Description:TECHNICAL FIELD
[001] The present invention pertains to the field of pharmaceutical compositions, particularly a stable pharmaceutical composition of ketorolac tromethamine injection and method thereof. More particularly, the present invention relates to a method for improving the storage stability of ketorolac tromethamine injection filled in a glass vials or ampules with product solution being substantially free from visible particulates that forms due to the interaction of ketorolac tromethamine injection with the leachable from the glass vials, mainly the calcium or such divalent ions.

BACKGROUND OF THE INVENTION
[002] The Ketorolac Tromethamine Injection, USP is a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory drugs (NSAIDs). Ketorolac tromethamine is a racemic mixture of [-]S- and [+]R-enantiomeric forms, with the S-form having analgesic activity. Ketorolac tromethamine possesses no sedative or anxiolytic properties. The mechanism of action of ketorolac, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.

[003] The chemical name for ketorolac tromethamine is (±)-5-benzoyl- 2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, compound with 2-amino-2-(hydroxymethyl)-1,3- propanediol (1:1), and the structural formula is:

[004] The reference product, Toradol (ketorolac tromethamine) Injection of Roche Palo Alto LLC (Roche®) was supplied in 15 mg/mL, 30 mg/mL, and 60 mg/2 mL filled in a 2 mL Single-Dose glass vial. Currently, multiple generic formulations are approved and being commercially supplied. The marketed product composition contains 10% (w/v) alcohol, USP, and 6.68 mg, 4.35 mg, and 8.70 mg, respectively, of sodium chloride in sterile water. The pH range is 6.9 to 7.9 and is adjusted with sodium hydroxide and/or hydrochloric acid. The sterile solutions are clear and slightly yellow in color.
[005] There have been multiple product recalls of pharmaceutical products containing the Ketorolac tromethamine injection USP, mainly related to visible particulates over the shelf life of the product as summarized in Table 1:
TABLE 1. Ketorolac tromethamine injection USP Product Recalls1

Product Manufacturer Recall date Number of lots recalled Reason
Ketorolac Tromethamine Injection, USP
30 mg / mL,
(1 mL and 2 mL fills in amber vial) Fresenius Kabi USA, LLC April 20, 2020 13 lots Presence of particulate matter
Ketorolac Tromethamine Injection, USP 30mg/mL,
1 mL Vial Hikma Pharma-ceuticals March 05, 2020 8 lots Presence of small visible particulate matters of a gelatinous/oily nature that appear black in some of the recalled lots.
Ketorolac Tromethamine Injection, USP
30 mg / mL,
(1 mL and 2 mL fills in amber vial) Hospira, Inc February 12, 2015 63 lots Report of calcium-ketorolac crystals floating in glass vials of the product
Ketorolac Tromethamine Injection, USP
30 mg / mL,
(1 mL and 2 mL fills in amber vial) Hospira, Inc MAY 4, 2015 29 lots Visible, floating particulate matter within glass flip-top vials.
Ketorolac Tromethamine Injection, USP
30 mg / mL,
(1 mL and 2 mL fills in amber vial) American Regent
October 21, 2009 Multiple lots Potential that particulate matter in conjunction with crystallization may be present in the product
1Information obtained through FDA Recall and Safety Alert Database.

[006] For the recalls with known reasons, those recalls were related to products that failed due to presence of visible particulates. Those failures were attributable, at least in part, to the report of small visible particulate matters or calcium ketorolac crystals floating in product solution supplied in glass vials.

[007] It is noted that the Ketorolac tromethamine injection, USP 30 mg/mL formulations (30 mg/ 1mL and 60 mg/2 mL filled in a 2 mL vials) is more prone to formation of visible particulates over the shelf-life storage compared to the lower strength, i.e., 15 mg/mL injection, which indicate a concentration dependency.

[008] Chinese patent CN101199514B shows composition to improve the clarity of ketorolac tromethamine injection and the visible particles after sterilization by adding 10-60% propylene glycol into the traditional formulation but the preparation uses propylene glycol solvent, which not preferred.

[009] Chinese patent CN110812325B discloses a method for improving the storage stability of ketorolac tromethamine injection comprises directly contacting the liquid medicine with packaging material such as polypropylene plastic ampoule or cycloolefin polymer plastic bottle. Preferably, the polypropylene plastic ampoule is packaged in a high barrier overwrap. Preferably, the high-barrier outer package is one of aluminum foil, aluminum plastic and PVA composite film bags so that visible foreign matters is solved, the number of insoluble particles is small, and the quality is stable. However, plastic vials are expensive compared to glass vials and require additional protection using high-barrier outer package such as aluminum foil and may have problems associated with the leachable from these plastic vial components. Hence, it was not preferred.

[0010] The methods described herein provide a stable formulation packaged in amber glass vials, ensuring the product remains substantially free from visible particulates throughout its shelf-life. Surprisingly, it was discovered that the issue of visible particulate formation can be effectively resolved by siliconizing the glass vials, eliminating the need for large quantities of solvents or the use of expensive plastic vials, as suggested in the prior art. This invention achieves a particulate-free solution for Ketorolac Tromethamine Injection, offering an economical and cost-effective approach to addressing a critical industry challenge.

