WO2007015724A1 - Tromethamine salt of valproic acid - Google Patents
Tromethamine salt of valproic acid Download PDFInfo
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- WO2007015724A1 WO2007015724A1 PCT/US2006/023106 US2006023106W WO2007015724A1 WO 2007015724 A1 WO2007015724 A1 WO 2007015724A1 US 2006023106 W US2006023106 W US 2006023106W WO 2007015724 A1 WO2007015724 A1 WO 2007015724A1
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- valproic acid
- tromethamine
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- tromethamine salt
- salt
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/126—Acids containing more than four carbon atoms
- C07C53/128—Acids containing more than four carbon atoms the carboxylic group being bound to a carbon atom bound to at least two other carbon atoms, e.g. neo-acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
Definitions
- the present invention relates to a novel tromethamine salt of valproic acid, a method for its preparation, methods for its use as a pharmaceutical agent and pharmaceutical compositions comprising the crystalline tromethamine salt of valproic acid
- Valproic acid is commonly used in the treatment of epileptic seizures and convulsions, as well as for treating bipolar disorders
- Valproic acid is a colorless clear liquid which is lightly soluble in water Oral formulations of valproic acid are therefore inconvenient to prepare and difficult to dispense
- the present invention is directed to developing valproic acid compositions that provide improved stability and tablet forming characteristics as well as exhibit improved patient tolerance
- the present invention relates to the novel tromethamine salt of valproic acid
- a crystalline form of tromethamine salt of valproic acid is provided The crystalline form is characterized by an x-ray diffraction pattern having characteristic scattering peaks expressed in units of degrees 2 ⁇ ( ⁇ 0 2°) at 54, 64, 6 8, 8 1, and 21 5
- a method of making tromethamine salt of valproic acid the method comprising dissolving the valproic acid in at least one solvent, adding the tromethamine to the at least one solvent to form a reaction mixture, and allowing the valproic acid and tromethamine to react to form the tromethamine salt of valproic acid 0008]
- Figure 1 is an x-ray powder diffraction pattern of a crystalline form of tromethamine salt of valproic acid of the present invention scanning calorimetry thermogram of a crystalline form of tromethamine salt of valproic acid of the present invention.
- Figure 3 is a Fourier-transform infrared absorption spectrum of a crystalline form of tromethamine salt of valproic acid of the present invention.
- TRIS- valproate an improved salt of valproic acid, the tromethamine salt
- TRIS- valproate an improved salt of valproic acid, the tromethamine salt
- Tromethamine (2-Amino-2-(hydroxymethyl)-1 ,3-propanediol or t ⁇ s(hydroxymethyl)aminomethane [77-86-1]) is also commonly referred to as TRIS or TRIS buffer.
- the TRI S- valproate of the present invention is a self-buffering compound possessing a high degree of water solubility. TRIS-valproate is easily manufactured, providing a highly crystalline form that is easily handled and dried, providing improved stability and tableting characteristics. The quality and purity of the TRIS-valproate of the present invention facilitates it being processed into drug dosage forms.
- the improved TRIS buffered salt disclosed herein results in less irritation of the Gl tract as compared to valproic acid or the conventional sodium salt formulations.
- the invention provides a crystalline form of TRIS-valproate.
- the crystalline form of TRIS-valproate has been characterized by powder X-ray diffraction ("PXRD”) analysis, by differential scanning calorimetry (“DSC”) and Fourier-transform infrared absorption (“FT-IR”).
