Claims:We claim:
1. A stable and highly pure crystalline Form S of Ketorolac tromethamine characterized by an X-ray powder diffraction (XPRD) pattern comprising 2-theta peaks at about 11.98 and 20.97 ± 0.2 degrees substantially in accordance with Figure 1, Figure 2 and/or Figure 3.

2. The crystalline Form S of Ketorolac tromethamine as claimed in claim 1, which is further characterized by: (i) an X-ray powder diffraction (XPRD) pattern comprising one or more additional 2-theta peaks at about 9.71, 12.38, 12.76, 14.17, 16.55, 17.01, 17.34, 17.75, 18.61, 19.43, 20.18, 22.12, 22.95 and 29.40 ± 0.2 degrees substantially in accordance with Figure 1, Figure 2 and/or Figure 3; (ii) an infrared (FT-IR) spectrum comprising one or more main bands at about 3452, 3350, 3082, 2990, 2953, 2921, 2889, 1615, 1595, 1567, 1548, 1492, 1469, 1431, 1383, 1310, 1275, 1191, 1174, 1144, 1088, 1077, 1048, 896, 798, 771, 726, 702 and 674 cm-1 ± 5 cm-1 substantially in accordance with Figure 4; and/or (iii) a Differential Scanning Calorimetric (DSC) thermogram comprising a sharp endothermic peak at about 169.4°C (± 3°C) substantially in accordance with Figure 5, Figure 6, Figure 7 and/or Figure 8.

3. A process for the preparation of the stable and highly pure crystalline Form S of Ketorolac tromethamine as claimed in claim 1 or claim 2, comprising:
(a) providing a first solution of Ketorolac tromethamine in an alcohol solvent at a temperature of above about 45°C;
(b) optionally, seeding the first solution obtained in step-(a) with a solution of Ketorolac tromethamine in a ketone solvent at a temperature of above about 45°C to obtain a second solution;
(c) combining the first solution obtained in step-(a) or the second solution obtained in step-(b) with an anti-solvent at a temperature of above about 45°C, followed by cooling the resulting mass while stirring at a temperature of below about 35°C to cause crystallization, wherein the anti-solvent is a ketone solvent; and
(d) collecting the highly pure Ketorolac tromethamine crystalline Form S obtained in step-(c).

4. The process as claimed in claim 3, wherein the alcohol solvent used in step-(a) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, and mixtures thereof; wherein the amount of alcohol solvent employed in step-(a) is about 1 volume to about 4 volumes with respect to the quantity of Ketorolac tromethamine used; wherein the solution obtained in step-(a) is optionally subjected to carbon treatment; wherein the ketone solvent used in step-(b) and step-(c), each independently, is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof; wherein the seeding in step-(b) is carried out either by adding the seeding solution to the first solution, or alternatively, the first solution is added to the seeding solution; wherein the combining of the solution of Ketorolac tromethamine with the ketone solvent in step-(c) is carried out, either by adding the first solution or the second solution to the ketone solvent, or by adding the ketone solvent to the first solution or the second solution; wherein the collection of the highly pure Ketorolac tromethamine crystalline Form S in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof; and wherein the crystalline Form S of Ketorolac tromethamine obtained has a chemical purity of greater than about 99.5% as measured by HPLC.

5. The process as claimed in claim 4, wherein the alcohol solvent used in step-(a) is methanol; wherein the amount of alcohol solvent employed in step-(a) is about 1.2 volumes to about 2.2 volumes with respect to the quantity of Ketorolac tromethamine used; wherein the ketone solvent used in step-(b) and step-(c) is acetone; and wherein the purity of the highly pure crystalline Form S of Ketorolac tromethamine obtained is about 99.5% to about 99.99% as measured by HPLC.

6. A stable and highly pure crystalline Form A of Ketorolac tromethamine characterized by an X-ray powder diffraction (XPRD) pattern comprising 2-theta peaks at about 8.79 and 11.40 ± 0.2 degrees substantially in accordance with Figure 9 and/or Figure 10.

7. The crystalline Form A of Ketorolac tromethamine as claimed in Claim 6, which is further characterized by: (i) an X-ray powder diffraction (XPRD) pattern comprising one or more additional 2-theta peaks at about 10.26, 12.73, 14.06, 17.59, 18.12, 18.76, 19.18, 19.36, 20.58, 23,33, 24.58 and 26.53 ± 0.2 degrees substantially in accordance with Figure 9 and/or Figure 10; (ii) an infrared (FT-IR) spectrum comprising one or more main bands at about 3350, 3082, 2990, 2953, 2921, 2889, 1615, 1595, 1567, 1548, 1492, 1469, 1431, 1383, 1310, 1275, 1191, 1174, 1144, 1088, 1077, 1048, 896, 798, 771, 726, 702 and 674 cm-1 ± 5 cm-1 substantially in accordance with Figure 11; (iii) a Differential Scanning Calorimetric (DSC) thermogram comprising two sharp endotherm peaks at about 160.11°C (± 3°C) and 168.29°C (± 3°C) respectively substantially in accordance with Figure 12; and/or a Differential Scanning Calorimetric (DSC) thermogram comprising two sharp endotherm peaks at about 159.58°C (± 3°C) and 169.69°C (± 3°C) respectively substantially in accordance with Figure 13.

8. A process for the preparation of a stable and highly pure crystalline Form A of Ketorolac tromethamine as claimed in claim 6 or claim 7, comprising:
a) providing a first solution of Ketorolac tromethamine in an alcohol solvent at a temperature of above about 45°C;
b) optionally, cooling the first solution at a temperature of about 35°C to about 40°C to obtain a second solution;
c) combining the first solution obtained in step-(a) or the second solution obtained in step-(b) with an anti-solvent, followed by cooling the resulting mass while stirring at a temperature of below about 35°C to cause crystallization, wherein the anti-solvent is selected from the group consisting of a hydrocarbon solvent, a halogenated hydrocarbon, an ester solvent and mixtures thereof; and
d) collecting the highly pure Ketorolac tromethamine crystalline Form A obtained in step-(c).