SUMMARY OF THE INVENTION

[0011] In the light of the disadvantages mentioned in the previous section, the following summary is provided to facilitate an understanding of some of the innovative features unique to the present invention and is not intended to be a full description. A full appreciation of the various aspects of the invention can be gained by taking the entire specification and drawings as a whole.
[0012] According to an embodiment of the present invention, a stable pharmaceutical composition of Ketorolac tromethamine Injection consisting of Ketorolac tromethamine is provided at a concentration between 0.5%w/v and 3.0%w/v filled into a siliconized glass container, wherein the product rejections related to intrinsic black particulates are <1% on visual inspection and the product solution is essentially free from visible particulates over the shelf-life storage.
[0013] According to an embodiment of the present invention, a stable pharmaceutical composition of Ketorolac Tromethamine Injection is provided, comprising ketorolac tromethamine at a concentration between 0.5% w/v and 3.0% w/v; alcohol USP at 10.0% w/v as a co-solvent; sodium chloride USP at a concentration between 0.435% w/v and 0.668% w/v as a tonicity-adjusting agent; a pH-adjusting agent comprising at least one of sodium hydroxide NF and hydrochloric acid NF, in quantities sufficient to achieve a pH range of 6.9 to 7.9; and water for injection USP as the vehicle, in quantity sufficient to make up the total composition to 100% w/v. The solution is filled into a siliconized glass container, wherein the product rejections related to intrinsic black particulates are <1% on visual inspection and the product solution is essentially free from visible particulates over the shelf-life storage.
[0014] According to an embodiment of the present invention, the pharmaceutical composition as claimed remains stable and free from visible particulates under accelerated conditions of 40°C/75%RH for at least 3 months.
[0015] According to an embodiment of the present invention, the pharmaceutical composition as claimed remains stable and free from visible particulates under long-term storage conditions of 25°C/60%RH for at least 12 months.
[0016] According to an embodiment of the present invention, a method for preparing a stable pharmaceutical composition of Ketorolac Tromethamine Injection is provided, comprising the steps of: collecting water for injection (approximately 90% of the batch size) in a manufacturing vessel and maintaining the temperature at 20–25°C while sparging nitrogen gas throughout the method except during material addition; adding sodium chloride USP, a buffering agent, and mixing for 20 minutes to obtain a clear solution; adding ketorolac tromethamine and stirring for 60 minutes to dissolve and obtain a clear solution; adding alcohol USP as a co-solvent and stirring for 10 minutes to ensure uniformity; adjusting the pH to 7.4 ± 0.1 using at least one of 0.5N sodium hydroxide (NaOH) and 0.5N hydrochloric acid (HCl); making up the volume to 100% of the batch size with water for injection and stirring for 20 minutes; aseptically filtering the solution through a 0.2 µm sterilizing-grade filter and filling it into siliconized amber glass containers, followed by stoppering and sealing; and terminally sterilizing the filled containers at 121.5°C for not less than 15 minutes.
[0017] According to an embodiment of the present invention, the method as claimed includes adjusting the pH to a range of 6.9 to 7.9, preferably 7.4 to 7.6.
[0018] According to an embodiment of the present invention, the method as claimed ensures that the headspace oxygen in the vials is reduced to less than 10%.
[0019] According to an embodiment of the present invention, the method as claimed is conducted under monochromatic light to prevent photodegradation.
[0020] According to an embodiment of the present invention, a stable pharmaceutical composition of Ketorolac Tromethamine Injection is provided, comprising ketorolac tromethamine at a concentration of about 0.5% w/v to about 3.0% w/v; sodium chloride USP at a concentration of about 0.435% w/v to about 0.668% w/v as a tonicity-adjusting agent; a pH-adjusting agent comprising at least one of sodium hydroxide NF and hydrochloric acid NF, in quantities sufficient to achieve a pH range of about 6.9 to about 7.9; and water for injection USP as the vehicle, in quantity sufficient to make up the total composition to 100% w/v, wherein the composition is free from alcohol or co-solvent. The solution is filled into a siliconized glass container, wherein the product rejections related to intrinsic black particulates are <1% on visual inspection and the product solution is essentially free from visible particulates over the shelf-life storage.
[0021] According to an embodiment of the present invention, the pharmaceutical composition as claimed remains stable and free from visible particulates under accelerated conditions of 40°C/75%RH for at least three months.
[0022] According to an embodiment of the present invention, the pharmaceutical composition as claimed remains stable and free from visible particulates under long-term storage conditions of 25°C/60%RH for at least 12 months.
[0023] According to an embodiment of the present invention, a method for preparing a stable pharmaceutical composition of Ketorolac Tromethamine Injection free from alcohol is provided, comprising the steps of: collecting water for injection (approximately 90% of the batch size) in a manufacturing vessel and maintaining the temperature at 20–25°C while sparging nitrogen gas throughout the method except during material addition; adding sodium chloride USP, a buffering agent, and mixing for 20 minutes to obtain a clear solution; adding ketorolac tromethamine and stirring for 60 minutes to dissolve and obtain a clear solution; adjusting the pH to 7.4 ± 0.1 using at least one of 0.5N sodium hydroxide (NaOH) and 0.5N hydrochloric acid (HCl); making up the volume to 100% of the batch size with water for injection and stirring for 20 minutes; aseptically filtering the solution through a 0.2 µm sterilizing-grade filter and filling it into siliconized amber glass containers, followed by stoppering and sealing; and terminally sterilizing the filled containers at 121.5°C for not less than 15 minutes.
[0024] According to an embodiment of the present invention, the method as claimed includes adjusting the pH to a range of 6.9 to 7.9, preferably 7.4 to 7.6.
[0025] According to an embodiment of the present invention, the method as claimed ensures that the headspace oxygen in the vials is reduced to less than 10%.
[0026] According to an embodiment of the present invention, the method as claimed is conducted under monochromatic light to prevent photodegradation.
[0027] Additional features and advantages of various embodiments will be set forth in part in the description that follows, and in part will be apparent from the description, or may be learned by practice of various embodiments. The objectives and other advantages of various embodiments will be realized and attained by means of the elements and combinations particularly pointed out in the description and appended claims.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
