FORMULAÇÃO INJETÁVEL DE BROMETO DE ROCURÔNIO E MÉTODO DE PREPARAÇÃO DA MESMA

Abstract

According to an embodiment of the present disclosure, the room-temperature stable, unbuffered rocuronium injection formulation for intravenous administration comprises of 1% w / v of rocuronium bromide, a pH adjusting agent comprising hydrochloric acid at a concentration between 125 mMol and 20 mMol for the adjustment of pH between 3.5 to 4.5 and a quantity sufficient of water to make the formulation to 1 mL. The proposed formulation of the present disclosure is stabilized through optimization of pH of the formulation using only hydrochloric acid and / or sodium hydroxide as the pH adjusting agents without use of any buffering agents is suitable for moist heat sterilization. Further, the rocuronium injection formulation of the present disclosure contains lower than 3% of rocuronium related compound C, more preferably less than 2% over the stability period at room temperature conditions.

Description

[0001] The present application claims priority from a complete patent application filed in India under patent application number IN 202341031271, filed on May 2, 2023, and entitled “Room temperature stable, unbuffered formulation of rocuronium bromide injection for intravenous administration and a method thereof.” Field of Invention

[0002] The present invention relates generally to pharmaceutical formulations for rocuronium bromide injection. More specifically, the present invention relates to the development of a stable and sterile rocuronium injection formulation with a preferred pH between 3.5 and 4.5, suitable for intravenous administration without the use of buffering agents, capable of prolonged storage at room temperature and capable of sterilization by moist heat. Background of the Invention

[0003] Rocuronium bromide is a popular non-depolarizing aminosteroid neuromuscular blocking agent with a rapid onset of action and blocking effects of intermediate duration. The reference products, Zemuron® / Esmeron®, are a sterile, pyrogen-free, clear, colorless to yellow / orange isotonic solution intended for intravenous injection.

[0004] The formulation of the reference products (Zemuron® / Esmeron®) is buffered with an acetate buffer (approximately 140 mMol), in which each ml contains 10 mg of rocuronium bromide, 2 mg of sodium acetate and approximately 7 mg of glacial acetic acid, and the pH is adjusted to 4 with acetic acid and / or sodium hydroxide. In addition, the aqueous solution is isotonic with sodium chloride.

[0005] Rocuronium is unstable in aqueous solutions and undergoes hydrolytic degradation to form primarily the deacetylated impurity known as rocuronium-related compound C. It is also worth noting that Zemuron® or Esmeron® reference products should be stored in a refrigerator between 2°C and 8°C (36°F and 46°F). Petition 870250083588, dated 09 / 17 / 2025, pp. 82 / 99 2 / 17 although, after removal from refrigeration, rocuronium bromide should be used within 60 days to 12 weeks, and opened rocuronium bromide vials within 30 days.

[0006] Several efforts have been made to improve the stability of rocuronium in an aqueous solution.

[0007] Document WO 2008 / 065142 describes a technique for stabilizing an aqueous solution containing rocuronium by adding to the solution a sulfoalkyl ether-β-cyclodextrin derivative or a pharmaceutically acceptable salt thereof. However, this technique requires a sulfoalkyl ether-β-cyclodextrin derivative or a pharmaceutically acceptable salt thereof, the use of which has been reported to cause renal dysfunction, etc. The prior art document further describes that the pH should be in the range of 3.5 to 7.5, and preferably 5.5 to 7.5, to reduce injection pain. In other words, in the document, the occurrence of injection pain in the pH range of 3.5 to 7.5 is acknowledged, and reducing the pH to 3.5 or less is not considered.

[0008] Administration of rocuronium is associated with severe burning pain, which occurs in up to 80% of patients and lasts approximately 10 to 20 seconds.Previous studies have shown that lidocaine, fentanyl, normal saline mixtures, dexmedetomidine, ketamine, and sodium thiopental reduce pain caused by rocuronium injection. However, studies indicate that a high concentration of acetate buffer used in the brand-name formulation, and not the active ingredient, may be the cause of vascular pain.

