MXPA99002202A - Computeros marcadores y su su - Google Patents
Computeros marcadores y su suInfo
- Publication number
- MXPA99002202A MXPA99002202A MXPA/A/1999/002202A MX9902202A MXPA99002202A MX PA99002202 A MXPA99002202 A MX PA99002202A MX 9902202 A MX9902202 A MX 9902202A MX PA99002202 A MXPA99002202 A MX PA99002202A
- Authority
- MX
- Mexico
- Prior art keywords
- sample
- solution
- lamotrigine
- compound
- dichlorophenyl
- Prior art date
Links
- PYZRQGJRPPTADH-UHFFFAOYSA-N Lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 claims abstract description 85
- 229960001848 lamotrigine Drugs 0.000 claims abstract description 84
- 150000001875 compounds Chemical class 0.000 claims abstract description 79
- -1 2,3-dichlorophenyl Chemical group 0.000 claims abstract description 15
- 230000015556 catabolic process Effects 0.000 claims abstract description 12
- 230000004059 degradation Effects 0.000 claims abstract description 12
- 238000006731 degradation reaction Methods 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 10
- RDUGDEWOUWFKPL-UHFFFAOYSA-N N-[5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl]-2,3-dichlorobenzamide Chemical compound N=1N=C(C=2C(=C(Cl)C=CC=2)Cl)C(N)=NC=1NC(=O)C1=CC=CC(Cl)=C1Cl RDUGDEWOUWFKPL-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000000243 solution Substances 0.000 claims description 70
- 239000012086 standard solution Substances 0.000 claims description 27
- 239000012488 sample solution Substances 0.000 claims description 24
- 239000003550 marker Substances 0.000 claims description 22
- 239000002552 dosage form Substances 0.000 claims description 19
- 238000004809 thin layer chromatography Methods 0.000 claims description 18
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 5
- YBONBWJSFMTXLE-UHFFFAOYSA-N 2,3-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC(Cl)=C1Cl YBONBWJSFMTXLE-UHFFFAOYSA-N 0.000 claims description 4
- FIBBFBXFASKAON-UHFFFAOYSA-N 2,3-dichlorobenzoyl cyanide Chemical compound ClC1=CC=CC(C(=O)C#N)=C1Cl FIBBFBXFASKAON-UHFFFAOYSA-N 0.000 claims description 4
- OTXHZHQQWQTQMW-UHFFFAOYSA-N (diaminomethylideneamino)azanium;hydrogen carbonate Chemical compound OC([O-])=O.N[NH2+]C(N)=N OTXHZHQQWQTQMW-UHFFFAOYSA-N 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 238000004448 titration Methods 0.000 claims description 3
- 230000001351 cycling Effects 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 239000003826 tablet Substances 0.000 description 15
- 239000000203 mixture Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000003814 drug Substances 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 239000012535 impurity Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000000356 contaminant Substances 0.000 description 6
- 230000000875 corresponding Effects 0.000 description 6
- 229940079593 drugs Drugs 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000003860 storage Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 230000002194 synthesizing Effects 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229960000583 Acetic Acid Drugs 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- CVHZOJJKTDOEJC-UHFFFAOYSA-N Saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000007857 degradation product Substances 0.000 description 4
- XNWFRZJHXBZDAG-UHFFFAOYSA-N ethylene glycol monomethyl ether Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000012085 test solution Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 3
- 230000001105 regulatory Effects 0.000 description 3
- 210000003169 Central Nervous System Anatomy 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 230000035969 Vmax Effects 0.000 description 2
- ZCHPKWUIAASXPV-UHFFFAOYSA-N acetic acid;methanol Chemical compound OC.CC(O)=O ZCHPKWUIAASXPV-UHFFFAOYSA-N 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- ZYBWTEQKHIADDQ-UHFFFAOYSA-N ethanol;methanol Chemical compound OC.CCO ZYBWTEQKHIADDQ-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- BXDSJOGMJUKSAE-CHHVJCJISA-N (1E)-2,3-dichloro-N-(diaminomethylideneamino)benzenecarboximidoyl cyanide Chemical compound NC(N)=N\N=C(\C#N)C1=CC=CC(Cl)=C1Cl BXDSJOGMJUKSAE-CHHVJCJISA-N 0.000 description 1