[0028] The 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 the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings wherein:
[0029] Fig. 1 illustrates a method for preparing a stable pharmaceutical composition of Ketorolac Tromethamine injection in accordance with the embodiment of the present invention;
[0030] Fig. 2 illustrates method for preparing a stable pharmaceutical composition of Ketorolac Tromethamine injection free from alcohol in accordance with the embodiment of the present invention;
[0031] Fig. 3 illustrates a graph of extent of visible particulate formation with different vial types in accordance with the embodiment of the present invention.
[0032] Fig. 4 illustrates a representative black particulate observed in the vials and filtered particulates in accordance with the embodiment of the present invention.
DETAILED DESCRIPTION
[0033] For the purpose of promoting an understanding of the principles of the disclosure, reference will now be made to the embodiment illustrated in the figures and specific language will be used to describe them. It will nevertheless be understood that no limitation of the scope of the disclosure is thereby intended. Such alterations and further modifications in the illustrated system, and such further applications of the principles of the disclosure as would normally occur to those skilled in the art are to be construed as being within the scope of the present disclosure.
[0034] The terms "comprises", "comprising", or any other variations thereof, are intended to cover a non-exclusive inclusion, such that a process or method that comprises a list of steps does not include only those steps but may include other steps not expressly listed or inherent to such a process or method. Similarly, one or more devices or sub-systems or elements or structures or components preceded by "comprises... a" does not, without more constraints, preclude the existence of other devices, sub-systems, elements, structures, components, additional devices, additional sub-systems, additional elements, additional structures, or additional components. Appearances of the phrase "in an embodiment", "in another embodiment" and similar language throughout this specification may, but not necessarily do, all refer to the same embodiment.
[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. The system, methods, and examples provided herein are only illustrative and not intended to be limiting.
[0036] In the following specification and the claims, reference will be made to a number of terms, which shall be defined to have the following meanings. The singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise.
[0037] According to an embodiment of the present invention, a stable pharmaceutical composition of Ketorolac tromethamine Injection consisting of Ketorolac tromethamine is provided at a concentration between 0.5%w/v and 3.0%w/v filled into a siliconized glass container, wherein the product rejections related to intrinsic black particulates are <1% on visual inspection and the product solution is essentially free from visible particulates over the shelf-life storage.
[0038] According to an embodiment of the present invention, a stable pharmaceutical composition of Ketorolac Tromethamine Injection is provided, comprising ketorolac tromethamine at a concentration between 0.5% w/v and 3.0% w/v; alcohol USP at 10.0% w/v as a co-solvent; sodium chloride USP at a concentration between 0.435% w/v and 0.668% w/v as a tonicity-adjusting agent; a pH-adjusting agent comprising at least one of sodium hydroxide NF and hydrochloric acid NF, in quantities sufficient to achieve a pH range of 6.9 to 7.9; and water for injection USP as the vehicle, in quantity sufficient to make up the total composition to 100% w/v. According to an embodiment of the present invention, the product rejections related to intrinsic black particulates are <1% on visual inspection and the product solution is essentially free from visible particulates over the shelf-life storage. The solution is filled into a siliconized glass container, wherein the product rejections related to intrinsic black particulates are <1% on visual inspection and the product solution is essentially free from visible particulates over the shelf-life storage.
[0039] According to an embodiment of the present invention, the pharmaceutical composition as claimed remains stable and free from visible particulates under accelerated conditions of 40°C/75%RH for at least 3 months.
[0040] According to an embodiment of the present invention, the pharmaceutical composition as claimed remains stable and free from visible particulates under long-term storage conditions of 25°C/60%RH for at least 12 months.
[0041] Fig. 1 illustrates a method (100) for preparing a stable pharmaceutical composition of Ketorolac Tromethamine injection in accordance with the embodiment of the present invention. According to an embodiment of the present invention, a method for preparing a stable pharmaceutical composition of Ketorolac Tromethamine Injection is provided, comprising the steps of: collecting water for injection (approximately 90% of the batch size) in a manufacturing vessel and maintaining the temperature at 20–25°C while sparging nitrogen gas throughout the method except during material addition at step 102. Next at 104, adding sodium chloride USP, a buffering agent, and mixing for 20 minutes to obtain a clear solution. Next at 106, adding ketorolac tromethamine and stirring for 60 minutes to dissolve and obtain a clear solution. Next at 108, adding alcohol USP as a co-solvent and stirring for 10 minutes to ensure uniformity. Further at 110, adjusting the pH to 7.4 ± 0.1 using at least one of 0.5N sodium hydroxide (NaOH) and 0.5N hydrochloric acid (HCl). Next at 112, making up the volume to 100% of the batch size with water for injection and stirring for 20 minutes. Further at 114, filtering the solution through a 0.2 µm sterilizing-grade filter and filling it into siliconized amber glass containers, followed by stoppering and sealing. Finally at 116, terminally sterilizing the filled containers at 121.5°C for not less than 15 minutes.
[0042] According to an embodiment of the present invention, the method as claimed includes adjusting the pH to a range of 6.9 to 7.9, preferably 7.4 to 7.6.
[0043] According to an embodiment of the present invention, the method as claimed ensures that the headspace oxygen in the vials is reduced to less than 10%.
[0044] According to an embodiment of the present invention, the method as claimed is conducted under monochromatic light to prevent photodegradation.
[0045] According to an embodiment of the present invention, a stable pharmaceutical composition of Ketorolac Tromethamine Injection is provided, comprising ketorolac tromethamine at a concentration of about 0.5% w/v to about 3.0% w/v; sodium chloride USP at a concentration of about 0.435% w/v to about 0.668% w/v as a tonicity-adjusting agent; a pH-adjusting agent comprising at least one of sodium hydroxide NF and hydrochloric acid NF, in quantities sufficient to achieve a pH range of about 6.9 to about 7.9; and water for injection USP as the vehicle, in quantity sufficient to make up the total composition to 100% w/v, wherein the composition is free from alcohol or co-solvent. According to an embodiment of the present invention, the product rejections related to intrinsic black particulates are <1% on visual inspection and the product solution is essentially free from visible particulates over the shelf-life storage. The solution is filled into a siliconized glass container, wherein the product rejections related to intrinsic black particulates are <1% on visual inspection and the product solution is essentially free from visible particulates over the shelf-life storage.