9. The process as claimed in claim 8, wherein the alcohol solvent used in step-(a) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, and mixtures thereof; wherein the amount of alcohol solvent employed in step-(a) is about 1 volume to about 5 volumes with respect to the quantity of Ketorolac tromethamine used; wherein the solution obtained in step-(a) is optionally subjected to carbon treatment; wherein the anti-solvent used in step-(c) is selected from the group consisting of toluene, xylene, dichloromethane, dichloroethane, chloroform, ethyl acetate, and mixtures thereof; wherein the combining of the solution of Ketorolac tromethamine with the ketone solvent in step-(c) is carried out, either by adding the first solution or the second solution to the anti-solvent, or by adding the anti-solvent to the first solution or the second solution; wherein the collection of the highly pure Ketorolac tromethamine crystalline Form A in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof; and wherein the crystalline Form A of Ketorolac tromethamine obtained has a chemical purity of greater than about 99.5% as measured by HPLC.

10. The process as claimed in claim 9, wherein the alcohol solvent used in step-(a) is methanol; wherein the amount of alcohol solvent employed in step-(a) is about 2 volumes to about 4 volumes with respect to the quantity of Ketorolac tromethamine used; and wherein the purity of the highly pure crystalline Form A of Ketorolac tromethamine obtained is about 99.5% to about 99.99% as measured by HPLC.
, Description:CROSS REFERENCE TO RELATED APPLICATION

This patent application is a Patent of Addition of Indian Patent Application No. 201741007811, having its complete specification filed on March 6, 2017, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to novel, commercially viable and consistently reproducible processes for the preparation of highly pure and stable crystalline forms of Ketorolac tromethamine (designated as Form S and Form A), which are free from other polymorphic forms. The present invention further relates to stable and highly pure crystalline forms of Ketorolac tromethamine (designated as Form S and Form A).

BACKGROUND OF THE INVENTION
U.S. Patent No. 4,089,969 discloses a variety of pyrole-1-carboxylic acid derivatives, specifically Ketorolac chemically named as (±)-5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, and pharmaceutically acceptable salts thereof, processes for the preparation, pharmaceutical compositions, and method of use thereof. Ketorolac is represented by the following structural formula 1:

Ketorolac was approved by the FDA for use in United States for the treatment of pain and inflammation following cataract surgery and it is sold under the trade names ACULAR®, ACUVAIL® and TORADOL®. It is administered as drops containing 0.5% solution, 0.45% solution; and orally administered as tablets containing 10 MG and also administered as injection containing 15 MG/ML and 30 MG/ML injectables of Ketorolac (as Ketorolac tromethamine salt).
Various processes for the preparation of Ketorolac, and its intermediates, and pharmaceutically acceptable salts, are disclosed in U.S. Patent Nos. 4,089,969; 4,347,185; 4,353,829; 5,082,950; 5,532,381; 6,197,976; and 6,559,319.
U.S. Patent No. 4,089,969 (hereinafter referred to as the US‘969 patent) describes the synthesis of Ketorolac in an analogous manner. According to the synthesis process, Ketorolac is prepared by refluxing a solution of N,N-dimethylbenzamide and phosphorous oxychloride for 30 minutes, followed by the addition of isopropyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate in 1,2-dichloroethane to produce isopropyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate, which is hydrolyzed with an aqueous solution of sodium hydroxide or potassium carbonate, followed by acidifying with 10% hydrochloric acid to produce Ketorolac, and finally treating the solution of Ketorolac in hot benzene with tromethamine to produce Ketorolac tromethamine salt. The synthesis of Ketorolac tromethamine is depicted in below scheme:

The Product Label of Ketorolac tromethamine (Brand Name: Toradol) states that Ketorolac tromethamine may exist in three crystal forms, and all forms are equally soluble in water (see page-2 of enclosed product Label). However, the Product Label does not disclose any information (characterization data and processes for the preparation) about the alleged crystalline forms of Ketorolac tromethamine.
Various crystalline forms of Ketorolac tromethamine are apparently reported in the following scientific journals: (i) Sci Pharm. 2010, 78, 79-92; (ii) International Journal of Drug Delivery 6 (2014), 121-132; (iii) AAPS Pharm SciTech, Vol. 10, No. 2, 355-360, June 2009; (iv) International Journal of Research in Pharmacy and Biosciences 2017, 4(1), January 2017, pp 17-23; (v) E-Journal of Chemistry Vol. 5, No, 2, 316-322, April 2008; and (vi) Journal of the Korean Chemical Society Vol. 58, No. 1, 92-99, 2014. However, the crystalline forms of Ketorolac tromethamine reported in the aforementioned literature are not well defined since the X-ray diffraction (XRPD) diffractograms of the crystalline forms of Ketorolac tromethamine reported in the aforementioned literature are not clear. However, processes for the preparation of the crystalline forms of Ketorolac tromethamine have not been reported in the aforementioned literature.
A need still remains for novel, commercially viable, consistently reproducible and industrially advantageous processes for the preparation of highly pure and stable crystalline forms of Ketorolac tromethamine essentially free of other crystalline forms.