- GKNCZOMKFQSLCL-WYMPLXKRSA-N (1Z)-2,3-dichloro-N-[[N'-(2,3-dichlorobenzoyl)carbamimidoyl]amino]benzenecarboximidoyl cyanide Chemical compound C=1C=CC(Cl)=C(Cl)C=1C(=O)N=C(N)N\N=C(/C#N)C1=CC=CC(Cl)=C1Cl GKNCZOMKFQSLCL-WYMPLXKRSA-N 0.000 description 1
- PQQZYNVQDUZLTQ-UHFFFAOYSA-N (2,3-dichlorobenzoyl) 2,3-dichlorobenzoate Chemical compound ClC1=CC=CC(C(=O)OC(=O)C=2C(=C(Cl)C=CC=2)Cl)=C1Cl PQQZYNVQDUZLTQ-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N Copper(I) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 206010015037 Epilepsy Diseases 0.000 description 1
- 102000014961 Protein Precursors Human genes 0.000 description 1
- 108010078762 Protein Precursors Proteins 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- RQBBFKINEJYDOB-UHFFFAOYSA-N acetic acid;acetonitrile Chemical compound CC#N.CC(O)=O RQBBFKINEJYDOB-UHFFFAOYSA-N 0.000 description 1
- UGAPHEBNTGUMBB-UHFFFAOYSA-N acetic acid;ethyl acetate Chemical compound CC(O)=O.CCOC(C)=O UGAPHEBNTGUMBB-UHFFFAOYSA-N 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000000451 chemical ionisation Methods 0.000 description 1
- 230000001143 conditioned Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001809 detectable Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000003883 substance clean up Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Abstract
A method for titrating the stability to degradation of a sample of lamotrigine or a pharmaceutical dosage comprising lamotrigine, evaluating said sample for the presence of a compound selected from 3-amino-6- (2,3-dichlorophenyl) -1,2,4-triazine-5- (4H) -one (compound A) and N- [5-amino-6- (2,3-dichlorophenyl) 1,2,4-triazine-3-yl] -2 , 3-dichlorobenzamide (compound B). A process is also described for producing compound B, which is
Description
- - COMPOUNDS MARKERS AND THEIR USE
The present invention relates to compounds used as reference markers for the analysis of otrigine and pharmaceutical formulations thereof. In order to secure marketing approval for a new medical product, a drug developer may provide detailed evidence to the appropriate regulatory authority to show that the product is suitable for release on the market. The regulatory authority must satisfy, inter alia, that the active agent is acceptable for administration to humans and that the particular formulation, which is to be marketed, is free of impurities at the time of release and has an adequate shelf life or storage. The provision of information made to regulatory authorities therefore typically includes analytical data that demonstrate that (a) the impurities are absent from the drug at the time of processing, or are present only at an insignificant level, and (b) that the storage stability, that is, the storage life of the medicine is acceptable. - These data are commonly obtained by the evaluation of the drug
REF .: 29577 against an external standard or reference marker, which is a suitably pure sample of a potential impurity or a potential degradation product
Potential impurities in pharmaceutically active agents and formulations containing them include residual amounts of synthetic precursors to the active agent, derivatives or by-products, which originate during the synthesis of the active agent, residual solvent, isomers of the active agent, contaminants which are present in the materials used in the synthesis of the active agent or in the preparation of the pharmaceutical formulation, and in unidentified foreign substances. Other impurities which may appear in storage include substances that result from the degradation of the active agent, for example by oxidation or hydrolysis. Lamotrigine is 3,5-diamino-6- (2,3-dichlorophenyl) -1,2,4-triazine of formula (IV).