[0046] According to an embodiment of the present invention, the pharmaceutical composition as claimed remains stable and free from visible particulates under accelerated conditions of 40°C/75%RH for at least three months.
[0047] According to an embodiment of the present invention, the pharmaceutical composition as claimed remains stable and free from visible particulates under long-term storage conditions of 25°C/60%RH for at least 12 months.
[0048] Fig. 2 illustrates method (200) for preparing a stable pharmaceutical composition of Ketorolac Tromethamine injection free from alcohol in accordance with the embodiment of the present invention. According to an embodiment of the present invention, a method for preparing a stable pharmaceutical composition of Ketorolac Tromethamine Injection free from alcohol is provided, comprising the steps of: collecting water for injection (approximately 90% of the batch size) in a manufacturing vessel and maintaining the temperature at 20–25°C while sparging nitrogen gas throughout the method except during material addition at step 202. Next at 204, adding sodium chloride USP, a buffering agent, and mixing for 20 minutes to obtain a clear solution. Next at 206, adding ketorolac tromethamine and stirring for 60 minutes to dissolve and obtain a clear solution. Further at 208, adjusting the pH to 7.4 ± 0.1 using at least one of 0.5N sodium hydroxide (NaOH) and 0.5N hydrochloric acid (HCl). Next at 210, making up the volume to 100% of the batch size with water for injection and stirring for 20 minutes. Further at 212, aseptically filtering the solution through a 0.2 µm sterilizing-grade filter and filling it into siliconized amber glass containers, followed by stoppering and sealing. Finally at 214, terminally sterilizing the filled containers at 121.5°C for not less than 15 minutes.
[0049] According to an embodiment of the present invention, the method as claimed includes adjusting the pH to a range of 6.9 to 7.9, preferably 7.4 to 7.6.
[0050] According to an embodiment of the present invention, the method as claimed ensures that the headspace oxygen in the vials is reduced to less than 10%.
[0051] According to an embodiment of the present invention, the method as claimed is conducted under monochromatic light to prevent photodegradation.
[0052] DISCUSSION
[0053] Ketorolac Tromethamine Injection, USP is formulated for intravenous (IV) and intramuscular (IM) administration, available in the following strengths: 15 mg per mL (1.5%) and 30 mg per mL (3%) as sterile solutions. A 60 mg dose in 2 mL (3%) is specifically intended for intramuscular use. These solutions include 10% (w/v) alcohol, USP, along with sodium chloride concentrations of 6.68 mg, 4.35 mg, and 8.70 mg per mL, respectively, dissolved in sterile water. The pH is maintained between 6.9 and 7.9, adjusted using sodium hydroxide and/or hydrochloric acid. The solutions are sterile, clear, and exhibit a slight yellow coloration.
[0054] Currently, the majority of commercially available Ketorolac Tromethamine Injection formulations are packaged in glass vials, typically amber glass, to safeguard the product from photodegradation. However, numerous recalls of Ketorolac Tromethamine Injection, USP have been reported. Among the documented reasons for these recalls, a common issue has been the presence of visible particulates, often identified as calcium-ketorolac crystals suspended in the solution within the glass vials.
[0055] It has been observed that Ketorolac Tromethamine Injection, USP formulations with a concentration of 30 mg/mL (available as 30 mg/1 mL and 60 mg/2 mL in 2 mL amber vials) are more susceptible to the formation of visible particulates during shelf-life storage compared to the lower-strength formulation of 15 mg/mL. This suggests a dependency on concentration, with higher concentrations being more prone to particulate formation.
[0056] Visible black particulates have been observed to develop within 2 days to 1 week after filling Ketorolac Tromethamine Injection, USP 30 mg/mL (in both 1 mL and 2 mL fills in 2 mL amber glass vials), regardless of whether the final product undergoes terminal sterilization or aseptic processing. The extent of particulate formation was found to depend on the type of glass vial and its processing. The black particulates are primarily attributed to interactions between Ketorolac Tromethamine and metal leachables, such as calcium and aluminum, from the glass vials.
[0057] Once the container, such as a vial or ampule, is filled, it is crucial to maintain the stability of the product throughout its shelf life. Any changes that occur as the product ages under normal storage conditions must be thoroughly characterized. Preventing the formation of intrinsic particulate matter, which can compromise product stability, requires careful evaluation of the entire product system. If intrinsic changes occur, they may lead to the development of particles, ranging from sub-visible to visible, which typically arise from gradual mechanisms that impact the product during its shelf life.
[0058] The administration of products containing particulate matter poses significant risks, including the potential obstruction of blood vessels, localized irritation, and swelling at the injection site. It can also lead to the formation of tissue masses that may become inflamed or infected, the development of blood clots that could travel to the lungs, scarring of lung tissues, and severe allergic reactions, which in some cases, may result in life-threatening consequences.
[0059] As part of the routine manufacturing process, all filled units, such as vials or ampules, undergo 100% inspection to detect and eliminate any observed defects. If there is any uncertainty regarding a defect, the unit should be removed. This inspection is most effective when conducted at a stage where defects are most easily identifiable. Each unit can be examined manually with the unaided eye, through semi-automated inspection methods, or using technologies such as light obscuration (LO) or automated inspection systems. During this process, limits on acceptable rejection rates should be established to identify and flag atypical lots. These limits can be categorized based on the severity of the defects (e.g., critical, major, or minor) or by specific defect types, such as particulate contamination.
[0060] While the detection and rejection of vials with visible particulates is an integral part of the visual inspection process, the formation of black particulates originating from intrinsic sources—such as the interaction between ketorolac tromethamine and leachable elements from glass vials—remains a significant and undesirable issue, particularly as these particulates may develop over the product's shelf life.