SUMMARY OF THE INVENTION
Provided herein are efficient, commercially viable and consistently reproducible processes for the preparation of highly pure crystalline forms of Ketorolac tromethamine (designated herein as “Form S” and “Form A”).
In one aspect, disclosed herein is a stable and highly pure crystalline Form S of Ketorolac tromethamine characterized by an X-ray powder diffraction (XPRD) pattern comprising 2-theta peaks at about 11.98 and 20.97 ± 0.2 degrees substantially in accordance with Figure 1, Figure 2 and/or Figure 3.
In another aspect, the stable and highly pure crystalline Form S of Ketorolac tromethamine is further characterized by an X-ray powder diffraction (XPRD) pattern comprising one or more additional 2-theta peaks at about 9.71, 12.38, 12.76, 14.17, 16.55, 17.01, 17.34, 17.75, 18.61, 19.43, 20.18, 22.12, 22.95 and 29.40 ± 0.2 degrees substantially in accordance with Figure 1, Figure 2 and/or Figure 3.
In another aspect, the stable and highly pure crystalline Form S of Ketorolac tromethamine is further characterised by an infrared (FT-IR) spectrum comprising one or more main bands at about 3452, 3350, 3082, 2990, 2953, 2921, 2889, 1615, 1595, 1567, 1548, 1492, 1469, 1431, 1383, 1310, 1275, 1191, 1174, 1144, 1088, 1077, 1048, 896, 798, 771, 726, 702 and 674 cm-1 ± 5 cm-1 substantially in accordance with Figure 4.
In another embodiment, the stable and highly pure crystalline Form S of Ketorolac tromethamine is further characterised by a Differential Scanning Calorimetric (DSC) thermogram comprising a sharp endothermic peak at about 169.4°C (± 2°C) substantially in accordance with Figure 5, Figure 6, Figure 7 and/or Figure 8.
The crystalline Form S of Ketorolac tromethamine is consistently reproducible does not have the tendency to convert to other forms and found to be thermally more stable.
It has been surprisingly and unexpectedly found that the highly pure crystalline Form S of Ketorolac tromethamine can be obtained by an efficient, consistently reproducible and commercially viable process which comprises: (a) providing a first solution of Ketorolac tromethamine in an alcohol solvent (preferably methanol) at a temperature of above about 45°C; (b) optionally, seeding the first solution obtained in step-(a) with a solution of Ketorolac tromethamine in a ketone solvent (preferably acetone) at a temperature of above about 45°C to obtain a second solution; (c) combining the first solution obtained in step-(a) or the second solution obtained in step-(b) with an anti-solvent at a temperature of above about 45°C, followed by cooling the resulting mass while stirring at a temperature of below about 35°C to cause crystallization, wherein the anti-solvent is a ketone solvent; and (d) collecting the highly pure Ketorolac tromethamine crystalline Form S obtained in step-(c).
In one embodiment, the crystalline Form S of Ketorolac tromethamine obtained by the processes disclosed herein is essentially free from other crystalline forms of Ketorolac tromethamine detectable by the spectral methods typically used, e.g., Powder X-ray diffraction.
The term “crystalline Form S of Ketorolac tromethamine essentially free of other crystalline forms” means that no other polymorphic forms of Ketorolac tromethamine can be detected within the limits of a powder X-ray diffractometer. The term “other polymorphic forms of Ketorolac tromethamine” is intended to mean the polymorphic forms of Ketorolac tromethamine other than crystalline Form S.
In another aspect, provided also herein is a novel, cost effective and consistently reproducible process for the preparation of highly pure crystalline Form S of Ketorolac tromethamine essentially free of other crystalline forms.
The highly pure crystalline Form S of Ketorolac tromethamine obtained by the process disclosed herein has a purity of greater than about 99.5%, specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC. For example, the purity of the highly pure crystalline Form S of Ketorolac tromethamine obtained by the processes disclosed herein is about 99.5% to about 99.99% as measured by HPLC.
In another aspect, disclosed herein is a stable and highly pure crystalline Form A of Ketorolac tromethamine characterized by an X-ray powder diffraction (XPRD) pattern comprising 2-theta peaks at about 8.79 and 11.40 ± 0.2 degrees substantially in accordance with Figure 9 and/or Figure 10.
In another aspect, the stable and highly pure crystalline Form A of Ketorolac tromethamine is further characterized by an X-ray powder diffraction (XPRD) pattern comprising one or more additional 2-theta peaks at about 10.26, 12.73, 14.06, 17.59, 18.12, 18.76, 19.18, 19.36, 20.58, 23,33, 24.58 and 26.53 ± 0.2 degrees substantially in accordance with Figure 9 and/or Figure 10.
In another aspect, the stable and highly pure crystalline Form A of Ketorolac tromethamine is further characterised by an infrared (FT-IR) spectrum comprising one or more main bands at about 3350, 3082, 2990, 2953, 2921, 2889, 1615, 1595, 1567, 1548, 1492, 1469, 1431, 1383, 1310, 1275, 1191, 1174, 1144, 1088, 1077, 1048, 896, 798, 771, 726, 702 and 674 cm-1 ± 5 cm-1 substantially in accordance with Figure 11.
In another embodiment, the stable and highly pure crystalline Form A of Ketorolac tromethamine is further characterised by a Differential Scanning Calorimetric (DSC) thermogram comprising two sharp endothermic peaks at about 160.11°C (± 3°C) and 168.29°C (± 3°C) respectively substantially in accordance with Figure 12.
In another embodiment, the stable and highly pure crystalline Form A of Ketorolac tromethamine is further characterised by a Differential Scanning Calorimetric (DSC) thermogram comprising two sharp endothermic peaks at about 159.58°C (± 3°C) and 169.69°C (± 3°C) respectively substantially in accordance with Figure 13.
The crystalline Form A of Ketorolac tromethamine is consistently reproducible does not have the tendency to convert to other forms and found to be thermally more stable.
It has been surprisingly and unexpectedly found that the highly pure crystalline Form A of Ketorolac tromethamine can be obtained by an efficient, consistently reproducible and commercially viable process which comprises: (a) providing a first solution of Ketorolac tromethamine in an alcohol solvent (preferably methanol) at a temperature of above about 45°C; (b) optionally, cooling the first solution at a temperature of about 35°C to about 40°C to obtain a second solution; (c) combining the first solution obtained in step-(a) or the second solution obtained in step-(b) with an anti-solvent, followed by cooling the resulting mass while stirring at a temperature of below about 35°C to cause crystallization, wherein the anti-solvent is selected from the group consisting of a hydrocarbon solvent (preferably toluene), a halogenated hydrocarbon (preferably dichloromethane), an ester solvent (preferably ethyl acetate) and mixtures thereof; and (d) collecting the highly pure Ketorolac tromethamine crystalline Form A obtained in step-(c).
In one embodiment, the crystalline Form A of Ketorolac tromethamine obtained by the processes disclosed herein is essentially free from other crystalline forms of Ketorolac tromethamine detectable by the spectral methods typically used, e.g., Powder X-ray diffraction.
The term “crystalline Form A of Ketorolac tromethamine essentially free of other crystalline forms” means that no other polymorphic forms of Ketorolac tromethamine can be detected within the limits of a powder X-ray diffractometer. The term “other polymorphic forms of Ketorolac tromethamine” is intended to mean the polymorphic forms of Ketorolac tromethamine other than crystalline Form A.
In another aspect, provided also herein is a novel, cost effective and consistently reproducible process for the preparation of highly pure crystalline Form A of Ketorolac tromethamine essentially free of other crystalline forms.
The highly pure crystalline Form A of Ketorolac tromethamine obtained by the process disclosed herein has a purity of greater than about 99.5%, specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC. For example, the purity of the highly pure crystalline Form A of Ketorolac tromethamine obtained by the processes disclosed herein is about 99.5% to about 99.99% as measured by HPLC.
The crystalline Form S of Ketorolac tromethamine is different from the crystalline Form A of Ketorolac tromethamine disclosed herein since both the crystalline forms are characterized by having distinct XRPD patterns, distinct IR Spectrums, and distinct Differential Scanning Calorimetric (DSC) thermograms. The phase distinguishing characteristic XRPD 2-theta peaks of crystalline Form A of Ketorolac tromethamine at about 8.79 and 11.40 ± 0.2 degrees are ABSENT in the XRPD Diffractogram of crystalline Form S of Ketorolac tromethamine. Moreover, the phase distinguishing characteristic XRPD 2-theta peaks of crystalline Form S of Ketorolac tromethamine at about 11.98 and 20.97 ± 0.2 degrees are completely ABSENT in the XRPD Diffractogram of crystalline Form A of Ketorolac tromethamine. The DSC thermogram of crystalline Form A of Ketorolac tromethamine is characterized by having two sharp endothermic peaks at about 160.50°C and 168.40°C. The DSC thermogram of crystalline Form S of Ketorolac tromethamine is characterized by having one sharp endothermic peak at about 169.74°C. Furthermore, the phase distinguishing characteristic IR band of crystalline Form S of Ketorolac tromethamine at about 3452 cm-1 is ABSENT in the IR Spectrum of crystalline Form A of Ketorolac tromethamine.
In another aspect, provided herein is a pharmaceutical composition comprising highly pure crystalline Form S of Ketorolac tromethamine essentially free of other crystalline forms as disclosed herein, and one or more pharmaceutically acceptable excipients.
In another aspect, provided herein is a pharmaceutical composition comprising highly pure crystalline Form A of Ketorolac tromethamine essentially free of other crystalline forms as disclosed herein, and one or more pharmaceutically acceptable excipients.
In another aspect, provided herein is a pharmaceutical composition comprising highly pure crystalline Form S of Ketorolac tromethamine essentially free of other crystalline forms made by the process disclosed herein, and one or more pharmaceutically acceptable excipients.
In another aspect, provided herein is a pharmaceutical composition comprising highly pure crystalline Form A of Ketorolac tromethamine essentially free of other crystalline forms made by the process disclosed herein, and one or more pharmaceutically acceptable excipients.
In still further aspect, encompassed herein is a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline Form S of Ketorolac tromethamine essentially free of other crystalline forms made by the process disclosed herein with one or more pharmaceutically acceptable excipients.
In still further aspect, encompassed herein is a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline Form A of Ketorolac tromethamine essentially free of other crystalline forms made by the process disclosed herein with one or more pharmaceutically acceptable excipients.
In another aspect, the highly pure crystalline Form S of Ketorolac tromethamine essentially free of other crystalline forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 300 microns, specifically about 1 microns to about 150 microns, and most specifically about 4 microns to about 100 microns.
In another aspect, the highly pure crystalline Form A of Ketorolac tromethamine essentially free of other crystalline forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 300 microns, specifically about 1 microns to about 150 microns, and most specifically about 4 microns to about 100 microns.
Unless otherwise specified, the term “crude or impure form of Ketorolac tromethamine” refers to any form of Ketorolac tromethamine having purity less than or equal to about 99% as measured by HPLC.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of crystalline Form S of Ketorolac tromethamine.
Figure 2 is a characteristic powder X-ray diffraction (XRPD) pattern of crystalline Form S of Ketorolac tromethamine.
Figure 3 is a characteristic powder X-ray diffraction (XRPD) pattern of crystalline Form S of Ketorolac tromethamine.
Figure 4 is a characteristic infra-red (IR) spectrum of crystalline Form S of Ketorolac tromethamine.
Figure 5 is a characteristic Differential Scanning Calorimetric (DSC) thermogram of crystalline Form S of Ketorolac tromethamine.
Figure 6 is a characteristic Differential Scanning Calorimetric (DSC) thermogram of crystalline Form S of Ketorolac tromethamine.
Figure 7 is a characteristic Differential Scanning Calorimetric (DSC) thermogram of crystalline Form S of Ketorolac tromethamine.
Figure 8 is a characteristic Differential Scanning Calorimetric (DSC) thermogram of crystalline Form S of Ketorolac tromethamine.
Figure 9 is a characteristic powder X-ray diffraction (XRPD) pattern of crystalline Form A of Ketorolac tromethamine.
Figure 10 is a characteristic powder X-ray diffraction (XRPD) pattern of crystalline Form A of Ketorolac tromethamine.
Figure 11 is a characteristic infra-red (IR) spectrum of crystalline Form A of Ketorolac tromethamine.
Figure 12 is a characteristic Differential Scanning Calorimetric (DSC) thermogram of crystalline Form A of Ketorolac tromethamine.
Figure 13 is a characteristic Differential Scanning Calorimetric (DSC) thermogram of crystalline Form A of Ketorolac tromethamine.

DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, provided herein is a stable and highly pure crystalline Form S of Ketorolac tromethamine characterized by an X-ray powder diffraction (XPRD) pattern comprising 2-theta peaks at about 11.98 and 20.97 ± 0.2 degrees substantially in accordance with Figure 1, Figure 2 and/or Figure 3.
In one embodiment, the stable and highly pure crystalline Form S of Ketorolac tromethamine is further characterized by an X-ray powder diffraction (XPRD) pattern comprising one or more additional 2-theta peaks at about 9.71, 12.38, 12.76, 14.17, 16.55, 17.01, 17.34, 17.75, 18.61, 19.43, 20.18, 22.12, 22.95 and 29.40 ± 0.2 degrees substantially in accordance with Figure 1, Figure 2 and/or Figure 3.
In another embodiment, the stable and highly pure crystalline Form S of Ketorolac tromethamine is further characterised by an infrared (FT-IR) spectrum comprising one or more main bands at about 3452, 3350, 3082, 2990, 2953, 2921, 2889, 1615, 1595, 1567, 1548, 1492, 1469, 1431, 1383, 1310, 1275, 1191, 1174, 1144, 1088, 1077, 1048, 896, 798, 771, 726, 702 and 674 cm-1 ± 5 cm-1 substantially in accordance with Figure 4.
In another embodiment, the stable and highly pure crystalline Form S of Ketorolac tromethamine is further characterised by a Differential Scanning Calorimetric (DSC) thermogram comprising a sharp endothermic peak at about 169.4°C (± 3°C) substantially in accordance with Figure 5, Figure 6, Figure 7 and/or Figure 8.
The crystalline Form S of Ketorolac tromethamine is consistently reproducible does not have the tendency to convert to other forms and found to be thermally more stable.
According to another aspect, there is provided a process for the preparation of a stable and highly pure crystalline Form S of Ketorolac tromethamine essentially free of other crystalline forms, comprising:
a) providing a first solution of Ketorolac tromethamine in an alcohol solvent at a temperature of above about 45°C;
b) optionally, seeding the first solution obtained in step-(a) with a solution of Ketorolac tromethamine in a ketone solvent at a temperature of above about 45°C to obtain a second solution;
c) combining the first solution obtained in step-(a) or the second solution obtained in step-(b) with an anti-solvent at a temperature of above about 45°C, followed by cooling the resulting mass while stirring at a temperature of below about 35°C to cause crystallization, wherein the anti-solvent is a ketone solvent; and
d) collecting the highly pure Ketorolac tromethamine crystalline Form S obtained in step-(c).
In one embodiment, the alcohol solvent used in step-(a) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, and mixtures thereof. A most specific solvent used in step-(a) is methanol.
Usually, the amount of alcohol solvent employed in step-(a) is about 1 volume to about 4 volumes, specifically about 1.2 volumes to about 2.2 volumes, and most specifically about 1.3 volumes to about 1.6 volumes, with respect to the quantity of Ketorolac tromethamine used.
Step-(a) of providing a first solution of Ketorolac tromethamine includes dissolving Ketorolac tromethamine (crude or pure) in the alcohol solvent used in step-(a), or obtaining an existing solution from a previous processing step.
Unless otherwise specified, the Ketorolac tromethamine as used herein above as starting material can be obtained, for example, by the processes reported in the prior art literature, for example as per the processes described in U.S. Patent No. 5,082,950 and Indian Patent Application No. 201741007811, or by the processes described hereinafter.
In another embodiment, the Ketorolac tromethamine is dissolved in the alcohol solvent used in step-(a) at a temperature of about 45°C to the reflux temperature of the solvent used, specifically at a temperature of about 55°C to about 65°C. After complete dissolution of Ketorolac tromethamine, the resulting solution is stirred at a temperature of about 45°C to the reflux temperature of the solvent used for at least 5 minutes, and more specifically at a temperature of about 55°C to about 65°C for about 10 minutes to about 1 hour.
In another embodiment, the solution in step-(a) is also prepared by treating Ketorolac free acid with tromethamine in a suitable solvent or a mixture of suitable solvents to produce a reaction mass containing Ketorolac tromethamine, followed by usual work up such as washings, seeding, extractions, evaporations or a combination thereof, and then dissolving or extracting the resulting Ketorolac tromethamine in the alcohol solvent. Specifically, the solvent used for treating Ketorolac free acid with tromethamine is acetone, water, and mixture thereof.
In one embodiment, the solution obtained in step-(a) is optionally subjected to carbon treatment. The carbon treatment is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon at a temperature of about 45°C to the reflux temperature of the solvent used for at least 5 minutes, specifically for about 10 minutes to about 30 minutes, and filtering the resulting mixture through charcoal bed to obtain a filtrate containing Ketorolac tromethamine by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.
In one embodiment, the ketone solvent used in step-(b) and step-(c), each independently, is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof. A most specific ketone solvent used in step-(b) and step-(c) is acetone.
The seeding in step-(b) is carried out either by adding the seeding solution to the first solution, or alternatively, the first solution is added to the seeding solution.
Combining of the solution of Ketorolac tromethamine with the ketone solvent in step-(c) is done in a suitable order, for example, the first solution or the second solution is added to the ketone solvent, or alternatively, the ketone solvent is added to the first solution or the second solution. The addition is, for example, carried out drop wise or in one portion or in more than one portion. The addition is specifically carried out under stirring at a temperature of about 45°C to the reflux temperature of the solvent used. After completion of the addition process, the resulting mass is cooled to a temperature of below about 35°C while stirring for at least 5 minutes, specifically at a temperature of about 0°C to about 30°C for about 10 minutes to 5 hours, and most specifically at a temperature of about 0°C to about 5°C for about 20 minutes to about 3 hours to cause crystallization.
The collection of the highly pure Ketorolac tromethamine crystalline Form S in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
The highly pure crystalline Form S of Ketorolac tromethamine obtained by the process described herein is found to be more stable.
The highly pure crystalline Form S of Ketorolac tromethamine obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
Preferably, the drying is carried out at atmospheric pressure at temperatures such as about 40°C to about 85°C and most preferably at about 50°C to about 70°C. In one embodiment, the drying is carried out for any desired time period that achieves the desired result, preferably for a period of about 1 hour to 25 hours, and more preferably about 5 hours to 20 hours. Drying can be suitably carried out in a tray dryer, a vacuum oven, an air oven, or using a fluidized bed drier, a spin flash dryer, a flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art.