[0009] US Patent 10,869,876 describes a buffered rocuronium preparation with an adjusted pH of 3.5 or less (preferably between 2.8 and 3.2). The buffer solution may include citric acid-sodium hydroxide, tartaric acid-sodium hydroxide, potassium hydrogen phthalate-hydrochloric acid, or glycine-hydrochloric acid. Such a rocuronium preparation exhibits a rocuronium-related Substance C generation rate of 5% or less after six months of storage at 40°C.

[00010] International publication WO2023275157 describes a room temperature stable aqueous composition comprising rocuronium, wherein the composition has a pH of 2.5 to 3.5, preferably a pH of 2.8 to 3.2, more preferably a pH of 3.0, and wherein the composition has a non-titratable acidity Petition 870250083588, dated 09 / 17 / 2025, pp. 83 / 99 3 / 17 greater than 35 mEq. The rocuronium composition is stable after thermal sterilization. Furthermore, the rocuronium composition is stable after storage at room temperature.

[00011] However, this low pH of around 3, described in the prior art, is generally not preferable due to the acidic pH, considering vascular irritation and injection pain. To keep the risk of local irritation low, pH values ​​should, however, be within the target pH range of 3.5 < pH < 9.0, unless there is a very compelling reason.

[00012] Other descriptions of prior patents, such as CN 101653412B, employ methods for stabilizing rocuronium using EDTA and a buffering agent. The prior art patent EP 2,900,216 B1 describes the composition of a rocuronium salt with an excipient selected from D-gluconic acid and buffering agents.

[00013] There is still a need for a room temperature stable injectable preparation of rocuronium suitable for intravenous administration, with a pH > 3.5 and closer to the reference products (i.e., pH around 4), but without the use of acetate buffer or any buffering agents and still capable of terminal sterilization by moist heat.

[00014] To address the challenges above, the inventors of the present invention have found a solution by optimizing the composition of the injection, allowing long-term storage at room temperature without the use of acetate or any other buffering agents and having a pH closer to the reference products, Zemuron® / Esmeron®. Brief Description of the Invention

[00015] Considering the disadvantages mentioned in the previous section, the following summary is provided to facilitate understanding of some of the unique innovative features of the present invention and is not intended to be a complete description. A complete understanding of the various aspects of the present invention can be obtained by considering the description and drawings as a whole.

[00016] In one embodiment, an injectable formulation of unbuffered rocuronium, stable at room temperature, for intravenous administration is described. Petition 870250083588, dated 09 / 17 / 2025, pp. 84 / 99 The 4 / 17 formulation comprises rocuronium bromide at 1% w / v, a tonicity adjusting agent at 0.7% to 0.9% w / v, a pH adjusting agent, wherein the pH adjusting agent comprises hydrochloric acid at a concentration between 12.5 mMol and 20 mMol for pH adjustment between 3.5 and 4.5, and a quantity of water sufficient to complete the formulation to 1 ml.

[00017] According to one embodiment of the present invention, the tonicity adjusting agent is selected from sodium chloride, mannitol, dextrose and sucrose, preferably sodium chloride in the range of 0.7% to 0.9% w / v.

[00018] According to one embodiment of the present invention, the concentration of hydrochloric acid is preferably in the range of 12.5 mMol to 20 mMol for pH adjustment between 3.5 and 4.5, preferably between pH 3.6 and 4.3, and most preferably between 3.6 and 3.8.

[00019] According to an embodiment of the present invention, the pH adjusting agent may also comprise sodium hydroxide to be used, if necessary, to adjust the pH to a preferred range.

[00020] According to one embodiment of the present invention, the formulation comprises less than 3% of rocuronium-related compound C, more preferably less than 2% during the stability period under ambient temperature conditions.

[00021] In another embodiment, a method is described for preparing an injectable formulation of unbuffered rocuronium, stable at room temperature, for intravenous administration. The method consists of collecting water for injection and maintaining it at a temperature range of 20 to 25°C, adding sodium chloride to the water and mixing for 10 minutes to dissolve, adding 0.5 N hydrochloric acid solution, equivalent to 2.5% of the batch volume, and then adding rocuronium bromide and stirring for 20 minutes to dissolve, checking the pH and adjusting it further between 3.5 and 4.5, more preferably between 3.6 and 3.8 using 0.1 N HCl solution and / or 0.1 N NaOH solution, if necessary, making up the volume to 100% of the batch size using water for injection and stirring for 20 minutes, aseptically filtering the solution through 0.2 μm sterilizing grade filters, filling approximately 5.3 ml of the filtered solution into Petition 870250083588, dated 09 / 17 / 2025, pages 85 / 99 5 / 17 USP Type 1 5 ml tubular flint vials and crimp the vials with 13 mm flip-top aluminum seals. The vials can be additionally subjected to moist heat sterilization at 121.5°C for 15 minutes, if desired.

