A brexpiprazole oral solution and a method of preparing the same

Abstract

This invention provides an birepiperazole oral solution, wherein the solution comprises birepiperazole 0.4-0.6 mg / ml, disodium edetate 0.1-0.5 mg / ml, methylparaben 1.5-2.0 mg / ml, propylparaben 0.15-0.25 mg / ml, an acidic pH adjuster 2.5-3.5 mg / ml, a flavoring agent 0.8-1.2 mg / ml, propylene glycol 40-60 mg / ml, glycerin 120-180 mg / ml, and a sodium hydroxide solution to adjust the pH to 2.9-3.3. The drug exhibits high stability during preparation, storage, and clinical formulation.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to an ibuprofen oral solution. Background Technology

[0002] Biriperazole, a compound that acts as a dopamine D2, 5-HT1A receptor agonist, and 5-HT2A receptor antagonist, is used as adjunctive therapy for major depressive disorder and schizophrenia. Compared to aripiprazole, biriperazole has increased affinity for 5-HT receptors, reduced activity on D2 receptors, better tolerability, a lower incidence of akathisia as a side effect, and shows a trend toward better efficacy in addressing negative symptoms and cognitive function in schizophrenia. When used as adjunctive therapy for depression, it has a rapid onset of action.

[0003] Currently, the marketed formulation of biriperazole is biriperazole tablets, whose active ingredient is biriperazole, a crystalline powder with the following chemical structure:

[0004] Currently available marketing formulations of birepiperazole are mainly tablets and orally disintegrating tablets. Both are oral preparations, but in patients with unstable mental states, the liquid formulation offers a significant advantage in terms of medication adherence. While orally disintegrating tablets improve patient adherence to some extent, they still have considerable limitations in dosage adjustment.

[0005] Invention patent CN115429753A discloses a composition consisting of active ingredient repiperazole, suspending agent, wetting agent, buffer, preservative, flavoring agent, etc. As a suspension oral liquid, its stability differs significantly from that of a regular oral liquid.

[0006] Invention patent CN118252793A discloses a composition consisting of active ingredient piperazole, liquid acid, antibacterial agent, flavoring agent, sodium acetate, purified water, etc. The stability data of this patent shows that the properties change significantly after 6 months, raising questions about the safety of the product. Furthermore, the high acidity of the preparation may reduce patient medication adherence. Summary of the Invention

[0007] To address the aforementioned technical problems, this invention provides an ibuprofen oral solution. The product is a metal chelating agent, has no safety issues, and exhibits good product stability.

[0008] To achieve the objectives of this invention, the technical solution adopted is as follows: An oral solution of birepiperazole, wherein the components of the solution include: Biriperazole 0.4-0.6 mg / ml Disodium edetate 0.1-0.5 mg / ml Methylparaben 1.5-2.0 mg / ml Propylparaben 0.15-0.25 mg / ml Propylene glycol 40-60 mg / ml Glycerin 120-180 mg / ml Acidic pH adjuster 2.0-4.0 mg / ml Flavoring agent 0.8-1.2mg / ml Add sodium hydroxide solution to adjust the pH to 2.9-3.3.

[0009] The present invention incorporates disodium edetate as a stabilizer into the birepiperazole oral solution. The chemical structure of birepiperazole typically contains a piperazine ring or aromatic heterocycle. These groups are prone to single-electron transfer in the presence of metal ions (especially variable-valence metals Fe²⁺ / Fe³⁺, Cu²⁺), initiating free radical chain reactions and leading to drug degradation. Simultaneously, the birepiperazole molecule contains specific electron-donating groups (such as nitrogen and sulfur atoms). These groups are not only easily oxidized but may also coordinate with metal ions to form "drug-metal" complexes, thereby accelerating degradation and resulting in poor stability. Disodium edetate acts as a "competitive chelator," forming stable water-soluble chelates with trace amounts of metal ions introduced during production, thus preventing birepiperazole degradation and improving the stability of the drug during preparation, storage, and clinical formulation.

[0010] The pH of the solution should be between 2.9 and 3.3. If the pH of the formulation is too low, disodium edetate will be severely protonated, resulting in a significant decrease in its chelating ability. If the pH is too high, some metal ions may form hydroxide precipitates, which will also weaken the effect of disodium edetate. The pH range of 2.9-3.3 is the highly efficient chelating range for disodium edetate.

[0011] The acidic pH adjuster described in this invention is one or more of citric acid, hydrochloric acid, malic acid, lactic acid, and acetic acid.