The highly pure crystalline Form S of Ketorolac tromethamine obtained by the process disclosed herein has a chemical purity of greater than about 99.5%, specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC. For example, the purity of the highly pure crystalline Form S of Ketorolac tromethamine obtained by the processes disclosed herein is about 99.5% to about 99.99% as measured by HPLC.
Unless otherwise specified, the Ketorolac free acid or Ketorolac Tromethamine as used herein as starting materials can be obtained, for example, by the processes reported in the prior art literature, for example as per the processes described in U.S. Patent No. 5,082,950 and Indian Patent Application No. 201741007811.
The stable and highly pure crystalline Form S of Ketorolac tromethamine obtained by the processes disclosed herein is free from other crystalline forms, which has very good flow properties and is consistently reproducible, and is found to be more stable. The highly pure crystalline Form S of Ketorolac tromethamine obtained by the process disclosed herein exhibits properties making it suitable for formulating Ketorolac tromethamine.
Further encompassed herein is the use of the highly pure crystalline Form S of Ketorolac tromethamine obtained by the process disclosed herein for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.
A specific pharmaceutical composition of highly pure crystalline Form S of Ketorolac tromethamine obtained by the processes disclosed herein is selected from a solid dosage forms and liquid dosage formulations.
In one embodiment, the highly pure crystalline Form S of Ketorolac tromethamine obtained by the processes disclosed herein, for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 300 microns, specifically about 1 microns to about 150 microns, and most specifically about 4 microns to about 100 microns.
In another embodiment, the particle sizes of the highly pure crystalline Form S of Ketorolac tromethamine obtained by the processes disclosed herein are accomplished by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.
According to another aspect, provided herein is a stable and highly pure crystalline Form A of Ketorolac tromethamine characterized by an X-ray powder diffraction (XPRD) pattern comprising 2-theta peaks at about 8.79 and 11.40 ± 0.2 degrees substantially in accordance with Figure 9 and/or Figure 10.
In one embodiment, the stable and highly pure crystalline Form A of Ketorolac tromethamine is further characterized by an X-ray powder diffraction (XPRD) pattern comprising one or more additional 2-theta peaks at about 10.26, 12.73, 14.06, 17.59, 18.12, 18.76, 19.18, 19.36, 20.58, 23,33, 24.58 and 26.53 ± 0.2 degrees substantially in accordance with Figure 9 and/or Figure 10.
In another embodiment, the stable and highly pure crystalline Form A of Ketorolac tromethamine is further characterised by an infrared (FT-IR) spectrum comprising one or more main bands at about 3350, 3082, 2990, 2953, 2921, 2889, 1615, 1595, 1567, 1548, 1492, 1469, 1431, 1383, 1310, 1275, 1191, 1174, 1144, 1088, 1077, 1048, 896, 798, 771, 726, 702 and 674 cm-1 ± 5 cm-1 substantially in accordance with Figure 11.
In another embodiment, the stable and highly pure crystalline Form A of Ketorolac tromethamine is further characterised by a Differential Scanning Calorimetric (DSC) thermogram comprising two sharp endotherm peaks at about 160.11°C (± 3°C) and 168.29°C (± 3°C) respectively substantially in accordance with Figure 12.
In another embodiment, the stable and highly pure crystalline Form A of Ketorolac tromethamine is further characterised by a Differential Scanning Calorimetric (DSC) thermogram comprising two sharp endotherm peaks at about 159.58°C (± 3°C) and 169.69°C (± 3°C) respectively substantially in accordance with Figure 13.
The crystalline Form A of Ketorolac tromethamine is consistently reproducible does not have the tendency to convert to other forms and found to be thermally more stable.
According to another aspect, there is provided a process for the preparation of a stable and highly pure crystalline Form A of Ketorolac tromethamine essentially free of other crystalline forms, comprising:
a) providing a first solution of Ketorolac tromethamine in an alcohol solvent at a temperature of above about 45°C;
b) optionally, cooling the first solution at a temperature of about 35°C to about 40°C to obtain a second solution;
c) combining the first solution obtained in step-(a) or the second solution obtained in step-(b) with an anti-solvent, followed by cooling the resulting mass while stirring at a temperature of below about 35°C to cause crystallization, wherein the anti-solvent is selected from the group consisting of a hydrocarbon solvent, a halogenated hydrocarbon, an ester solvent and mixtures thereof; and
d) collecting the highly pure Ketorolac tromethamine crystalline Form A obtained in step-(c).
In one embodiment, the alcohol solvent used in step-(a) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, and mixtures thereof. A most specific solvent used in step-(a) is methanol.
Usually, the amount of alcohol solvent employed in step-(a) is about 1 volume to about 5 volumes, specifically about 2 volumes to about 4 volumes, and most specifically about 2.2 volumes to about 2.6 volumes, with respect to the quantity of Ketorolac tromethamine used.
Step-(a) of providing a first solution of Ketorolac tromethamine includes dissolving Ketorolac tromethamine (crude or pure) in the alcohol solvent used in step-(a), or obtaining an existing solution from a previous processing step.
In another embodiment, the Ketorolac tromethamine is dissolved in the alcohol solvent used in step-(a) at a temperature of about 45°C to the reflux temperature of the solvent used, specifically at a temperature of about 55°C to about 65°C. After complete dissolution of Ketorolac tromethamine, the resulting solution is stirred at a temperature of about 45°C to the reflux temperature of the solvent used for at least 5 minutes, and more specifically at a temperature of about 55°C to about 65°C for about 10 minutes to about 1 hour.
In another embodiment, the solution in step-(a) is also prepared by treating Ketorolac free acid with tromethamine in a suitable solvent or a mixture of suitable solvents to produce a reaction mass containing Ketorolac tromethamine, followed by usual work up such as washings, seeding, extractions, evaporations or a combination thereof, and then dissolving or extracting the resulting Ketorolac tromethamine in the alcohol solvent. Specifically, the solvent used for treating Ketorolac free acid with tromethamine is acetone, water, and mixture thereof.
In one embodiment, the solution obtained in step-(a) is optionally subjected to carbon treatment. The carbon treatment is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon at a temperature of about 45°C to the reflux temperature of the solvent used for at least 5 minutes, specifically for about 10 minutes to about 30 minutes, and filtering the resulting mixture through charcoal bed to obtain a filtrate containing Ketorolac tromethamine by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.
In another embodiment, the anti-solvent used in step-(c) is selected from the group consisting of toluene, xylene, dichloromethane, dichloroethane, chloroform, ethyl acetate, and mixtures thereof. A most specific anti-solvent used in step-(c) is toluene or dichloromethane.