(V) It is a known compound which is used in the treatment of alterations of the central nervous system (CNS), in particular epilepsy, as described for example in EP-A-0021121. Any lamotrigine itself and its pharmaceutical formulations are elaborated, relatively free of impurities. In particular, lamotrigine remains stable during the manufacture of its pharmaceutical formulations. It will now be appreciated that two compounds can be used as reference markers for the analysis of lamotrigine or dosage forms comprising lamotrigine. One of the compounds is a potential degradation product of lamotrigine and the other is a potential contaminant originated from lateral reactions during the synthesis of lamotrigine. The present invention therefore provides a method of testing the purity or stability to degradation of a lamotrigine sample or a pharmaceutical dosage form comprising lamotrigine, wherein the method comprises assaying said sample for the presence of a compound selected from 3-amino-6- (2,3-dichlorophenyl) -1,2,4-tri.azine-5- (4H) -one ... and N- [5-amino-6- (2 , 3-dichlorophenyl) -1, 2,4-triazine-3-yl] -2, 3-dichlorobenzamide. In the method of the invention said compound is activated as a reference marker. 3-Amino-6- (2,3-dichlorophenyl) -1,2,4-triazine-5- (4H) -one is a compound of formula A:
The compound of formula A (compound A) is a potential degradation product of lamotrigine which occurs upon hydrolysis of the medicament. The compound of formula A can therefore be produced by hydrolysis of lamotrigine under basic conditions. The hydrolysis is suitably conducted by the combination of lamotrigine and a base with water, and then heating the resulting solution under reflux. The base is preferably a strong base, for example an alkali metal hydroxide. Sodium hydroxide is particularly preferred. The basic solution in water can be heated under reflux for a period of 1 hour to 48 hours, for example 10 hours to 36 hours, preferably 24 hours. The other compound used as a reference marker is new. The invention therefore provides a compound which is N- [5-amino-6- (2,3-dichlorophenyl) -1,2,4-triazine-3-yl] -2,3-dichlorobenzamide of formula B :
The compound of formula B (compound B) can be produced directly by treating lamotrigine with 2,3-dichlorobenzoyl chloride in pyridine. However, it has been useful as a reference marker for lamotrigine since it is a potential contaminant originating from side reactions which may occur during the "synthesis of the drug." In practice, the level of this contaminant is controlled to a maximum of 0.5% in crude lamotrigine by thin layer chromatography (TLC). Recrystallization of the crude drug of this quality then results in the production of lamotrigine suggesting the level of purity required for commercial production of no more than 2% of the total of impurities The synthesis of lamotrigine is illustrated in Reference Example 1. The cyanide 2,3-dichlorobenzoyl, which is the intermediate 1.4 in the synthesis, can contain up to 10% of 2,3-dichlorobenzoic anhydride as a contaminant When the 2,3-dichlorobenzoyl cyanide is treated with a solution of aminoguanidine bicarbonate in sulfuric acid, which is step (d) in the from Reference 1, the adduct (Z) -2- (2,3-dichlorophenyl) -2- (guanidinoimino) acetonitrile (intermediate 1.5) is produced. The anhydride contaminant can then be reacted with the last adduct to form (Z) 2- (2,3-dichlorophenyl) -2- [N '- (2,3-dichlorobenzoyl) guanidinoimino] acetonitrile, which is the direct precursor to the compound B. Cycles or cyclization of the precursor in the propan-1-ol under reflux provide compound B. The present invention therefore further provides a process for producing compound B, in which the process comprises. (i) reacting 2 equivalents of 2,3-dichlorobenzoyl chloride with 1 equivalent of lamotrigine dissolved in pyridine at a temperature of less than 35 ° C; or (ii) cyclizing a compound of formula (I): in propan-1-ol under reflux.