[0012] The flavoring agent described in this invention is one or more of aspartame, sucralose, sodium saccharin, fructose, sucrose, and sodium chloride.

[0013] The mass ratio of propylene glycol to glycerol in this invention is 1:3.

[0014] Propylene glycol is miscible with water in any proportion. By lowering the dielectric constant of water, it increases the solubility of hydrophobic drug molecules, thereby significantly improving the apparent solubility of birepiperazole. Glycerin acts as a solubilizer, helping to maintain the homogeneity of the solution system and preventing drug precipitation after storage or dilution. The high viscosity of glycerin can increase the consistency of the solution, improving the taste and sedimentation properties of oral solutions.

[0015] Preferably, the solution comprises: Biriperazole 0.5 mg / ml Disodium edetate 0.25 mg / ml Methylparaben 1.8 mg / ml Propylparaben 0.2 mg / ml Propylene glycol 50mg / ml Glycerin 150mg / ml Acidic pH adjuster 3.0 mg / ml Flavoring agent 1.0 mg / ml Add sodium hydroxide solution to adjust the pH to 2.9-3.3.

[0016] The present invention provides a method for preparing birepiperazole oral solution, comprising the following steps: A. First, add the organic solvent to the mixing tank, then add methylparaben, propylparaben, and an acidic pH adjuster. After stirring thoroughly, add the prescribed amount of biriperazole and stir thoroughly to obtain the organic phase. The mixing temperature is 50-60℃ to ensure that the active pharmaceutical ingredient can be fully dissolved, shorten the dissolution time, and keep impurities under control.

[0017] B. Add 50-70% of the batch volume of purified water to another mixing tank, then add the flavoring agent, stir thoroughly, then add disodium edetate, stir thoroughly to obtain the aqueous phase; C. Mix the organic phase with the aqueous phase and stir until the mixture is homogeneous; D. Adjust the pH of the solution, then weigh it to the batch size using purified water, and stir to mix thoroughly.

[0018] Preferably, in step A, methylparaben and propylparaben are added first, followed by an acidic pH adjuster. This allows for a longer dissolution time for methylparaben and propylparaben.

[0019] Preferably, the pH of the organic phase in step A is 3.0-3.2. Within this pH range, birepiperazole exhibits good solubility, meeting the formulation requirements.

[0020] Preferably, in step C, the organic phase is added to the aqueous phase, which is more compatible with the liquid preparation tank in the workshop and optimizes the process.

[0021] The beneficial effects of this invention are as follows: 1. This invention addresses the poor solubility and easy oxidation of buripiperazole by selecting disodium edetate as a stabilizer. The product is a metal complexing agent, which prevents the degradation of buripiperazole. The optimal formulation of the oral solution was selected, which effectively improves the stability of the drug during preparation, storage and clinical preparation, without any safety issues. The product maintains good stability even after long-term storage.

[0022] 2. The solution preparation process was optimized by preparing the organic phase and aqueous phase separately and strictly controlling the order of preparation. The preservatives (methylparaben and propylparaben) and the active pharmaceutical ingredient (API) are both poorly soluble in water and are added to the organic phase. Malic acid is added to the organic phase to promote the dissolution of the API. The API is added last to minimize the residence time of the API in the high-temperature solution preparation process and ensure the stability of the solution. Detailed Implementation

[0023] To more clearly and in detail illustrate the objective and technical solution of this invention, the invention will be further described below through relevant embodiments. These embodiments are merely illustrative of the implementation methods of this invention and do not limit the scope of protection of this invention.

[0024] Malic acid addition amount investigation Acidic pH adjusters can be one or more of citric acid, hydrochloric acid, malic acid, lactic acid, and acetic acid. Their function is to increase the solubility of biriperazole in the organic phase. After the organic phase is completely dissolved, it is mixed with the aqueous phase to obtain a colorless and clear solution. The effect of adding different malic acids on the solubility of the active pharmaceutical ingredient (API) was first investigated to preliminarily screen for malic acid ranges that meet the requirement of achieving an API solubility of 1.0 mg / ml.

[0025] Propylene glycol, glycerin, methylparaben, and propylparaben were added to a 50ml volume of the formula. After dissolving the malic acid in different amounts, 50mg of biriperazole was added. The solubility of biriperazole in the organic phase was observed. Then, the aqueous phase was added to bring the volume to 50ml for stability testing.