[00022] The filling volume and vial size of the product can be varied according to the required dose, for example, 10 mg / 1 ml in a 2 ml vial, 20 mg / 2 ml in a 2 ml vial, 50 mg / 5 ml in a 5 ml vial, or 100 mg / 10 ml in a 10 ml vial. Similarly, the moist heat sterilization cycle can be appropriately altered to reduce the overall thermal exposure of the vials, for example, moist heat sterilization at 121°C for 8 minutes of exposure, etc.

[00023] According to one embodiment of the present invention, the injection water is sprayed with nitrogen throughout the process, except during the addition of materials.

[00024] According to an embodiment of the present invention, the sterilizing grade filters used to aseptically filter the solution comprise a pore size of 0.2 μm.

[00025] According to one embodiment of the present invention, USP Type 1 flint tubular bottles comprise a 13 mm neck and are closed with 13 mm West 4031 / 45 bromobutyl stoppers or any alternative stoppers and crimped with 13 mm aluminum flip-top seals.

[00026] According to one embodiment of the present invention, the pH of the solution is adjusted using 0.1 N HCl solution and, if necessary, additionally using 0.1 N NaOH solution to obtain a pH between 3.5 and 4.5, preferably between 3.6 and 4.3 and, more preferably, between 3.6 and 3.8. Brief Description of the Drawings

[00027] A detailed description is provided with reference to the accompanying figures. These and other features and advantages of the present invention will be readily appreciated, as it becomes better understood by reference to the detailed description below, when considered in conjunction with the accompanying drawings, in which: Petition 870250083588, dated 09 / 17 / 2025, pp. 86 / 99 6 / 17

[00028] Figure 1 illustrates a method for preparing an injectable formulation of unbuffered rocuronium, stable at room temperature, for intravenous administration according to an embodiment of the present invention.

[00029] Figure 2 is a graph illustrating the comparative levels of compound C in the control formulation and the proposed formulation according to an embodiment of the present invention under controlled ambient temperature conditions.

[00030] Figure 3 is a graph illustrating the change in product pH with moist heat sterilization at 121°C for 15 minutes, according to an embodiment of the present invention. Detailed Description of the Invention

[00031] In order to promote understanding of the principles of the invention, reference will be made to the embodiment illustrated in the figures, and specific language will be used to describe them. However, it is understood that this is not intended to limit the scope of the present invention. Such further alterations and modifications to the illustrated system, as well as other applications of the principles of the present invention, which would normally occur to those skilled in the art, should be interpreted as being within the scope of the present invention.

[00032] The terms "comprises," "comprising," or any other variations thereof are intended to encompass a non-exclusive inclusion, such that a process or method comprising a list of steps does not include only those steps, but may include other steps not expressly listed or inherent to such process or method. Similarly, one or more devices, subsystems, elements, structures, or components preceded by "comprises" do not, without further restriction, preclude the existence of other additional devices, subsystems, elements, structures, components, additional devices, additional subsystems, additional elements, additional structures, or additional components. The occurrence of the expressions "in one embodiment," "in another embodiment," and similar language throughout this descriptive report may, but does not necessarily, refer to the same embodiment.Unless otherwise defined, all technical and scientific terms used herein have the same meaning commonly understood by those skilled in the art to which the present invention relates. Petition 870250083588, dated 09 / 17 / 2025, pp. 87 / 99 7 / 17 refers to this. The system, methods, and examples provided herein are for illustrative purposes only and are not intended to be exhaustive.

[00033] In the descriptive report and claims that follow, references will be made to various terms, which will be defined with the meanings below. The singular forms a, an, and the include plural references, unless the context clearly indicates otherwise.

[00034] As used herein, the term rocuronium bromide refers to a drug used in anesthesia to help relax muscles during surgery or other medical procedures. It belongs to a class of drugs called neuromuscular blockers, which work by blocking the transmission of nerve impulses to muscles, resulting in muscle relaxation and paralysis.