In step (ii), the compound of formula (1) is produced by reacting it together with the compounds of formula (II) and (III):
('> (lll) in the presence of a mineral acid, for example sulfuric acid The compound of formula (II) is produced by the treatment of 2,3-dichlorobenzoyl cyanide with a solution of aminoguanidine bicarbonate in sulfuric acid When compounds A and B are used as reference markers, they may be in an adequately pure form Compounds A and B produced as described above can be purified if necessary to achieve the desired level of purity. invention to produce the compound B as described above can therefore include the further step of purification of the resulting compound Purification can be carried out by conventional methods which are routine in the organic synthesis For example, the compound can be heated in an organic solvent such as C?-C6 alkanol, filtered and dried under vacuum.The heating is typically carried out at the reflux temperature of the solv An alkanol of C? -C6 is preferably propanol. Alternatively, the compound can be recrystallized from a hot C?-C6 alkanol solvent, preferably hot pr.opanol. The compounds A and B are preferably, finally recovered in a substantially pure form. The level of purity of a final sample of any compound is typically at least 80%, for example at least 85%, more preferably at least 90%. Purity levels above 90% may be desirable but not essential. The level of purity can be, for example, at least 92%, at least 95% or at least 98%. Even more desirably the level of purity is 99% or 99.5%. Either lamotrigine itself (also referred to as a drug substance) or a pharmaceutical dosage form comprising lamotrigine (also referred to as a drug product) can be analyzed for purity or stability for degradation. For example, it is necessary to ensure that lamotrigine is pure following its manufacture. The drug substance is therefore typically valued by either the degradation product (compound A) and the impurity of the product (compound B). The pharmaceutical dosage forms of lamotrigine need to be analyzed to verify that the active agent remains stable to degradation either during the manufacture of the drug product and after several years of storage. Pharmaceutical dosage forms, which include conventional oral tablets and dispersion tablets, are therefore typically rated for compound A only. The tested sample of the substance of the medicament or the product of the medicament to be analyzed can be evaluated by one or more conventional analytical techniques. Analytical techniques include high performance liquid chromatography (HPLC) and thin layer chromatography (TLC). The results obtained are compared with the results obtained from the experiments of a substantially pure reference sample of compound A or B. The content of the or each compound in the test sample can then be determined. In one aspect, the method of the invention is to assess the purity of a lamotrigine sample, and includes the steps of; (i) dissolving a sample of lamotrigine in a solvent to produce a solution sample; (ii) dissolving a sample of 3-amino-6- (2,3-dichlorophenyl) -1,2,4-triazine-5- (4H) -one or N- (5-amino-6- (2, 3) -dichlorophenyl) -1,2,4-triazine-3-yl] -2,3-dichlorobenzamide in a solvent to produce a standard solution of the reference marker (iii) subjecting the sample solution and the standard solution to thin layer to obtain a TLC chromatogram for each one, and (iv) estimate the intensity of any secondary spot obtained in the chromatogram of the sample solution, which corresponds in Rt value to the reference marker, against the spot due to the reference marker in the chromatogram of the standard solution In another aspect, the method of the invention is to assess the degradation stability of a pharmaceutical dosage form comprising lamotrigine, and includes the steps of: (i) dissolving a sample of the dosage form in a solvent to produce a sample solution; (ii) dissolve a sample 3-amino-6- (2,3-dichlorophenyl) -1,2,4-triazine-5- (4H) -one in a solvent to produce a standard reference marker solution; (iii) submit the sample solution and the standard solution to thin layer chromatography to obtain a TLC chromatogram for each; and (iv) estimating the intensity of any secondary spot obtained in the chromatogram of the sample solution, which corresponds in value to the reference marker against the spot due to the reference marker in the chromatogram of the standard solution. In a further aspect, the method of the invention is to undergo or assess the degradation stability of a pharmaceutical dosage form comprising lamotrigine, and includes the steps of: (i) dissolving a sample of the dosage form in a solvent to produce one or more sample solutions; (ii) dissolving a standard reference lamotrigine sample in a solvent to produce a standard