- the PXRD pattern was obtained using a Rigaku MiniFlex powder diffraction system, equipped with a horizontal goniometer in the ⁇ /2 ⁇ mode
- the x-ray source was nickel-filtered K- ⁇ emission of copper (1 55314 A)
- Samples were packed into an aluminum holder using a back-fill procedure, and were scanned over the range of 6 to 48 degrees 2 ⁇ , at a scan rate of 0 5 degrees 2 ⁇ /m ⁇ n Using a data acquisition rate of 1 point per second, the scanning parameters equate to a step size of 0 0084 degrees 2 ⁇
- Calibration of each powder pattern was effected using the characteristic scattering peaks of aluminum at 44 738 and 38 472 degrees 2 ⁇ so the useful range for sample characterization range was 6 to 36 degrees 2 ⁇
- TRIS-valproate was further characterized by DSC ( Figure 2) Fig 2 possesses a sharp melting endotherm with an onset temperature of 55 6 0 C and a maximum at 57 8 0 C Due to differences in equipment and rate of heating, among other things, TRIS-valproate that produces a thermal analysis result e g measured melting point, maximum melting endotherm inflection point in heat absorption curve and the like, that is indicative of melting at about 55 0 C to about 60 0 C is consistent with its identity as depicted in Fig 2 The enthalpy of fusion was determined to be 130 5 J/g 1
- DSC was performed using a TA Instruments 2910 thermal analysis system Samples of approximately 1-2 mg were accurately weighed into an aluminum DSC pan and covered with an alurininumiiafhat ⁇ itrfftiieffin place The samples were then heated over the range of 25°C to 240 0 C, at a heating rate of 10°C/min.
- valproic acid is dissolved in at least one solvent while stirring Suitable solvents include any pharmaceutically acceptable non-reactive solvent into which the valproic acid dissolves, including but not limited to alcohols such as methanol, ethanol, propanol and mixtures thereof.
- alcohols such as methanol, ethanol, propanol and mixtures thereof.
- an equimolar amount of tromethamine is added, and the resulting reaction mixture is stirred until the reaction is substantially complete, typically about 30 to about 60 minutes at room temperature.
- the reaction is not temperature sensitive, with a suitable temperature range from about 30°C to about 90°C.
- the alcohol is then removed under vacuum to yield the TRIS-valproate.
- the TRIS-valproate of the present invention is suitable for use as an active pharmaceutical ingredient (API) in a pharmaceutical composition.
- API active pharmaceutical ingredient
- Illustrative, non-limiting uses of the TRIS-valproate are for treating patients suffering from epileptic seizures and/or convulsions, as well as for the treatment of bipolar disorders
- the TRIS-valproate is typically administered to the patient using a solid dosage form, with a tablet or capsule being presently preferred.
- Pharmaceutical compositions in solid dosage form may include tablets, powders, capsules, suppositories, sachets, troches and lozenges.
- the TRIS-valproate of the present invention may be administered in any suitable dosage form, by any suitable method without limitation.
- Valproic acid (5.6 g, 40 mmol, 100 mol %) was added to methanol (50 mL) and stirred until the valproic acid was substantially dissolved Tris(hydroxymethyl)am ⁇ nomethane (4.8 g, 40 mmol, 100 mol %) was then added and the resulting mixture was stirred for 30 minutes at room temperature. The methanol was removed under vacuum at 180 mbar at 60°C. The isolated product is crystalline, and has a melting point of about 65°C to about 66 0 C. The product (10.1 g, 97 % yield) was determined to be TRIS-valproate.
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Abstract
An improved valproic acid salt, the tromethamine salt of valproic acid (TRIS-valproate) is disclosed. TRIS-valproate provides superior stability, storage, tableting and patient tolerance. A crystalline form of TRIS-valproate, a method of making TRIS-valproate, as well as pharmaceutical dosage forms and methods of treating patients comprising TRIS-valproate are also disclosed.