[00035] As used herein, the term room temperature stable refers to a substance or material that can be stored and maintained at normal room temperature (generally around 20-25°C or 68-77°F) without significant degradation or loss of quality for an extended period of time.

[00036] As used herein, the term unbuffered or without buffer refers to a substance or solution that does not contain a buffering agent. Buffers are commonly used in biological and chemical processes to prevent pH changes that could affect the stability and activity of active substances, proteins, enzymes, and other molecules.

[00037] As used herein, the term intravenous administration, often abbreviated as IV administration, refers to the administration of drugs or fluids directly into a vein by means of a needle or catheter. This method of administration allows for the rapid and efficient delivery of drugs or fluids into the bloodstream, bypassing the digestive system, and providing more immediate effects. The embodiments described herein describe an unbuffered, room temperature stable injectable formulation of rocuronium for intravenous administration and a method for such administration.

[00038] According to an embodiment of the present invention, an unbuffered, room temperature stable injectable formulation of rocuronium for administration Petition 870250083588, dated 09 / 17 / 2025, pages 88 / 99 8 / 17 intravenous comprises rocuronium bromide at 1% w / v, a pH adjusting agent, wherein the pH adjusting agent comprises hydrochloric acid at a concentration between 12.5 mMol and 20 mMol for pH adjustment between 3.5 and 4.5, more preferably between 3.6 and 3.8, and a sufficient quantity of water to make up the formulation to 1 ml.

[00039] According to an embodiment of the present invention, the tonicity adjusting agent is selected from sodium chloride, mannitol, dextrose and sucrose, preferably sodium chloride in the range of 0.7% to 0.9% w / v.

[00040] According to one embodiment of the present invention, the concentration of hydrochloric acid is preferably in the range of 12.5 mMol to 20 mMol for pH adjustment between 3.5 and 4.5, preferably between 3.6 and 4.3 and most preferably between 3.6 and 3.8.

[00041] According to an embodiment of the present invention, the pH adjusting agent may further comprise sodium hydroxide, used when necessary for pH adjustment.

[00042] According to one embodiment of the present invention, the formulation comprises less than 3% of the rocuronium-related compound C, more preferably less than 2% during the stability period under ambient temperature conditions.

[00043] Figure 1 illustrates a method for preparing a room temperature stable unbuffered rocuronium injectable formulation for intravenous administration according to an embodiment of the present invention.

[00044] According to an embodiment of the present invention, the method for preparing a room temperature stable unbuffered rocuronium injection formulation for intravenous administration comprises collecting water for injection and maintaining it at a temperature range of 20-25°C in step 102. In step 104, adding sodium chloride to the water and mixing for 10 minutes to dissolve and adding 0.5 N hydrochloric acid solution, equivalent to 2.5% of the batch volume. In step 106, adding rocuronium bromide and stirring for 20 minutes to dissolve and checking the pH and further adjusting the pH between 3.5 and 4.5 using 0.1 N HCl solution and / or 0.1 N NaOH solution, if necessary. In step 108, making up the volume to 100% of the batch size using Petition 870250083588, dated 09 / 17 / 2025, pp. 89 / 99 9 / 17 water for injection and shake for 20 minutes and aseptically filter the solution through 0.2 μm sterilizing grade filters. Finally, in step 110, fill approximately 5.3 ml of the filtered solution into 5 ml USP Type 1 flint tubular vials and crimp the vials with 13 mm flip-top aluminum stoppers. The filled vials can additionally be subjected to moist heat sterilization at 121.5°C for 15 minutes, if desired.

[00045] In the process described above, the filling volume and vial size of the product can be varied according to the required dose, for example, 10 mg / 1 ml in a 2 ml vial, 20 mg / 2 ml in a 2 ml vial, 50 mg / 5 ml in a 5 ml vial, or 100 mg / 10 ml in a 10 ml vial. Similarly, the moist heat sterilization cycle can be appropriately altered to reduce the overall thermal exposure of the vials, for example, moist heat sterilization at 121°C for 8 minutes of exposure, etc.

[00046] According to one embodiment of the present invention, the injection water is sprayed with nitrogen throughout the process, except during the addition of materials.