solution; (iii) injecting the sample and the standard solutions into or onto an HPLC column, and (iv) determining the areas of the main peak of each solution and calculating from these, the reference marker of the compound 3-amino-6- (2 , 3-dichlorophenyl) -1,2,4-triazine-5- (4H) -one in the or each of the sample solutions. In this additional aspect it may be necessary to run a solution system properly through the HPLC column before step (iii) in order to determine the resolution factor between lamotrigine and any formulation excipient present in the pharmaceutical dosage form. In this case the method includes the additional step of: (iia) dissolving the lamotrigine and the reference standards of the formulation excipient in a solvent to produce a suitably HPLC system solution, and injecting the solution appropriately into the HPLC column for Determine the resolution factor between lamotrigine and the formulation excipient. The formulation excipient, for example, can be sodium saccharin. The invention also provides the use of a compound selected from 3-amino-6- (2,3-dichlorophenyl) -1,2,4-triazine-5- (4H) -one and N- [5-amino- β- (2,3-dichlorophenyl) -1,2,4-triazine-3-yl] -2,3-dichlorobenzamide as a reference marker in the analysis of the purity or stability for the degradation of a sample of lamotrigine or a sample of a pharmaceutical dosage form comprising lamotrigine. In practice lamotrigine is relatively pure and is rapidly stable in storage. The analytical titration of the same substance of the medicament, or of a pharmaceutical dosage form containing lamotrigine, therefore, serves primarily to confirm that compounds A and / or B are absent or present only at levels below the limit of detection for the analytical technique in question (approximately 0.3% w / w for TLC and 0.06% w / w for HPLC). As an alternative for the experimentation or testing of a sample of the reference marker, separately each time it is desirable to assess the data obtained from the analysis of a sample of the substance of the drug or the drug product, a parameter known as the Response factor (R) can, for example, be used. A Response Factor is a previously determined proportion of a numerical result obtained by the evaluation of a sample of compound A or B using a given analytical technique, to the corresponding numerical result obtained by the titration of pure lamotrigine at an equivalent concentration. The numerical result in question can be, for example, a response value of the HPLC peak area. Further, giving the appropriate analytical results for pure lamotrigine and for an experienced sample of a pharmaceutical dosage form of lamotrigine, the known Response factor for compound A or B can be used to calculate the amount of the particular reference marker in the Experimented sample. The calculation can be illustrated with reference to the results of the HPLC analysis as follows:
% p / p of compound A or B in = Ar x Ws the test sample relative As R to lamotrigine
where:
Ar = main peak area of the compound in the HPLC test solution As = main peak area of lamotrigine alone in the standard solution HPLC R = Compound Response Factor Ws ~ weight (in mg) of the standard intake
For compound A of the invention, the response of the HPLC factor is 0.79.
The invention will be further described in the following Examples.
Reference Example 1: Preparation of lamotrigine 1-1 1-2 (b) (d)
Stage a: Preparation of 1.2
A solution of 1.1 (1 mole), tertiary butyl alcohol, water and sodium hydroxide (2 moles) was stirred and a solution of hydrogen peroxide (35% w / w, 4 moles) was added at 50-60 ° C during 3 hours. After stirring at 55-60 ° C for 30 minutes, the tertiary butyl alcohol was removed by distillation and the aqueous solution was washed with toluene. The aqueous solution was acidified to pH 1-2, and the product was filtered and washed with water. The wetted solid was used either directly in the next stage of the process or dried at 8 ° -90 ° C to provide a white solid in 75% yield.
Stages (b) and (c) Preparation of 1
A solution of 1.2 (1 mole) in toluene was stirred and dried by distillation. Then it was cooled and pyridine (0.005 mole) was added, followed by the slow addition of thionyl chloride (1.1 mole). The solution was heated under reflux for 1 hour, then concentrated in vacuo to provide crude 1.3. Potassium iodide- (1-2 moles) was added, followed by cuprous cyanide (1.2 moles) and any remaining solvent was removed by distillation until the internal temperature was 140-144 ° C. This temperature was maintained for 18-24 hours, then the reaction mixture was cooled, diluted with toluene and filtered to remove the inorganic salts. The solution was evaporated to dryness in vacuo at 60-70 ° C, and the residual oil was crystallized from petroleum either to obtain 1.4 as a yellow solid in a yield of 77%.