[0026] Table 1. Statistical analysis of dissolution results with different amounts of malic acid added.

[0027] Conclusion: When 2.0 mg / ml of malic acid is added, the API in the organic phase can be completely dissolved, and no precipitation occurs after the prepared solution is allowed to stand for more than 16 hours. Therefore, the amount of malic acid added must be greater than 2.0 mg / ml. When the amount of malic acid added is 4.0 mg / ml to 16.0 mg / ml, the RRT0.53, RRT0.62, RRT0.78 and total impurities all increase. Therefore, the amount of malic acid added should be between 2.0 and 3.0 mg / ml. Considering that the central control pH range is 3.0 to 3.2, the amount of malic acid added is selected as 3.0 mg / ml, which can ensure that the biriperazole in the organic phase is completely dissolved.

[0028] To investigate the stabilizing effect of disodium edetate, the original formulation of the drug solution is as follows: Biriperazole 0.5 mg / ml Methylparaben 1.8 mg / ml Propylparaben 0.2 mg / ml L-malic acid 3.0 mg / ml Propylene glycol 50mg / ml Glycerin 150mg / ml Sucralose 1.0 mg / ml The pH value was adjusted to 3.1 using sodium hydroxide solution.

[0029] Add disodium edetate to the original formula for stability comparison: Table 2. Stability comparison of disodium edetate

[0030] Conclusion: The original prescription without disodium edetate showed poor drug stability, indicating that disodium edetate acts as a stabilizer in the prescription.

[0031] Investigation on the amount of disodium edetate added Based on the original prescription, samples with different concentrations of disodium edetate were prepared according to Table 3 and kept at 60℃ for 5, 10, and 30 days. The samples were then sent for testing to determine their appearance, content, related substances, pH value, methylparaben, and propylparaben. The test results are shown in Table 4.

[0032] Table 3. Investigation of the amount of disodium edetate added

[0033] Table 4. Statistical Table of Sodium Edesmonic Acid Addition Amount -60℃

[0034] Continued from Table 4

[0035] Conclusion: The batch without disodium edetate (BR20231214-01) exhibited the worst stability. Among the batches with disodium edetate (BR20231214-02~04), the sample with an addition of 0.1 mg / ml (BR20231214-02) showed slightly worse stability, with slightly higher RRT0.95 impurities and total impurities. The batches with an addition of more than 0.25 mg / ml (BR20231214-03~04) had essentially the same stability level. Therefore, the optimal addition amount of disodium edetate is 0.25 mg / ml.

[0036] In summary, BR20231214-03 is the optimal component for ibuprofen oral solution, and the solution contains: Biriperazole 0.5 mg / ml Disodium edetate 0.25 mg / ml Methylparaben 1.8 mg / ml Propylparaben 0.2 mg / ml Propylene glycol 50mg / ml Glycerin 150mg / ml L-malic acid 3.0 mg / ml Sucralose 1.0 mg / ml Add sodium hydroxide solution to adjust the pH to 3.0-3.2.

[0037] Malic acid in the prescription can be replaced by citric acid, hydrochloric acid, lactic acid, or acetic acid, all of which are common acidic pH adjusters and can lower the pH value and promote the dissolution of biriperazole.

[0038] Sucralose in the prescription can be replaced with aspartame, sodium saccharin, fructose, sucrose, or sodium chloride. These are all common flavoring agents that can be used to improve the taste of oral solutions and have no effect on the stability of the solution. Example 1

[0039] An oral solution of birepiperazole, wherein the components of the solution include: Biriperazole 0.4 mg / ml Disodium edetate 0.1 mg / ml Methylparaben 1.5 mg / ml Propylparaben 0.15 mg / ml Propylene glycol 40mg / ml Glycerin 120mg / ml Citric acid 4.0 mg / ml Sucrose 0.8 mg / ml Add sodium hydroxide solution to adjust the pH to 2.9. Example 2

[0040] An oral solution of birepiperazole, wherein the components of the solution include: Biriperazole 0.6 mg / ml Disodium edetate 0.5 mg / ml Methylparaben 2.0 mg / ml Propylparaben 0.25 mg / ml Propylene glycol 60mg / ml Glycerin 180mg / ml Hydrochloric acid 2.0 mg / ml Fructose 1.0 mg / ml Sodium chloride 0.2 mg / ml Add sodium hydroxide solution to adjust the pH to 3.3. Example 3

