, pharmacologically inactive substance used in pharmaceutical formulations.

5. The pharmaceutical composition of claim 2 , wherein the dosage form of the pharmaceutical composition comprises a solution, emulsion, suspension, powder, tablet, pill, troche, or capsule.

6. 2. Use of triethylenetetramine tetrahydrochloride or a crystal thereof according to claim 1 in the manufacture of a pharmaceutical composition for preventing or treating Wilson's disease.

Images