Stage d: Preparation of 1.5
The bicarbonate of aminoguanidine (1.75 moles) was dissolved in a solution of sulfuric acid 9.3-10.0 M. A solution of 2,3-dichlorobenzoyl cyanide (1 mole) in acetonitrile was added and the suspension was stirred at 20-30 ° C. for 42-48 hours. The crude product was filtered and washed with water. The solid was added to the sodium hydroxide solution under 35 ° C, then the product was filtered, washed with water and dried at 8 ° -90 ° C to obtain 1.5 as a yellow solid in a 66% yield.
Stage (e) Preparation of raw lamotrigine
A solution of 1.5 in propan-1-ol was stirred under reflux for 90-120 minutes, cooled to 15-25 ° C and the crude lamotrigine was filtered to obtain a pale yellow solid in a yield of 90% (on a dry basis ). The crude lamotrigine was purified by recrystallization of propan-1-ol, using mineral charcoal, and cooling the solution at 15-25 ° C. The solid was filtered, washed with propan-1-ol and dried at 80-90 ° C to obtain pure lamotrigine.
Example 1: Preparation of 3-amino-6- (2,3-dichlorophenyl) -1,2-triazine-5 (4H) -one (Compound A)
Lamotrigine (614.4g, 2.4 moles) and sodium hydroxide (242.4g) were combined with water (60 1) and refluxed with stirring for 24 hours. The resulting solution was cooled to 15-20 ° C and the pH adjusted from 5.5 to 6.0 with hydrochloric acid. The resulting solid was filtered and dried for 24 hours, first at 40 ° C, then at 50 ° C and finally at 70 ° C. The purity of the product was determined by HPLC as 82%. The HPLC conditions were as follows: Column:. Spherisorb 50 DS Eluent: Water (600): Acetonitrile (400) 0.5 M, sulfuric acid (15) Flow ratio: 2.0 ml / min Sample: 50 mg in 100 ml Injection: 5 or 10 μl Detection: 270 nm
A sample of 82% crude product (583g) was combined with propanol (151) and refluxed for 0.5 hour. Following the extraction and drying, Compound A was obtained in a pure 96.2% form as determined by HPLC using the conditions described above. An additional purification step was carried out by refluxing a sample of 96.2% of the crude product in propanol (51) for 1 hour, with stirring. The solid was filtered and dried at 40 ° C under vacuum to obtain the title compound (460.7g, 74.7% yield). The final product has a purity of 99.1% as determined by HPLC. The product has the following physical characteristics:
Molecular formula: C9H6C12N 0 Molecular mass: 257.08
Elemental analysis C H N calculated 42.06% 2.35% 21.80% found 42.02% 2.25% 21.23%
TLC (silica gel with chloroform: methanol: glacial acetic acid: Butan-I-ol 80: 10: 10: 5) - main stain at RF = 0.3? -trace to RF 0.82
infra-red (Kbr): vmax (cm 3301, 3127, 1655 1556, 1484, 1413, 1290, 1200, 1056 812, 785, 748 737, 719
**? nmr: d / ppm in d6-dmso (22 mg ml ^ / SOOMHz: 12.43 (1H, bs), 7.71, 7.68 (lH, m), 7.40 (2H, m), 6.99 (2H, bs), 3.3 (bs) (water)), 2.5 (q (dmso-d5)), or (s, TMS), Mass spectrum: m / z: 256 (M +), 258 and 260 (associated isotope ions), 221, 186, 171, 85 (fragments of ions as indicated by aba or:)
Example 2: Preparation of N- [5-amino-6- (2,3-dichloro-enyl) -1,2,4-triazine-3-yl] -2,3-dichlorobenzamide (Compound B)
Lamotrigine (512.OOg, 2.00 mol) was dissolved in pyridine (3 I) and 2,3-dichlorobenzoyl chloride (873. 96% pure OOg, equivalent to 838.10 g, 4.00 mol) was added under 35 ° C with stirring under anhydrous conditions. The acid chloride was added in two equal portions. The second portion of the acid chloride was added after 30 minutes of the start of the reaction and stirred under 35 ° C for about 30 more minutes.