[0041] An oral solution of birepiperazole, wherein the components of the solution include: Biriperazole 0.5 mg / ml Disodium edetate 0.3 mg / ml Methylparaben 1.7 mg / ml Propylparaben 0.18 mg / ml Propylene glycol 50mg / ml Glycerin 150mg / ml Lactic acid 3.0 mg / ml Aspartame 0.9mg / ml Sodium chloride 0.2 mg / ml Add sodium hydroxide solution to adjust the pH to 3.1. Example 4

[0042] An oral solution of birepiperazole, wherein the components of the solution include: Biriperazole 0.5 mg / ml Disodium edetate 0.25 mg / ml Methylparaben 1.8 mg / ml Propylparaben 0.2 mg / ml Propylene glycol 50mg / ml Glycerin 150mg / ml Acetic acid 2.8 mg / ml Sodium saccharin 1.0 mg / ml Add sodium hydroxide solution to adjust the pH to 3.0.

[0043] Examination of the order of adding ingredients Organic phase: Based on the malic acid addition experiment, the active pharmaceutical ingredient (API) only dissolves after malic acid is added to the organic phase. Therefore, malic acid must be added before the API. Since methylparaben and propylparaben are poorly soluble in water and easily hydrolyze to produce impurities, adding them to the organic phase ensures complete dissolution and reduces the introduction of impurities.

[0044] Based on the investigation of the active pharmaceutical ingredient (API) dissolution process, the shorter the dissolution time of the API under high temperature heating, the smaller the degradation impurities. Methylparaben, propylparaben, and malic acid all require a certain dissolution time. Therefore, the API is added last to minimize the residence time of the API in the high temperature stage.

[0045] Aqueous phase: The flavoring agent and disodium edetate were dissolved and mixed with the organic phase, which would not affect the stability of the raw material after mixing. Therefore, the order of addition was not investigated, and the preparation was carried out according to the existing addition steps: purified water → sweetener → disodium edetate. In the early stage of process development, sucrose was used as a sweetener, and in the later stage, sucralose was used as a sweetener. During this investigation, sucrose and fructose were used as sweeteners.

[0046] According to the solution formula of BR20231214-03, the solution preparation process specifically includes the following steps: A. Add the organic solvent to the mixing tank first, then add methylparaben and propylparaben, stir thoroughly, add L-malic acid, continue stirring, add the prescribed amount of bripiprazole, stir thoroughly to obtain the organic phase, and the mixing temperature is 50-60℃. B. Add purified water (50-70% of the batch volume) to another mixing tank, then add sucralose, stir thoroughly, then add disodium edetate, stir thoroughly to obtain the aqueous phase; C. Add the organic phase to the aqueous phase and stir until the mixture is homogeneous; D. Adjust the pH of the solution to 3.1, then weigh it to the batch size using purified water, and stir to mix thoroughly.

[0047] Comparison Group 1: (1) Mix glycerol and a portion (20-30%) of purified water, then add and disperse the active pharmaceutical ingredient while stirring, and add L-malic acid to the solution; (2) Add methylparaben and propylparaben to a mixture of propylene glycol and a portion (10-20%) of purified material, mix and dissolve them while maintaining a temperature of 50-60°C.

[0048] (3) Add the above solution (2) to the above solution (1), add the remaining components, adjust the pH of the solution to 3.1, then weigh it to batch size with purified water, and stir to mix well.

[0049] Comparison Group 2: Based on this process, the preparation of the oil phase is as follows: first add organic solvent to the mixing tank, then add malic acid, stir, then add buriperazole, continue stirring, then add methylparaben and propylparaben, and stir thoroughly to obtain the organic phase; Table 5 Statistical Analysis of Feeding Sequence - Day 0

[0050] Conclusion: The results in the table above show that the drug content in the process group was significantly lower than that in the control group 1. This is mainly because buriperazole is poorly soluble in water, so the active pharmaceutical ingredient (API) needs to be dissolved in an organic solvent before it can be completely dissolved. Water was pre-added in the control group 1, resulting in a lower buriperazole content. Compared with both control groups 1 and 2, the related substances in this process group were significantly lower than those in control groups 1 and 2.

[0051] The pH value of the prepared organic phase is 3.0-3.2, preferably 3.1, which is the same as the final pH value of the solution; within this pH range, birepiperazole has good solubility and can meet the formulation requirements.

[0052] The preparation process of this invention can be either adding the aqueous phase to the organic phase or adding the organic phase to the aqueous phase. The two schemes were investigated, and the further specific investigation content is shown in the table below.