Description
if Ml If , f PS f If* - 1,LJJ I fcteoHETHAMINE SALT OF VALPRO.C ACID
BACKGROUND OF INVENTION
[0001] The present invention relates to a novel tromethamine salt of valproic acid, a method for its preparation, methods for its use as a pharmaceutical agent and pharmaceutical compositions comprising the crystalline tromethamine salt of valproic acid
[0002] The drug substance valproic acid, or 2-propylpentanoιc acid, is known for its anticonvulsant properties Valproic acid is commonly used in the treatment of epileptic seizures and convulsions, as well as for treating bipolar disorders Valproic acid is a colorless clear liquid which is lightly soluble in water Oral formulations of valproic acid are therefore inconvenient to prepare and difficult to dispense
[0003] The sodium salt of valproic acid, sodium valproate is a white crystalline powder Unfortunately, because of its high degree of hygroscopicity, sodium valproate is difficult to handle and process, resulting in difficulties in storage and tablet formulation Further, the free acid and the sodium salt frequently cause adverse Gl effects such as nausea, vomiting and indigestion For these reasons, both valproic acid and sodium valproate have limited utility in the preparation of oral dosage forms
[0004] Abbott Laboratories has developed a hemi-sodium salt of valproic acid known as divalproex sodium Divalproex sodium commercialized under the trade name Depakote® is a stable polymeric compound consisting of valproic acid and valproate sodium in a 1 1 molar ratio whose use is purported to reduce adverse Gl affects
[0005] Accordingly, the present invention is directed to developing valproic acid compositions that provide improved stability and tablet forming characteristics as well as exhibit improved patient tolerance
SUMMARY OF INVENTION [0006] The present invention relates to the novel tromethamine salt of valproic acid In one aspect of the present invention a crystalline form of tromethamine salt of valproic acid is provided The crystalline form is characterized by an x-ray diffraction pattern having characteristic scattering peaks expressed in units of degrees 2Θ (± 0 2°) at 54, 64, 6 8, 8 1, and 21 5 [0007] In another aspect of the present invention there is provided a method of making tromethamine salt of valproic acid the method comprising dissolving the valproic acid in at least one solvent, adding the tromethamine to the at least one solvent to form a reaction mixture, and allowing the valproic acid and tromethamine to react to form the tromethamine salt of valproic acid 0008] In further aspects of the present invention there are provided a pharmaceutical dosage form and a method of treating a patient with a pharmaceutical composition of tromethamine salt of valproic acid
BRIEF DESCRIPTION OF DRAWINGS
[0009] Figure 1 is an x-ray powder diffraction pattern of a crystalline form of tromethamine salt of valproic acid of the present invention
scanning calorimetry thermogram of a crystalline form of tromethamine salt of valproic acid of the present invention. [0011] Figure 3 is a Fourier-transform infrared absorption spectrum of a crystalline form of tromethamine salt of valproic acid of the present invention.
DETAILEΞD DESCRIPTION
[0012] There is provided an improved salt of valproic acid, the tromethamine salt (hereinafter TRIS- valproate.) Tromethamine (2-Amino-2-(hydroxymethyl)-1 ,3-propanediol or tπs(hydroxymethyl)aminomethane [77-86-1]) is also commonly referred to as TRIS or TRIS buffer.
[0013] The TRI S- valproate of the present invention is a self-buffering compound possessing a high degree of water solubility. TRIS-valproate is easily manufactured, providing a highly crystalline form that is easily handled and dried, providing improved stability and tableting characteristics. The quality and purity of the TRIS-valproate of the present invention facilitates it being processed into drug dosage forms. The improved TRIS buffered salt disclosed herein results in less irritation of the Gl tract as compared to valproic acid or the conventional sodium salt formulations.
[0014] In another aspect, the invention provides a crystalline form of TRIS-valproate. The crystalline form of TRIS-valproate has been characterized by powder X-ray diffraction ("PXRD") analysis, by differential scanning calorimetry ("DSC") and Fourier-transform infrared absorption ("FT-IR").