The resulting mixture was concentrated for dryness and then triturated with chloroform (1300 ml) for 10 minutes with stirring. The resulting solid was filtered and washed with chloroform (3 x 50 ml) and dried at room temperature to a weight of 308 g, 36% (based on compound B). A sample of the crude product (50.Og) was heated with methanol (500 ml) at reflux temperature with stirring for 1 hour and the resulting hot mixture was filtered to provide compound B in a very pure form (37.Og). The product has the following physical characteristics:
Molecular Formula: Ci6H5Cl4N5? Molecular mass: 429.09
Infra-red (KCl): vmax (cm "• ii 3466, 3300, 3202 3365, 3277, 1687, 1625, 1559, 1414, 1387, 1538, 1459, 1253, 1157, 1136, 1116, 790, 775, 741, 724
• - • H nmr: d / ppm in d6-dmso (39 mg ml 1) / 300MHz: 10.85 (lH, bs); 7.8 (1H, bs); 7.1 (1H, bs); 7.77 (1H, d, J = 7Hz); 7.73 (1H, d, J = 7Hz); 7.5 (4H, m); 4.08 (bs); 3.32 (bs, water); 3.16 (s); 2.50 (quintet, dmso-ds); 2.31 (methane sulfonate); 0.00 (s, TMS).
Mass spectroscopy
Chemical ionization (Cl): m / z: 428 (M + 1) +; 430, 432 and 434 (associated isotope ions)
Impact of the electron (El): m / z: 428 (m + l) +; 392, 199, 185, 173, 145 (fragments of ions as indicated below :)
Example 3: Assay for lamotrigine and Compound A in a drug product (dispersion tablets) by HPLC
Preparation of suitably standard and system solutions
A standard solution was prepared by transferring the standard reference lamotrigine (approximately 100 mg, accurately weighed) into a 500 ml volumetric flask. Methanol (200 ml) was added to dissolve the solid, followed by hydrochloric acid (100 ml, 0.5 M) with mixing. The resulting solution was allowed to cool to room temperature and was diluted to volume with water.
A solution system was suitably prepared by transferring the standard reference lamotrigine (100 mg) and standard reference sodium saccharin (20 mg) in a 500 ml volumetric flask and diluting to volume with water.
Preparation of sample solutions
SI Solution
From the information given in Table 1 below, the SI solution was prepared by transferring the specified number of tablets to the specified volumetric flask. The specified volume of hydrochloric acid (0.5 M) was added and the solution was stirred until the tablets disintegrated and the resulting effervescence ceased. The specified volume of methanol was added and the solution was placed in an ultrasonic bath for 10 minutes. The solution was then allowed to equilibrate at room temperature and diluted to volume with water.
Table 1
Solution S2
a) 5 mg tablets
The SI solution, prepared as described above, was filtered through a No. 1 Whatman filter paper. The first 10 ml of the filtrate were discharged. The clear filtrate was the sample solution.
b) 25 mg, 50 mg, 100 mg and 200 mg tablets
The SI solution was filtered through a No.l Whatman filter paper. The first 10 ml of the filtrate were discharged.
The filtrates (10.0 ml) were transferred into a 50 ml volumetric flask and diluted to volume with a mixture of hydrochloric acid (0.5 M): water: methanol (20:20:40 v / v).
Chromatographic procedure
The following conditions were used:
Column: 125 x 4.6 mm (ie,) packed in stainless steel with Spherisorb 5 μm ODS 1 or validated equivalent.