[00047] According to an embodiment of the present invention, the sterilizing grade filters used to aseptically filter the solution comprise a pore size of 0.2 μm.

[00048] According to an embodiment of the present description, USP Type 1 flint tubular vials comprise a 13 mm neck and are closed with 13 mm West 4031 / 45 bromobutyl stoppers or any other stopper, and sealed with 13 mm flip-top aluminum seals. Depending on the desired dose, the filling volume and vial size of the product may be varied.

[00049] According to one embodiment of the present invention, the pH of the solution is adjusted using 0.1 N HCl solution and / or 0.1 N NaOH solution, if necessary, to obtain a pH between 3.5 and 4.5, preferably between 3.6 and 4.3, and most preferably between 3.6 and 3.8. Petition 870250083588, dated 09 / 17 / 2025, pp. 90 / 99 10 / 17

[00050] Overall, the formulation of the present invention comprises 0.7% to 0.9% w / w of sodium chloride as tonicity agents to make the formulation isotonic and obtain an osmolarity of approximately 290 mOsmol / l.

[00051] On the other hand, in the commercially available RLD product and in Zemuron®, the tonicity is adjusted using approximately 3.3 mg / ml of sodium chloride to obtain an isotonic solution. The formulation of the reference products (Zemuron® / Esmeron®) is buffered with an acetate buffer (approximately 140 mMol), in which each ml contains 10 mg of rocuronium bromide, 2 mg of sodium acetate and approximately 7 mg of glacial acetic acid, and the pH is adjusted to 4 with acetic acid and / or sodium hydroxide.

[00052] The comparative composition of the reference products Zemuron® or Esmeron® and the formulation of the present invention are summarized in Table 1. Table 1 - Comparative composition of the reference products and formulation of the present invention. Serial No. Ingredient Function Control formulation similar to reference products Claimed formulation without any buffer agent Each ml contains (mg / ml) Each ml contains (mg / ml) % w / v 1 Rocuronium bromide USP Active substance 10.0 mg 10.0 mg 1.00 2 Sodium chloride USP Tonicity adjusting agent Approximately 3.3 mg 8.0 mg 0.80 3 Anhydrous sodium acetate USP Buffering agent 2.0 mg Acetate buffer or any other buffer is not used in the formulation 4 Glacial acetic acid, USP pH adjusting agents Approximately 7.0 mg (Note 1) 5 Sodium hydroxide NF qs to adjust pH qs to adjust pH between 3.5 and 4.5 (Note 2) 6 Hydrochloric acid NF pH adjusting agent Not used 7 Water for injection USP Vehicle qs 1 ml qs 1 ml Petition 870250083588, dated 09 / 17 / 2025, pp. 91 / 99 11 / 17

[00053] From the above description, it can be observed (Note 1) that the RLD formulation, ZEMURON® contains an acetate buffer containing approximately 2.0 mg of sodium acetate and approximately 7 mg of glacial acetic acid. In addition, glacial acetic acid and / or sodium hydroxide are used for pH adjustment, if necessary, to achieve approximately 4.

[00054] On the other hand, it can also be observed (Note 2) from the above description that the formulation proposed for the present invention is not buffered and does not contain acetate or other buffering agents. The pH of the formulation is adjusted using hydrochloric acid and / or sodium hydroxide to about 3.5 to 4.5, preferably between 3.6 and 4.3 and, more preferably, between 3.6 and 3.8. Examples Steps in the method for preparing the control formulation, similar to the reference products.

[00055] Step 1. Collect water for injection (approximately 90.0%) of the batch size in the manufacturing container and maintain it at a temperature of 20-25°C. Spray nitrogen throughout the process, except during the addition of the material.

[00056] Step 2. Add the required amount of sodium chloride from the batch and mix for 10 minutes to dissolve and obtain a clear solution.

[00057] Step 3. Add the required amount of anhydrous sodium acetate from the batch and stir for 10 minutes to dissolve and obtain a clear solution.

[00058] Step 4. Add the required amount of glacial acetic acid batch (equivalent to 7 mg / ml) and stir for 10 minutes to obtain a clear solution.

[00059] Step 5. Add the required amount of rocuronium bromide from the batch and stir for 20 minutes to dissolve and obtain a clear solution.

[00060] Step 6. Check the pH and, if necessary, adjust it to 4.0 ± 0.1 using 10% acetic acid and / or 0.1 N NaOH solution.