[0061] The methods described herein address these challenges by offering a stable formulation packaged in glass vials, preferably amber glass, that remains substantially free from visible particulates throughout its shelf-life. Notably, it was unexpectedly discovered that the issue of visible particulate formation can be effectively resolved by siliconizing the glass vials, eliminating the need for large proportions of solvents or the reliance on costly plastic vials, as suggested in prior art.
[0062] Significant visible particulates, exceeding five black particulates per vial, were observed in the 30 mg/mL and 60 mg/2 mL formulations, with slightly fewer particulates noted in the 15 mg/mL presentation. These particulates appeared in both aseptically filled vials and vials subjected to terminal sterilization within two weeks of filling. Interestingly, analytical tests indicated that sub-visible particle levels remained within the acceptable limits specified by the USP monograph. Further investigations were conducted to identify the root cause of the visible black particulate formation.
[0063] The observed particles were black, with a small particle size and a gelatinous or oily texture. Upon filtration of the sample solution, these particulates adhered to the filter paper, but no solid residue could be scraped off, indicating the absence of dry, powdery particulates.
[0064] To identify the true underlying cause of the particulate formation, several factors were systematically examined. It is known that the residual calcium content in the drug substance should be controlled to levels below 5 ppm. However, visible particulates were observed even in products manufactured with drug substances meeting this specification. Consequently, various hypotheses were evaluated, including the active pharmaceutical ingredient (API) source, the order of ingredient addition, the type and use of filters, fill volume and headspace effects, as well as the packaging materials such as vials and stoppers. Each of these variables was assessed to exclude potential contributors to the problem.
[0065] Experimental results revealed that packaging materials play a significant role in the formation of intrinsic visible black particulates. To address this issue, various types of vials, including untreated amber-colored vials, sulfur-treated vials, and siliconized vials, were evaluated. Surprisingly, siliconized vials demonstrated a markedly lower propensity for black particulate formation compared to both untreated and sulfur-treated vials, making them a superior choice for mitigating this problem.
[0066] The extent of visible particulates observed in different vial types are summarized in Table 2 and Figure 3.
Table 2. Extend of visible particulate formation with different vial types
Time Period Untreated
USP Type-1
“51 expansion” vials (A) Untreated
USP Type-1
“33 expansion vials (B) Sulphur treated USP Type-1 vials (C) Siliconized vials (D)
Composition containing Alcohol as Co-Solvent (D1) Aqueous composition without any alcohol or cosolvents (D2)
1 week 100 % 20% 20 % 0 % 0 %
2 week 100 % 35% 38 % 0 % 0 %
3 week 100 % 47% 53 % 0 % 0 %
4 week 100 % 73% 63 % 0 % 0 %
[0067] It is hypothesized that the siliconization of vials minimizes the interaction between Ketorolac Tromethamine Injection and the glass surface, thereby reducing the leaching of elemental impurities, such as calcium, from the glass composition. This reduction in leachables contributes to the prevention of visible particulate formation.
[0068] The typically observed visible black particulates with untreated and sulfur treated glass vials and filtered particulates are provided in Figure 4.
METHOD OF MAKING AND USE
[0069] In various embodiments, the present invention provides an injectable pharmaceutical composition comprising a co-solvent, isotonic agents, and pH-adjusting agents. The composition is prepared by first mixing an aqueous vehicle, such as water for injection, with the co-solvent to form a homogeneous mixture. Subsequently, the active pharmaceutical ingredient (Ketorolac Tromethamine) and isotonic agents are added to the mixture, resulting in a stable pharmaceutical composition.
[0070] If required, the pH of the composition can be adjusted using a suitable acid or base to achieve the desired range. Optionally, buffering agents, including but not limited to citrate, phosphate, or acetate buffers, may be incorporated to further stabilize the pH of the formulation.
[0071] Given the light-sensitive nature of Ketorolac Tromethamine, the mixing and preparation process are performed under monochromatic light conditions to prevent photodegradation and maintain the integrity of the active ingredient. The resulting composition is designed to be stable and free from visible particulates, ensuring safety and efficacy throughout its shelf life.
[0072] In some embodiments, the components of the pharmaceutical composition, including the active ingredient, co-solvent, isotonic agent, buffering agent, and other excipients, can be combined in any sequence during the manufacturing process. Following the addition and mixing of the components, the pH of the composition can be further adjusted as needed using a suitable acid or base to achieve the desired pH range for optimal stability and performance.
[0073] Following the addition and dissolution of the components, the pharmaceutical composition may be subjected to filtration using a polyethersulfone (PES) membrane filter (0.22 µm), a polyvinylidene difluoride (PVDF) membrane filter (0.22 µm), or other suitable sterilizing-grade filters. The filtered composition is then filled into an appropriate pharmaceutically acceptable container, such as a syringe, vial, or ampule. The containers are stoppered and sealed, preferably under a reduced oxygen headspace, ensuring the oxygen content is not more than 10% to enhance stability.
[0074] The pH of the pharmaceutical composition is adjusted during the compounding process to a range of 6.9 to 7.9, with a preferred range of 7.4 to 7.6, to ensure optimal stability and compatibility. After filling, the pharmaceutical composition may be subjected to terminal sterilization, typically at a temperature of 121°C for not less than 15 minutes, to ensure sterility and compliance with pharmacopeial standards.
[0075] In some embodiments, Ketorolac Tromethamine Injection is formulated by incorporating Ketorolac Tromethamine along with the following components: Sodium Chloride USP as a tonicity-adjusting agent, Alcohol USP as a co-solvent, and Sodium Hydroxide NF and/or Hydrochloric Acid NF as pH-adjusting agents. The formulation process and specific composition details are provided in Example 1.
Example 1. Composition of Ketorolac Tromethamine Injection USP
Material Functional category Each mL contains (mg/ mL)
30 mg/mL and
60 mg/2 mL vials 15 mg/mL vials
Ketorolac Tromethamine, USP Active pharmaceutical ingredient 30.0 15.0
Alcohol, USP Co-Solvent 100.0 100.0
Sodium Chloride, USP Tonicity adjusting agent 4.35 6.68
Sodium Hydroxide, NF pH adjusting agent Q.S for pH Q.S for pH
Hydrochloric acid, NF pH adjusting agent Q.S for pH Q.S for pH
Water for Injection, USP Vehicle Q.S. to 1.0 mL Q.S. to 1.0 mL
Nitrogen, NF Processing aid Q.S Q.S