Combining of the solution of Ketorolac tromethamine with the anti-solvent in step-(c) is done in a suitable order, for example, the first solution or the second solution is added to the anti-solvent, or alternatively, the anti-solvent is added to the solution. The addition is, for example, carried out drop-wise or in one portion or in more than one portion. The addition is specifically carried out under stirring at a temperature of about 45°C to the reflux temperature of the solvent used. After completion of the addition process, the resulting mass is cooled to a temperature of below about 35°C while stirring for at least 5 minutes, specifically at a temperature of about 0°C to about 30°C for about 10 minutes to 5 hours, and most specifically at a temperature of about 0°C to about 5°C for about 20 minutes to about 3 hours to cause crystallization.
The collection of the highly pure Ketorolac tromethamine crystalline Form A in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
As used herein, the term “reflux temperature” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
As used herein, the term “room temperature” refers to a temperature of about 20°C to about 35°C, and specifically to a temperature of about 25°C to about 30°C.
The highly pure crystalline Form A of Ketorolac tromethamine obtained by the process described herein is found to be more stable.
The highly pure crystalline Form A of Ketorolac tromethamine obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
Preferably, the drying is carried out at atmospheric pressure at temperatures such as about 40°C to about 85°C and most preferably at about 50°C to about 70°C. In one embodiment, the drying is carried out for any desired time period that achieves the desired result, preferably for a period of about 1 hour to 25 hours, and more preferably about 5 hours to 20 hours. Drying can be suitably carried out in a tray dryer, a vacuum oven, an air oven, or using a fluidized bed drier, a spin flash dryer, a flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art.
The highly pure crystalline Form A of Ketorolac tromethamine obtained by the process disclosed herein has a chemical purity of greater than about 99.5%, specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC. For example, the purity of the highly pure crystalline Form A of Ketorolac tromethamine obtained by the processes disclosed herein is about 99.5% to about 99.99% as measured by HPLC.
Unless otherwise specified, the Ketorolac free acid or Ketorolac Tromethamine as used herein as starting materials can be obtained, for example, by the processes reported in the prior art literature, for example as per the processes described in U.S. Patent No. 5,082,950 and Indian Patent Application No. 201741007811.
The stable and highly pure crystalline Form A of Ketorolac tromethamine obtained by the processes disclosed herein is free from other crystalline forms, which has very good flow properties and is consistently reproducible, and is found to be more stable. The highly pure crystalline Form A of Ketorolac tromethamine obtained by the process disclosed herein exhibits properties making it suitable for formulating Ketorolac tromethamine.
Further encompassed herein is the use of the highly pure crystalline Form A of Ketorolac tromethamine obtained by the process disclosed herein for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.
A specific pharmaceutical composition of highly pure crystalline Form A of Ketorolac tromethamine obtained by the processes disclosed herein is selected from a solid dosage forms and liquid dosage formulations.
In one embodiment, the highly pure crystalline Form A of Ketorolac tromethamine obtained by the processes disclosed herein, for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 300 microns, specifically about 1 microns to about 150 microns, and most specifically about 4 microns to about 100 microns.
In another embodiment, the particle sizes of the highly pure crystalline Form A of Ketorolac tromethamine obtained by the processes disclosed herein are accomplished by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.
The term “micronization” used herein means a process or method by which the size of a population of particles is reduced.
As used herein, the term “micron” or “µm” both are equivalent and refer to “micrometer” which is 1x10–6 meter.
As used herein, “crystalline particles” means any combination of single crystals, aggregates and agglomerates.
According to another aspect, there are provided pharmaceutical compositions comprising highly pure crystalline Form S of Ketorolac tromethamine obtained by the processes disclosed herein and one or more pharmaceutically acceptable excipients.
According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline Form S of Ketorolac tromethamine obtained by the processes disclosed herein, with one or more pharmaceutically acceptable excipients.
According to another aspect, there are provided pharmaceutical compositions comprising highly pure crystalline Form A of Ketorolac tromethamine obtained by the processes disclosed herein and one or more pharmaceutically acceptable excipients.
According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline Form A of Ketorolac tromethamine obtained by the processes disclosed herein, with one or more pharmaceutically acceptable excipients.
Yet in another embodiment, pharmaceutical compositions comprise at least a therapeutically effective amount of highly pure crystalline Form S of Ketorolac tromethamine or highly pure crystalline Form A of Ketorolac tromethamine obtained by the processes disclosed herein. Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, syrups, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, parenteral, ophthalmic, or any other acceptable route of administration. Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, suspensions, powders, and the like.
The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinbelow.
Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.
INSTRUMENTAL DETAILS:
X-Ray Powder Diffraction (P-XRD):
The X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X-ray powder diffractometer equipped with a Cu-anode (copper-Ka radiation). Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees 2-theta, at 0.03 degrees to theta per step and a step time of 0.4 seconds. The sample was simply placed on the sample holder. The instrument is operated at a voltage 40 kV and current 35 mA.
Infra-Red Spectroscopy (FT-IR):
FT-IR spectroscopy was carried out with a Bruker vertex 70 spectrometer. For the production of the KBr compacts approximately 5 mg of sample was powdered with 200 mg of KBr. The spectra were recorded in transmission mode ranging from 3800 cm-1 to 650cm-1.
Differential Scanning Calorimeter (DSC):
Differential Scanning Calorimetry (DSC) measurements were performed with a Differential Scanning Calorimeter (DSC Q200, Q Series Version-2.7.0.380, TA Instruments-Waters LLC) equilibrated at 50°C and Ramp at a scan rate of 10°C per minute to 250°C.
HPLC Method for measuring Chemical Purity:
The chemical purity was measured by HPLC system with UV detector or its equivalent under the following conditions: Column = Agilent, Zorbax RX-C8 (250 × 4.6) mm, 5 µm; Detector wavelength = 313 nm; Flow Rate = 1.5 ml/minute; Injection volume = 10 µL; Oven temperature = 40°C; Run time = 40 minutes; Diluent = Water and tetrahydrofuran in the ratio of 70:30, (v/v); Elution = Isocratic; and Sample Concentration: 0.4 mg/ml.
Mobile Phase: A mixture of buffer and Tetrahydrofuran in the ratio of 70:30, (v/v).