[0053] Table 6. Feeding Sequence Examination Table

[0054] Table 7 Statistical Analysis of Feeding Sequence - Day 0

[0055] Table 8. Statistical analysis of the results of the feeding sequence investigation (-60℃, 5 days)

[0056] Table 9. Statistical Analysis of Feeding Sequence (-60℃, 10 days)

[0057] Conclusion: Comparison of the test results of influencing factors at 5 days and 10 days showed no significant difference in the stability of the finished product among the four feeding sequences, indicating that all four feeding sequences are acceptable.

[0058] Based on the experimental results, methylparaben and propylparaben take longer to dissolve than malic acid. Therefore, the preservatives are dissolved first, followed by the malic acid. In the workshop, considering the compatibility with the mixing tank, the oil phase is added to the aqueous phase first.

[0059] The preferred feeding sequence of this invention is as follows: Organic phase: Organic solvent → Preservative → L-malic acid → API Aqueous phase: purified water → sweetener → disodium edetate Mixing method: Organic phase is added to aqueous phase.

[0060] The present invention prepared a batch of pilot samples using a preferred feeding sequence, and tested the batch of pilot samples (upright and upside down) under long-term conditions (25℃±month / 60%±5%RH) for 12 months. The results are shown in Table 10.

[0061] Table 10. Results of long-term stability tests on biriperazole oral solution.

[0062] Conclusion: After 12 months of long-term conditions, all indicators of the pilot-scale samples met the requirements, and there were no significant changes in the physicochemical test items, contents, methylparaben, and propylparaben contents of the samples.

[0063] The embodiments described above are merely illustrative of specific implementations of the present invention, and while the descriptions are detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention.

Claims

1. An ibuprofen oral solution, characterized in that, The solution contains: Biriperazole 0.4-0.6 mg / ml Disodium edetate 0.1-0.5 mg / ml Methylparaben 1.5-2.0 mg / ml Propylparaben 0.15-0.25 mg / ml Propylene glycol 40-60 mg / ml Glycerin 120-180 mg / ml Acidic pH adjuster 2.0-4.0 mg / ml Flavoring agent 0.8-1.2mg / ml Add sodium hydroxide solution to adjust the pH to 2.9-3.

3.

2. The birepiperazole oral solution according to claim 1, characterized in that, The acidic pH adjuster is one or more of citric acid, hydrochloric acid, malic acid, lactic acid, and acetic acid.

3. The birepiperazole oral solution according to claim 1, characterized in that, The flavoring agent is one or more of aspartame, sucralose, sodium saccharin, fructose, sucrose, and sodium chloride.

4. The birepiperazole oral solution according to claim 1, characterized in that, The mass ratio of propylene glycol to glycerol is 1:

3.

5. The birepiperazole oral solution according to claim 1, characterized in that, The components of the solution include Biriperazole 0.5 mg / ml Disodium edetate 0.25 mg / ml Methylparaben 1.8 mg / ml Propylparaben 0.2 mg / ml Propylene glycol 50mg / ml Glycerin 150mg / ml Acidic pH adjuster 3.0 mg / ml Flavoring agent 1.0 mg / ml Add sodium hydroxide solution to adjust the pH to 2.9-3.

3.

6. The method for preparing the birepiperazole oral solution according to claim 1, characterized in that, Includes the following steps: A. First, add the organic solvent to the solution preparation tank, then add methylparaben, propylparaben, and an acidic pH adjuster. After stirring thoroughly, add the prescribed amount of bripiprazole and stir thoroughly to obtain the organic phase. The solution preparation temperature is 50-60℃. B. Add 50-70% of the batch volume of purified water to another mixing tank, then add the flavoring agent, stir thoroughly, then add disodium edetate, stir thoroughly to obtain the aqueous phase; C. Mix the organic phase with the aqueous phase and stir until the mixture is homogeneous; D. Adjust the pH of the solution, then weigh it to the batch size using purified water, and stir to mix thoroughly.

7. The method for preparing the birepiperazole oral solution according to claim 6, characterized in that, In step A, methylparaben and propylparaben are added first, followed by an acidic pH adjuster.

8. The method for preparing the birepiperazole oral solution according to claim 6, characterized in that, The pH value of the organic phase in step A is 3.0-3.

2.

9. The method for preparing the birepiperazole oral solution according to claim 6, characterized in that, In step C, the organic phase is added to the aqueous phase.

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