[0076] A composition without alcohol is preferred, as the currently marketed Ketorolac Tromethamine Injection is contraindicated for intrathecal or epidural administration due to its alcohol content. By utilizing the proposed siliconized vials, it has been observed that the formation of visible black particulates is eliminated even in the absence of a co-solvent. A detailed example of such an alcohol-free composition is provided in Example 2.
Example 2. Composition of Ketorolac Tromethamine Injection USP without Alcohol
Material Functional category Each mL contains (mg/ mL)
30 mg/mL and
60 mg/2 mL vials 15 mg/mL vials
Ketorolac Tromethamine, USP Active pharmaceutical ingredient 30.0 15.0
Sodium Chloride, USP Tonicity adjusting agent 4.35 6.68
Sodium Hydroxide, NF pH adjusting agent Q.S for pH Q.S for pH
Hydrochloric acid, NF pH adjusting agent Q.S for pH Q.S for pH
Water for Injection, USP Vehicle Q.S. to 1.0 mL Q.S. to 1.0 mL
Nitrogen, NF Processing aid Q.S Q.S

[0077] An example manufacturing process for present disclosure is provided below:
[0078] Step 1. Collect Water for injection (about 90.0%) of batch size in the manufacturing vessel and maintain at a temperature of 20-25°C. Sparge the nitrogen throughout the process except during the material addition.
[0079] Step 2. Add batch quantity of sodium chloride and buffering agent (as applicable) and mix for 20 minutes to dissolve and obtain a clear solution.
[0080] Step 3. Add batch quantity of Ketorolac Tromethamine and stir for 60 minutes to dissolve and obtain a clear solution.
[0081] Step 4. Add batch quantity of Alcohol (as applicable) and stir for 10 minutes to dissolve and obtain a clear solution. This step is not applicable for compositions not containing cosolvents.
[0082] Step 5. Check the pH and if required adjust the pH to 7.4 ± 0.1 using 0.5N NaOH and/ or 0.5N HCl solution.
[0083] Step 6. Make up the volume to 100% of batch size using the Water for injection and stir for 20 minutes.
[0084] Step 7. Aseptically filter the solution through 0.2 µm sterilizing grade filters. Fill the filtered solution in 2mL/13mm Neck Dark Amber siliconised glass vial (or ampule or prefilled syringe). Stopper the vials with 13 mm West 4031/45 Bromobutyl stoppers and crimp the vials with 13 mm Aluminum flip-top seals.
[0085] Step 8: Terminally sterilize the product by subjecting the vials to moist heat sterilization, for example at 121.5°C for NLT 15 minutes.
EXPERIMENTAL RESULTS
[0086] The comparative stability of the product solution from Example 1, filled in untreated USP Type-1 amber vials, sulfur-treated USP Type-1 amber vials, and siliconized USP Type-1 amber vials, was evaluated to assess the stability trends. The stability of the product was analyzed under both accelerated stability conditions (40°C/75%RH) and long-term stability conditions (25°C/60%RH). The results of these assessments are summarized in Table 3 and Table 4, respectively.
[0087] Table 3. Comparative stability of the product solution in different glass vial types in accelerated stability condition (40°C/75%RH)
Test Parameter Acceptance Criteria Product filled in
Untreated USP
Type-1 Amber vials Product Filled in Sulphur Treated, USP Type-1 Amber vials Product filled in
Siliconized,
USP Type-1 Amber vials
Initial 3 Month Initial 3 Month Initial 1
Month 3 Month
Description Clear colorless or pale yellow colour solution, essentially free from visible particulates Clear, pale yellow solution with few visible black particulates Clear, pale yellow solution with few visible black particulates Clear pale yellow solution, essentially free from visible particulates
pH 6.9-7.9 7.41 7.35 7.63 7.68 7.58 7.64 7.62
Assay 90.0-110.0% 100% 99.0% 99.9 100.4 98.8 99.0% 99.5%
Alcohol content 80.0-120.0% 97.3% 97.7% 91.6 94.3 100.3 100.4% 98.1%
Visible particles Essentially free from visible particulates Does not comply Does not comply Complies
Particulate matter by Light obscuration particle count test ≥10 µm –NMT 6000/container 705.33 369.60 276.8 608.27 79.47 Not analyzed 46.27
≥25 µm – NMT 600/container 34.53 9.07 31.07 29.6 20.27 Not analyzed 1.47
Related compound A NMT 0.20% 0.07% 0.04 BDL 0.04 0.08 BQL (0.03%) BQL (0.03%)
Related compound B NMT 0.5% BDL BDL 0.04 BDL BDL BDL BDL
Related compound C NMT 0.5% BDL
(0.02) 0.07 BDL 0.04 BQL (0.02%) BQL (0.03%) BQL (0.05%)
Related compound D NMT 0.20% BDL BDL BDL BDL BDL BDL BDL
Any unspecified Impurity NMT 0.20% BQL (0.04) 0.05 0.07 0.03 BQL (0.04%) BQL (0.04%) BQL (0.04%)
Total impurities NMT 1.50% 0.07% 0.16 0.13 0.13 0.08% BQL BQL