[0015] The PXRD pattern for the crystalline form of TRIS-valproate of the present invention is depicted
Figure 1. The scale of the region encompassing 12 to 37 degrees 2Θ was multiplied by a factor of 4.0 in Fig. 1. The scattering angles and d-spacings in the PXRD pattern for the crystalline form of TRIS- valproate are given in Table 1, below:
J "if [0046] ' ;i oιr Table 1
[0017] The PXRD pattern was obtained using a Rigaku MiniFlex powder diffraction system, equipped with a horizontal goniometer in the θ /2Θ mode The x-ray source was nickel-filtered K-α emission of copper (1 55314 A) Samples were packed into an aluminum holder using a back-fill procedure, and were scanned over the range of 6 to 48 degrees 2Θ, at a scan rate of 0 5 degrees 2θ/mιn Using a data acquisition rate of 1 point per second, the scanning parameters equate to a step size of 0 0084 degrees 2Θ Calibration of each powder pattern was effected using the characteristic scattering peaks of aluminum at 44 738 and 38 472 degrees 2Θ so the useful range for sample characterization range was 6 to 36 degrees 2Θ
[0018] The crystalline form of TRIS-valproate was further characterized by DSC (Figure 2) Fig 2 possesses a sharp melting endotherm with an onset temperature of 55 60C and a maximum at 57 80C Due to differences in equipment and rate of heating, among other things, TRIS-valproate that produces a thermal analysis result e g measured melting point, maximum melting endotherm inflection point in heat absorption curve and the like, that is indicative of melting at about 550C to about 600C is consistent with its identity as depicted in Fig 2 The enthalpy of fusion was determined to be 130 5 J/g 1
[0019] DSC was performed using a TA Instruments 2910 thermal analysis system Samples of approximately 1-2 mg were accurately weighed into an aluminum DSC pan and covered with an
alurininumiiafhat^itrfftiieffin place The samples were then heated over the range of 25°C to 2400C, at a heating rate of 10°C/min.
[0020] An FT-IR absorption spectrum, shown in Figure 3, was obtained at a resolution of 2 cm"1 using a Shimadzu model 8400 FT-IR spectrometer, and represents the averaging of 25 interferograms. The data were acquired using the attenuated total reflectance sampling mode, where the samples were clamped against the ZnSe crystal of a Pike MIRacle™ single reflection horizontal ATR sampling accessory. Absorption bands characteristic of the TRIS-valproate compound were observed at 1059, 1535 and 1586 cm"1
[0021] In an illustrative, non-limiting method of production, valproic acid is dissolved in at least one solvent while stirring Suitable solvents include any pharmaceutically acceptable non-reactive solvent into which the valproic acid dissolves, including but not limited to alcohols such as methanol, ethanol, propanol and mixtures thereof. In a preferred, non-limiting embodiment, an equimolar amount of tromethamine is added, and the resulting reaction mixture is stirred until the reaction is substantially complete, typically about 30 to about 60 minutes at room temperature. The reaction is not temperature sensitive, with a suitable temperature range from about 30°C to about 90°C. The alcohol is then removed under vacuum to yield the TRIS-valproate.
[0022] The TRIS-valproate of the present invention is suitable for use as an active pharmaceutical ingredient (API) in a pharmaceutical composition. Illustrative, non-limiting uses of the TRIS-valproate are for treating patients suffering from epileptic seizures and/or convulsions, as well as for the treatment of bipolar disorders The TRIS-valproate is typically administered to the patient using a solid dosage form, with a tablet or capsule being presently preferred. Pharmaceutical compositions in solid dosage form may include tablets, powders, capsules, suppositories, sachets, troches and lozenges. However, it is noted that the TRIS-valproate of the present invention may be administered in any suitable dosage form, by any suitable method without limitation.
[0023] The following example is given for illustrative purposes only and is not intended to limit the invention disclosed herein or the appended claims in any way EXAMPLE
[0024] Valproic acid (5.6 g, 40 mmol, 100 mol %) was added to methanol (50 mL) and stirred until the valproic acid was substantially dissolved Tris(hydroxymethyl)amιnomethane (4.8 g, 40 mmol, 100 mol %) was then added and the resulting mixture was stirred for 30 minutes at room temperature. The methanol was removed under vacuum at 180 mbar at 60°C. The isolated product is crystalline, and has a melting point of about 65°C to about 660C. The product (10.1 g, 97 % yield) was determined to be TRIS-valproate.