The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.
EXAMPLES
Example 1
Preparation of Ketorolac tromethamine
Acetone (980 ml) and Ketorolac (90 g) were taken into a clean reaction flask at 25-35°C and the contents were stirred for 30 minutes at the same temperature to form a clear solution. To the resulting solution, carbon (13 g) was added and the mixture was stirred for 10-15 minutes. The resulting mixture was filtered through carbon bed and washed with acetone (155 ml) and the filtrate obtained was kept aside. Tromethamine (42.7 g) was added to water (50 ml) at 25-35°C and the contents were stirred for 15 minutes at the same temperature to form a clear solution. The resulting tromethamine solution was filtered and washed with water (13 ml). The tromethamine solution was added to the filtrate containing Ketorolac at 25-35°C and then stirred for 25 minutes at the same temperature. The resulting mass was seeded with 0.2 g of Ketorolac tromethamine, followed by stirring for 2 hours 30 minutes at 25-35°C. The solid obtained was filtered, washed with acetone (155 ml) to produce 130 g of crude Ketorolac tromethamine.
Example 2
Purification of crude Ketorolac tromethamine
Methanol (300 ml) was added to crude Ketorolac tromethamine (130 g) at 50-55°C and then stirred for 10-15 minutes at the same temperature to form a clear solution. The resulting solution was filtered and washed with hot methanol (35 ml). To the resulting filtrate, acetone (1500 ml) was added at 25-35°C and stirred for 15 minutes at the same temperature. The resulting mass was cooled to 0-5°C and maintained for 45 minutes at the same temperature. The solid obtained was filtered, washed with acetone (90 ml) and then dried for 2 hours 30 minutes at 60-70°C to produce 103 g of highly pure Ketorolac tromethamine (HPLC Purity: 99.9%).
Example 3
Preparation of highly pure and stable crystalline Form S of Ketorolac tromethamine
Methanol (220 ml) and Ketorolac tromethamine (155 g) were taken into a reaction flask at 25-30°C and the resulting suspension was heated to 60-65°C, followed by stirring the suspension for 10-15 minutes at the same temperature to obtain a clear solution. The resulting solution was filtered and washed with hot methanol (15 ml) and the solution was kept aside (first solution). Acetone (30 ml) was taken into a reaction flask and added Ketorolac tromethamine (2 g) seeding material, followed by the addition of the first solution (10 ml) and then stirring the resulting mass for 5-10 minutes to obtain a seeding solution. Acetone (1220 ml) was taken into a reaction flask and heated to 45-50°C, and then the seeding solution was added, followed by the addition of the first solution. The resulting mass was cooled to 25-30°C and then subsequently cooled to 0-5°C, followed by stirring the mass for 1 hour to 1 hour 30 minutes. The solid obtained was filtered, washed with acetone (100 ml) and then dried the material at 65-70°C for 4 to 5 hours to produce 105 g of highly pure crystalline Form S of Ketorolac tromethamine (Purity by HPLC: 99.98%).