[00061] Step 7. Make up the volume to 100% of the batch size using water for injection and shake for 20 minutes.

[00062] Step 8. Aseptically filter the solution through 0.2 μm sterilizing filters and fill approximately 5.3 ml of the filtered solution into tubular flint vials. Petition 870250083588, dated 09 / 17 / 2025, pp. 92 / 99 12 / 17 5 ml USP Type 1 vials with a 13 mm neck. Cap the vials with 13 mm West 4031 / 45 bromobutyl stoppers and seal them with 13 mm flip-top aluminum stoppers. Steps of the Method for the Claimed Formulation of the Present Invention

[00063] Step 1: Collect water for injection (about 90.0%) of batch size in the manufacturing vessel and maintain it at a temperature of 20-25°C. Spray nitrogen throughout the process, except during the addition of the material.

[00064] Step 2: Add the required amount of sodium chloride from the batch and mix for 10 minutes to dissolve and obtain a clear solution.

[00065] Step 3: Add 0.5 N hydrochloric acid solution, an amount equivalent to 2.5% of the batch volume. This amount of hydrochloric acid is equivalent to approximately 12.5 mmol.

[00066] Step 4: Slowly add the required amount of rocuronium bromide from the batch and stir for 20 minutes to dissolve and obtain a clear solution.

[00067] Step 5: Check the pH and, if necessary, adjust it between 3.5 and 4.5, preferably between 3.6 and 4.3, and most preferably between 3.6 and 3.8 using 0.1 N HCl solution and / or 0.1 N NaOH solution, if necessary.

[00068] Step 6: Make up the volume to 100% of the batch size using water for injection and shake for 20 minutes.

[00069] Step 7: Aseptically filter the solution through 0.2 μm sterilizing filters and fill approximately 5.3 ml of the filtered solution into 5 ml USP Type 1 tubular flint bottles with a 13 mm neck. Stopper the bottles with 13 mm West 4031 / 45 bromobutyl stoppers and seal them with 13 mm flip-top aluminum stoppers.

[00070] Step 8: If desired, Results

[00071] The room temperature stability (25°C / 60% RH) of the control formulation (formula similar to commercially available reference products) is given in Table 2. Table 2 - Stability profile of the aseptically filtered control formulation under ambient temperature conditions (25°C / 60% RH) Petition 870250083588, dated 09 / 17 / 2025, pp. 93 / 99 13 / 17 Controlled ambient temperature condition (25°C / 60% RH) Serial No. Test Parameters Acceptance Criteria Aseptically Filtered Solution 3M 6M 1 Description A clear, colorless to pale yellow solution, free from visible particles Meets Meets Meets 2 pH Between 3.5 and 4.5 4.08 4.09 4.11 3 Osmolality (mOsm / kg) For information 325 325 331 4 Rocuronium Bromide Assay NLT 90.0% and NMT 110.0% 101.4 99.8 100.1 5 HPLC Related Substances Compound C related to rocuronium NMT 1.5% 0.12 0.68 1.39 Any individual impurity NMT 0.2% BDL 0.14 0.13 Total impurities NMT 3.0% 0.12 0.82 1.57

[00072] The stability of the claimed formulation of the present invention at controlled ambient temperature (25°C / 60% RH) is given in Table 3. Table 3 - Stability profile of the proposed formulation under controlled ambient temperature conditions (25°C / 60% RH) Controlled ambient temperature condition (25°C / 60% RH) Serial number Test parameters Acceptance criteria Aseptically filled vials Terminally sterilized product Initial (T0) 3M 6M 12M 1 Appearance A clear, colorless to pale yellow solution, free from visible particles Complies Complies Complies Complies Complies 2 pH Between 3.5 and 4.5 3.66 3.57 3.67 3.65 3.68 3 Osmolality (mOsm / kg) Between 250 and 340 269 271 267 260 270 4 NLT 90.0% and NMT 110.0% assay 100.8 99.5 102.9 101.3 99.6 Petition 870250083588, dated 09 / 17 / 2025, pp. 94 / 99 14 / 17 Related Substances Test Compound C related to rocuronium NMT 3.0% 0.36 0.41 0.66 0.76 1.02 Any individual impurity NMT 0.2% 0.11 0.11 0.18 BDL 0.05 Total impurities NMT 3.0% 0.59 0.78 1.13 0.85 1.18

[00073] Figure 2 is a graph illustrating the levels of the related compound C in the control formulation and in the proposed formulation, according to an embodiment of the present invention. The data demonstrate that the proposed formulation of the present invention is significantly stable and suitable for long-term storage under ambient temperature conditions, compared to the control formulation.