[0025] The product was characterized by PXRD, which was consistent with that shown in Fig 1 , by
DSC, which was consistent with Fig 2, and by FT-IR, which was consistent with Fig. 3. Elemental Analysis
[0026] The calculated and empirically determined elemental analyses for the anhydrous tromethamine salt of valproic acid are as follows and as in Table 2:
[0027] Empirical formula = C12H17NO5
[0028] Molecular weight = 265 35
!,>
[0029] ' Table 2
[0030] Having described the invention in detail, those skilled in the art will appreciate that modifications may be made of the invention without departing from its spirit and scope. Therefore, it is not intended that the scope of the invention be limited to the specific embodiments described. Rather, it is intended that the appended claims and their equivalents determine the scope of the invention.
Claims
C allfoS1
We claim 1 Tromethamine salt of valproic acid 2 A crystalline form of the tromethamine salt of valproic acid 3 The crystalline form of tromethamine salt of valproic acid of Claim 2 characterized by an x-ray diffraction pattern having characteristic peaks expressed in degrees 2Θ (+ 02°) at 54 64, 6 8, 8 1, and 24 5
4 The crystalline form of tromethamine salt of valproic acid of Claim 2 characterized by an x-ray diffraction pattern having characteristic peaks expressed in degrees 2Θ (+ 0 2°) at 54, 64, 6 8, 73, 8 1 87, and 24 5
5 The crystalline form of tromethamine salt of valproic acid of Claim 2 characterized by an x-ray diffraction pattern having characteristic peaks expressed in degrees 2Θ (+ 0 2°) at 54, 64, 6 8, 7 3, 8 1 8 7, 24 5, 27 0, and 294
6 The crystalline form of tromethamine salt of valproic acid of Claim 2 characterized by a thermal analysis result indicative of a melting point range of about 550C to about 6O0C
7 The crystalline form of tromethamine salt of valproic acid of Claim 6, wherein the thermal analysis result is a differential scanning calonmetry thermogram taken at a heating rate of 10°C/mιn in a closed pan that exhibits a melting endotherm with a maximum at about 55°C to about 60°C
8 The crystalline form of trometham ne salt of valproic acid of claim 7 wherein the melting endotherm has a magnitude of about 130 J/g 1
9 The crystalline form of trometham ne salt of valproic acid of Claim 2 characterized by an infrared absorption spectrum containing peaks at 1059, 1535, and 1586 crrf1
10 The crystalline form of tromethamine salt of valproic acid of claim 2, wherein said form provdes an X-ray powder diffraction pattern substantially in accordance with FIG 1
11 The crystalline form of tromethamine salt of valproic acid of claim 2, wherein said form provides an X-ray powder diffraction pattern substantially in accordance with Table 1
12. The crystalline form of tromethamine salt of valproic acid of claim 2, wherein said form provides a differential scanning calorimetry thermogram substantially in accordance with FIG. 2.
13. The crystalline form of claim 2, wherein said form provides an infrared spectrum substantially in accordance with FIG. 3.
14. A method of making a tromethamine salt of valproic acid, the method comprising: dissolving the valproic acid in at least one solvent; adding the tromethamine to the at least one solvent to form a reaction mixture; and allowing the valproic acid and tromethamine to react to form the tromethamine salt of valproic acid.
15. The process of Claim 14 further including evaporating the at least one solvent after the tromethamine salt of valproic acid is formed.
16. The process of Claim 14 wherein the valproic acid and tromethamine are in substantially equimolar amounts.
17. The method of Claim 14 wherein the at least one solvent is at least one pharmaceutically acceptable πoπ-reactive solvent into which the valproic acid substantially dissolves.