Example 4
Preparation of highly pure and stable crystalline Form A of Ketorolac tromethamine
Methanol (60 ml) was added to Ketorolac tromethamine (25 g) at 25-30°C and the resulting mixture was heated to 55-60°C, followed by stirring the mass for 10 to 15 minutes at 55-60°C to obtain a clear solution. The resulting hot solution was cooled to 40-45°C, followed by the addition of toluene (200 ml) at the same temperature. The resulting mass was cooled to 25-30°C and stirred for 30 minutes at the same temperature. The resulting mass was cooled to 0-5°C and then stirred for 1 hour at the same temperature. The solid obtained was filtered, washed with pre-cooled toluene (35 ml) and then dried the resulting wet material at 65-70°C for 4 to 5 hours to produce 23 g of pure crystalline Form A of Ketorolac tromethamine (Purity by HPLC: 99.95%).

Example 5
Preparation of highly pure and stable crystalline Form A of Ketorolac tromethamine
Methanol (60 ml) was added to Ketorolac tromethamine (25 g) at 25-30°C and the resulting suspension was heated to 55-60°C, followed by stirring the suspension for 10-15 minutes at the same temperature to obtain a clear solution. The resulting hot solution was cooled to 40-45°C followed by the addition of dichloromethane (200 ml) at the same temperature. The resulting mass was cooled to 25-30°C and stirred for 30 minutes at the same temperature. The resulting mass was cooled to 0-5°C and stirred for 1 hour at the same temperature. The solid obtained was filtered, washed with pre-cooled dichloromethane (35 ml) and dried the material at 65-70°C for 4 to 5 hours to produce 21 g of pure crystalline Form A of Ketorolac tromethamine (Purity by HPLC: 99.96%).

Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The term “pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and includes that which is acceptable for human pharmaceutical use.
The term “pharmaceutical composition” is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, and pharmaceutically acceptable excipients.
The term “therapeutically effective amount” as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
The term “delivering” as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host, e.g., human, animal, etc.
The term “buffering agent” as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate and other such materials known to those of ordinary skill in the art.
The term “sweetening agent” as used herein is intended to mean a compound used to impart sweetness to a formulation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.

The term “binders” as used herein is intended to mean substances used to cause adhesion of powder particles in granulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, polyvinylpyrrolidone, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch, starch, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers, collagen, albumin, celluloses in non-aqueous solvents, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, microcrystalline cellulose, combinations thereof and other material known to those of ordinary skill in the art.
The term “diluents” or “filler” as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage formulations. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “glidant” as used herein is intended to mean agents used in solid dosage formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “lubricant” as used herein is intended to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “disintegrant” as used herein is intended to mean a compound used in solid dosage formulations to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pregelatinized, sweeteners, clays, such as bentonite, microcrystalline cellulose, carsium, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “wetting agent” as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP).
All ranges disclosed herein are inclusive and combinable. While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.