[00074] Furthermore, the stability profile of the formulations with the composition as per the proposed formulation at different pH within the desired pH range was evaluated and is provided in Table 4. Table 4 - Comparative stability profile of the claimed formulation under controlled ambient temperature conditions (25°C / 60% RH) Table 4a - Formulation with a pH of approximately 3.7 Test Parameters Limited Formulation with pH of approximately 3.7 Aseptically filled vials Vials after terminal sterilization 1 month (40°C / 74% RH) 1 month (25°C / 60% RH) Description A clear yellow, colorless to pale solution, free from visible particles Meets Meets Meets Meets pH 3.5-4.5 3.72 3.68 3.7 3.73 Rocuronium bromide assay NLT 90.0% and NMT 110.0% 106 102.9 100.3 100 Other impurities Compound C related to rocuronium NMT 3.5% 0.11 0.22 0.64 0.5 Any impurity NMT 0.2% BDL BDL BDL BDL Petition 870250083588, dated 09 / 17 / 2025, pages 95 / 99 15 / 17 Individual Total Impurities NMT 4.5% 0.11 0.22 0.64 0.5 Table 4b - Formulation with a pH of approximately 4.0 Test Parameters Limited Formulation with pH of approximately 4.0 Aseptically filled vials Vials after terminal sterilization 1 month (40°C / 74% RH) 1 month (25°C / 60% RH) Description A clear yellow, colorless to pale solution, free from visible particles Complies Complies Complies Complies pH 3.5-4.5 3.88 3.94 3.98 4.02 Rocuronium bromide assay NLT 90.0% and NMT 110.0% 104.9 102.9 99.7 100.6 Other impurities Compound C related to rocuronium NMT 3.5% 0.11 0.23 0.78 0.4 Any individual impurity NMT 0.2% BDL BDL BDL BDL Total impurities NMT 4.5% 0.11 0.23 0.78 0.4 Table 4c - Formulation with pH around 4.2 Test Parameters Limited Formulation with pH of approximately 4.2 Aseptically filled vials Vials after terminal sterilization 1 month (40°C / 74% RH) 1 month (25°C / 60% RH) Description A clear yellow, colorless to pale solution, free from visible particles Meets Meets Meets Meets pH 3.5-4.5 4.17 4.22 4.16 4.2 Rocuronium bromide assay NLT 90.0% and NMT 110.0% 105.1 103.1 100.2 100.9 Other impurities Compound C related to rocuronium NMT 3.5% 0.11 0.23 0.7 0.49 Any individual impurity NMT 0.2% BDL BDL BDL BDL Petition 870250083588, dated 09 / 17 / 2025, pp. 96 / 99 16 / 17 Total impurities NMT 4.5% 0.11 0.23 0.7 0.49

[00075] Stability trend data demonstrate that the product is stable in the desired pH range. There was no significant change in parameters such as pH, osmolarity, and potency during the stability evaluation. The stability trend of the related compound C was comparable across the entire desired pH range.

[00076] Furthermore, trend data demonstrate that the formulation of the present invention is suitable for terminal sterilization, as no significant change is observed when the product is sterilized by moist heat sterilization at 121°C for 15 minutes.

[00077] Figure 3 is a graph illustrating the effect of moist heat sterilization at 121°C for 15 minutes on the pH of the formulation at different pHs within the desired pH range, according to an embodiment of the present invention. The data demonstrate that there is no significant change in pH with terminal moist heat sterilization. Several embodiments of the unbuffered, room temperature-stable injectable rocuronium formulation for intravenous administration, and the method described above, provide several advantages. The proposed formulation of the present invention is stabilized by optimizing the pH of the formulation using only hydrochloric acid and / or sodium hydroxide as pH adjusting agents, without the use of any buffering agents.Through this optimization, the inventors of the present invention have achieved a surprising technical breakthrough in improving stability, suitable for moist heat sterilization and long-term storage at room temperature, without the use of acetate or other buffering agents.