 
[0088] Table 4. Comparative stability of the product solution in different glass vial types in long term stability condition (25°C/60%RH)
Test Parameter Acceptance Criteria Product filled in
Untreated USP
Type-1 Amber vials Product Filled in Sulphur Treated, USP Type-1 Amber vials Product filled in
Siliconized,
USP Type-1 Amber vials
Initial 3 Month Initial 3 Month Initial 1
Month 3 Month
Description Clear colorless or pale yellow colour solution, essentially free from visible particulates Clear, pale yellow solution with few visible black particulates Clear, pale yellow solution with few visible black particulates Clear pale yellow solution, essentially free from visible particulates
pH 6.9-7.9 7.41 7.37 7.63 7.69 7.58 7.58 7.58
Assay 90.0-110.0% 100% 99.2% 99.9 100.1 98.8 98.9% 100.4%
Alcohol content 80.0-120.0% 97.3% 97.6% 91.6 94.0 100.3 100.5% 98.3%
Visible particles Essentially free from visible particulates Does not comply Does not comply Complies
Particulate matter by Light obscuration particle count test ≥10 µm –NMT 6000/container 705.33 322.40 276.8 381.6 79.47 Not analyzed 46.40
≥25 µm – NMT 600/container 34.53 16.00 31.07 20.67 20.27 Not analyzed 1.43
Related compound A NMT 0.20% 0.07% BQL
(0.03) BDL 0.04 0.08 BQL (0.04%) BQL (0.03%)
Related compound B NMT 0.5% BDL BDL 0.04 BDL BDL BDL BDL
Related compound C NMT 0.5% BDL
(0.02) BQL
(0.03) BDL 0.03 BQL (0.02%) BQL (0.03%) BQL (0.04%)
Related compound D NMT 0.20% BDL BDL BDL BDL BDL BDL BDL
Any unspecified Impurity NMT 0.20% BQL (0.04) BQL
(0.04%) 0.07 0.04 BQL (0.04%) BQL (0.04%) BQL (0.04%)
Total impurities NMT 1.50% 0.07% BQL 0.13 0.12 0.08% BQL BQL
[0089] Observations: The product solution filled in untreated USP Type-1 amber vials and sulfur-treated USP Type-1 amber vials exhibited visible particulates. Additionally, while the sub-visible particulate levels remained within the specification limits, they were notably higher in these vials. In contrast, the product solution filled in siliconized USP Type-1 amber vials showed no formation of visible particulates under both accelerated stability conditions and long-term stability conditions, demonstrating superior stability.
[0090] The stability of the alcohol-free product solution described in Example 2, filled in the proposed siliconized USP Type-1 amber vials, was evaluated to assess its stability trends. Stability assessments were conducted under accelerated conditions (40°C/75%RH) and long-term storage conditions (25°C/60%RH). The resulting data are detailed in Table 5 below:
[0091] Table 5. Stability data of alcohol-free products in siliconized amber glass vials
Test Parameter acceptance criteria Initial Accelerated stability condition (40°C/75%RH) long-term stability condition (25°C/60%RH)
3 Month 6 Month 3 Month 6 Month
Description Clear colorless or pale yellow colour solution Complies Complies Complies Complies Complies
pH 6.9-7.9 7.37 7.41 7.46 7.42 7.48
Assay (By HPLC) 90.0-110.0% 101.3 99.6 102.9 100.3 102.8
Particulate matter by Light obscuration particle count test (Method 1 test I.B) ≥10 µm –NMT 6000/container 10.27 47.53 46.6 Not
analyzed 71.2
≥25 µm – NMT 600/container 0.33 3.87 1.87 7.73
Ketorolac related compound A NMT 0.20% 0.03 0.03 0.02 0.02 0.02
Ketorolac related compound B NMT 0.5% BDL BDL BDL BDL BDL
Ketorolac related compound C NMT 0.5% 0.02 0.09 0.11 0.08 0.09
Ketorolac related compound D NMT 0.20% BDL BDL BDL BDL BDL
Any unspecified Impurity NMT 0.20% 0.10 0.06 0.06 0.06 0.06

[0092] Observations: The stability characteristics of the product solution were satisfactory, with all critical quality attributes meeting the acceptance criteria, even in the absence of alcohol as a co-solvent. No visible particulates were observed in the product filled in siliconized USP Type-1 amber vials under both accelerated stability conditions and long-term storage conditions, confirming the effectiveness of the siliconized vials in ensuring particulate-free stability.
, Claims:1. A stable, pharmaceutical composition of Ketorolac tromethamine Injection consisting of Ketorolac tromethamine at a concentration between 0.5%w/v and 3.0%w/v filled into a siliconized glass container, wherein the product rejections related to intrinsic black particulates are <1% on visual inspection and the product solution is essentially free from visible particulates over the shelf-life storage.