18. The method of Claim 17 wherein the at least one solvent is selected from the group consisting of methanol, ethanol, propanol and mixtures thereof.
19. The method of Claim 14, wherein the step of allowing the valproic acid and tromethamine to react comprises: stirring the reaction mixture until the valproic acid and the tromethamine react to form tromethamine valproate; and removing the at least one solvent to yield the tromethamine valproate.
20. A pharmaceutical dosage form comprising tromethamine salt of valproic acid and a pharmaceutically acceptable carrier.
21. A pharmaceutical dosage form comprising a crystalline form of tromethamine salt of valproic acid and a pharmaceutically acceptable carrier.
22. The dosage form of Claim 21 wherein the crystalline form of tromethamine salt of valproic acid is characterized by at least one of:
(i) an x-ray diffraction pattern having characteristic peaks expressed in degrees 2Θ (+ 0.2°) at 5.4, 6.4, 6.8, 8.1 , and 24.5; " indicative of a melting point range of about 550C to about 600C, and
(ιiι) an infrared absorption spectrum containing peaks at 1059, 1535, and 1586 cm"1.
23. The dosage form of Claim 21 wherein the dosage form is a solid dosage form
24. A method of treating a patient, the method comprising administering an effective amount of a crystalline composition of tromethamine salt of valproic acid characterized by at least one of
(ι) an x-ray diffraction pattern having characteristic peaks expressed in degrees 2Θ (± 0 2°) at 54, 64, 6 8, 8 1, and 245,
(ιi) a thermal analysis result indicative of a melting point range of about 550C to about 6O0C; and
(in) an infrared absorption spectrum containing peaks at 1059, 1535, and 1586 cm"1
25. The method of Claim 23 wherein the patient is being treated for epileptic seizures, convulsions or bipolar disorder
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010049525A1 (en) * | 2008-10-31 | 2010-05-06 | C-A-I-R Biosciences Gmbh | Choline and tromethamine salt of licofelone |
WO2016067297A1 (en) * | 2014-10-27 | 2016-05-06 | Cellix Bio Private Limited | Salts of valproic acid with piperazine, ethylenediamine, lysine and/or eicosapentaenoic ecid (epa) amine derivatives for the treatment of epilepsy |
Citations (2)
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US4988731A (en) * | 1979-08-20 | 1991-01-29 | Abbott Laboratories | Sodium hydrogen divalproate oligomer |
US5212326A (en) * | 1979-08-20 | 1993-05-18 | Abbott Laboratories | Sodium hydrogen divalproate oligomer |
-
2006
- 2006-06-11 WO PCT/US2006/023106 patent/WO2007015724A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4988731A (en) * | 1979-08-20 | 1991-01-29 | Abbott Laboratories | Sodium hydrogen divalproate oligomer |
US5212326A (en) * | 1979-08-20 | 1993-05-18 | Abbott Laboratories | Sodium hydrogen divalproate oligomer |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010049525A1 (en) * | 2008-10-31 | 2010-05-06 | C-A-I-R Biosciences Gmbh | Choline and tromethamine salt of licofelone |
CN102264741A (en) * | 2008-10-31 | 2011-11-30 | C-A-I-R生物科学有限公司 | Choline and tromethamine salt of licofelone |
JP2012506899A (en) * | 2008-10-31 | 2012-03-22 | ツェー・アー・イー・エルバイオサイエンスシーズ、ゲーエムベーハー | Choline and tromethamine salts of lycoferon |
US8519155B2 (en) | 2008-10-31 | 2013-08-27 | C-A-I-R Biosciences Gmbh | Choline and tromethamine salt of licofelone |
WO2016067297A1 (en) * | 2014-10-27 | 2016-05-06 | Cellix Bio Private Limited | Salts of valproic acid with piperazine, ethylenediamine, lysine and/or eicosapentaenoic ecid (epa) amine derivatives for the treatment of epilepsy |
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