[00078] Furthermore, the rocuronium injection formulation of the present invention contains less than 3% of the rocuronium-related compound C, more preferably less than 2% during the stability period at ambient temperature conditions.

[00079] Those skilled in the art will understand that the above general description and the following detailed description are illustrative and explanatory of the present invention and are not intended to restrict it. Although specific language has been used to describe the present invention, any limitations arising therefrom are unintentional. Petition 870250083588, dated 09 / 17 / 2025, pp. 97 / 99 17 / 17

[00080] The figures and the preceding description provide examples of embodiments. Those skilled in the art will understand that one or more of the elements described may be combined into a single functional element. Alternatively, certain elements may be divided into multiple functional elements. Elements of one embodiment may be added to another embodiment. For example, the order of the processes described herein may be altered and is not limited to the manner described herein. Furthermore, the actions of any flowchart need not be implemented in the order shown; not all acts need necessarily be executed. In addition, those acts that do not depend on other acts may be executed in parallel with the others. The scope of embodiments is by no means limited by these specific examples.

Claims

1. Unbuffered, room temperature stable injectable formulation of rocuronium bromide for intravenous administration, with a pH between 3.5 and 4.5, characterized by the formulation comprising: a) rocuronium bromide at 1% w / v; b) tonicity adjusting agent at 0.7% to 0.9% w / v; c) pH adjusting agent concentration, hydrochloric acid, maintained between 12.5 mMol and 20 mMol; d) sufficient water to complete the formulation to 1 ml.

2. FORMULATION, according to claim 1, characterized in that the tonicity adjusting agent is selected from sodium chloride, mannitol, dextrose and sucrose, preferably sodium chloride in the range of 0.7% to 0.9% w / v.

3. FORMULATION, according to claim 1, characterized in that the concentration of hydrochloric acid is preferably in the range of 12.5 mMol to 20 mMol for pH adjustment between 3.5 and 4.

5.

4. Formulation according to claim 1, characterized in that the pH adjusting agent may additionally comprise sodium hydroxide, to be used if necessary for pH adjustment.

5. FORMULATION, according to claim 1, characterized in that the formulation comprises less than 3% of rocuronium-related compound C, more preferably less than 2% during the stability period at ambient temperature conditions.

6. METHOD FOR PREPARING AN UNBUFFERED, ROCURONIUM BROMIDE INJECTABLE FORMULATION, Stable at Room Temperature, for Intravenous Administration, Characterized by the Method Comprising: a) Collecting water for injection and maintaining it within a temperature range of 20 to 25°C; b) Adding sodium chloride to the water and mixing for 10 minutes to dissolve; Petition 870250083588, dated 09 / 17 / 2025, p.77 / 99 2 / 2 c) Add 0.5N hydrochloric acid solution, equivalent to 2.5% of the batch volume; d) Add rocuronium bromide and stir for 20 minutes to dissolve; e) Check the pH and adjust it between 3.5 and 4.5 using 0.1N HCl solution and / or 0.1N NaOH solution; f) Make up the volume to 100% of the batch size using water for injection and stirring for 20 minutes; g) Aseptically filter the solution through 0.2 μm sterilizing filters; h) Fill the vials with the filtered solution and close them with flip-top aluminum stoppers; i) If desired, subject the vials to additional moist heat sterilization, for example at 121.5°C for 15 minutes.

7. METHOD, according to claim 6, characterized in that the injection water is sprayed with nitrogen throughout the process, except during the addition of materials.

8. METHOD, according to claim 6, characterized in that the sterilizing grade filters used to aseptically filter the solution comprise a pore size of 0.2 μm.

9. METHOD, according to claim 6, characterized in that tubular USP Type 1 flint bottles comprise a 13 mm neck and are closed with 13 mm West 4031 / 45 bromobutyl stoppers or any alternative stoppers and crimped with 13 mm aluminum flip-top seals.

10. METHOD, according to claim 6, characterized in that the pH of the solution is adjusted using 0.1 N HCl solution and / or 0.1 N NaOH solution to obtain a pH between 3.5 and 4.5, preferably between 3.6 and 4.3 and, more preferably, between 3.6 and 3.8.

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