2. A stable pharmaceutical composition of Ketorolac Tromethamine injection, comprising:
• ketorolac tromethamine at a concentration between 0.5% w/v and 3.0% w/v;
• sodium chloride USP at a concentration between 0.435% w/v and 0.668% w/v as a tonicity-adjusting agent;
• alcohol USP at 10.0% w/v as a co-solvent;
• a pH-adjusting agent comprising at least one of sodium hydroxide NF and hydrochloric acid NF, in quantities sufficient to achieve a pH range of 6.9 to 7.9; and
• water for injection USP as the vehicle, in quantity sufficient to make up the total composition to 100% w/v,
and the solution is filled into a siliconized glass container, wherein the product rejections related to intrinsic black particulates are <1% on visual inspection and the product solution is essentially free from visible particulates over the shelf-life storage.

3. The pharmaceutical composition as claimed in claim 1, wherein the composition remains stable and free from visible particulates under accelerated conditions of 40°C/75%RH for at least 3 months.

4. The pharmaceutical composition as claimed in claim 1, wherein the composition remains stable and free from visible particulates under long-term storage conditions of 25°C/60%RH for at least 12 months.

5. A method for preparing a stable pharmaceutical composition of Ketorolac Tromethamine injection, comprising the steps of:
collecting water for injection (approximately 90% of the batch size) in a manufacturing vessel and maintaining the temperature at 20–25°C while sparging nitrogen gas throughout the method except during material addition;
adding sodium chloride USP, a buffering agent, and mixing for 20 minutes to obtain a clear solution;
adding ketorolac tromethamine and stirring for 60 minutes to dissolve and obtain a clear solution;
adding alcohol USP as a co-solvent and stirring for 10 minutes to ensure uniformity;
adjusting the pH to 7.4 ± 0.1 using at least one of 0.5N sodium hydroxide (NaOH) and 0.5N hydrochloric acid (HCl);
making up the volume to 100% of the batch size with water for injection and stirring for 20 minutes;
aseptically filtering the solution through a 0.2 µm sterilizing-grade filter and filling it into siliconized amber glass containers, followed by stoppering and/ or sealing; and
terminally sterilizing the filled containers at 121.5°C for not less than 15 minutes.
6. The method as claimed in claim 5, wherein the pH is adjusted to a range of 6.9 to 7.9, preferably 7.4 to 7.6.

7. The method as claimed in claim 5, wherein the filling method ensures that the headspace oxygen in the vials is reduced to less than 10%.

8. The method as claimed in claim 5, wherein the method is conducted under monochromatic light to prevent photodegradation.

9. A stable pharmaceutical composition of Ketorolac Tromethamine injection, comprising:
• ketorolac tromethamine at a concentration between 0.5% w/v and 3.0% w/v;
• sodium chloride USP at a concentration between 0.435% w/v and 0.668% w/v as a tonicity-adjusting agent;
• a pH-adjusting agent comprising at least one of sodium hydroxide NF and hydrochloric acid NF, in quantities sufficient to achieve a pH range of 6.9 to 7.9; and
• water for injection USP as the vehicle, in quantity sufficient to make up the total composition to 100% w/v.
wherein the composition is free from alcohol or co-solvent and the solution is filled into a siliconized glass container, wherein the product rejections related to intrinsic black particulates are <1% on visual inspection and the product solution is essentially free from visible particulates over the shelf-life storage.

10. The pharmaceutical composition as claimed in claim 9, wherein the product remains stable and free from visible particulates under accelerated conditions of 40°C/75%RH for at least three months.

11. The pharmaceutical composition as claimed in claim 9, wherein the product remains stable and free from visible particulates under long-term storage conditions of 25°C/60%RH for at least 12 months.

12. A method for preparing a stable pharmaceutical composition of Ketorolac Tromethamine injection free from alcohol, comprising the steps of:
collecting water for injection (approximately 90% of the batch size) in a manufacturing vessel and maintaining the temperature at 20–25°C while sparging nitrogen gas throughout the method except during material addition;
adding sodium chloride USP, a buffering agent, and mixing for 20 minutes to obtain a clear solution;
adding ketorolac tromethamine and stirring for 60 minutes to dissolve and obtain a clear solution;
adjusting the pH to 7.4 ± 0.1 using at least one of 0.5N sodium hydroxide (NaOH) and 0.5N hydrochloric acid (HCl);
making up the volume to 100% of the batch size with water for injection and stirring for 20 minutes;
aseptically filtering the solution through a 0.2 µm sterilizing-grade filter and filling it into siliconized amber glass container, followed by stoppering and/or sealing; and
terminally sterilizing the filled vials at 121.5°C for not less than 15 minutes.
13. The method as claimed in claim 12, wherein the pH is adjusted to a range of 6.9 to 7.9, preferably 7.4 to 7.6.

14. The method as claimed in claim 12, wherein the filling method ensures that the headspace oxygen in the vials is reduced to less than 10%.

15. The method as claimed in claim 12, wherein the method is conducted under monochromatic light to prevent photodegradation.

Dated this 16th day of December 2024
Signature

Gokul Nataraj E
Patent Agent (IN/PA-5309)
Agent for the Applicant