Mobile phase: water / methanol / acetonitrile / glacial acetic acid / n-octylamine (700/100/100/20 / 0.5 v.v)
Room temperature
Flow rate: 2.0 ml / minute
Wavelength: 275 nm
injection volume: 20- μl Notes: (a) The columns were conditioned before being used by pumping through methanol at a slow flow rate for approximately 30 minutes. (b) The specificity was influenced by the proportion of water to methanol: acetonitrile (c) Methanol decrease: the acetonitrile content of the mobile phase increases the resolution of lamotrigine and sodium saccharin; The retention time of all components also increases. (d) Minor changes in the methanol concentration of the acid to the acetonitrile ratio and the acetylamine levels have no significant impact on the chromatographic specificity. (e) after use, the column was washed with methanol: water (1.9) followed by methanol.
Injection procedure:
When stable petroleum jelly was obtained, the suitably system solution was injected and the resolution factor was calculated between lamotrigine and sodium saccharin. The symmetric factor and the number of the theoretical plates for lamotrigine were also calculated using the General Method of the European Pharmacopedia for the calculation of the appropriate parameters of the system). The values obtained were as follows: Resolution 10 Symmetric factor 1.2 No. of theoretical plates 1400 The standard solution and the sample solution S2 were then injected into the column.
Calculations
From the main peak area of the standard solution the response factor (R) for lamotrigine was calculated as follows:
R Ws x P AS x 100
where :
Ws = weight (mg) of the standard lamotrigine intake P =% purity of the reference standard lamotrigine s = lamotrigine peak area in the injection of the standard solution. . ...
The main response factor (MR) was used to calculate the lamotrigine content of the sample as follows:
Lamotrigine content (mg / tablet) = Au x MR x DFu DFs x N
Lamotrigine content Au x MR x DFu x 100 (% of the label claim) DFs x N x L
where :
Au = area of the lamotrigine peak in the S2 injection of the sample solutions N = number of tablets rated DFs = dilution factor for the standard solution (500) DFu = dilution factor for the sample solution (250 for tablets) 5 mg, 1000 for 25 mg tablets,
1250 for 50 mg tablets, 2500 for 100 mg tablets and
5000 for 200 mg tablets). L = label claim The content of any secondary component eluting at the time of resolution of the compound. A was calculated with respect to standard lamotrigine as follows:
Content of Compound A (w / w) with respect to lamotrigine
= Ai x Ws AS x 0.79
where Ai = area of the peak for compound A in an injection S2 of sample solution Ws = weight (mg) of the standard reference lamotrigine intake As = area of the lamotrigine peak in a standard solution injection 0.79 response factor relative for compound A
Similarly, the level of any of the other secondary components related to lamotrigine was calculated on a% w / w basis assuming a relative response factor of 1.0. The following results were obtained in Table 2:
Table 2
Example: Determination of compounds A and B in a medical substance (lamotrigine, particle size 125 μ) by TLC.
Test 1 - compound B
The following standard and test solutions were prepared in a mixture of equal volume of methanol and 2-methoxyethanol solution 1: 5.0% w / v of the solution of the sample solution 2: 5.0% w / v of the sample solution of reference lamotrigine solution 3: 0.02% w / v solution of compound B solution 4: 1.0 ml of solution 2 diluted to 250 ml. solution 5: 10.0 ml of solution 4 diluted with 10.0 ml of solution 3 solution 6: 7.5 ml of solution 5 diluted to 10.0 ml solution 7: 5.0 ml of solution 5 diluted to 10.0 ml solution 8: 2.5 ml of solution solution 5 diluted to 10.0 ml
The following operating conditions of
TLC:
plate: 20 x 20 cm plate covered with a 0.25 ml layer of silica gel 60 F 254 mobile phase: ethyl acetate / glacial acetic acid / methanol (85: 10: 5 v / v) charged spot: 10 μl each solution length of the run: 10 cm
the TLC plate was allowed to dry in air and then checked under ultraviolet light at 254 nm. The test did not validate at least the chromatogram obtained with solution 5 showing 2 clearly separated spots and the corresponding spots in the chromatogram of solution 8 were both detectable. The intensity of any of the corresponding secondary spots in R value was estimated to compound B contained in the chromatogram of solution 1 against the spots due to compound B obtained in the chromatograms of solutions 5, 6, 7 and 8 (equivalent to 0.2, 0.15, 0.1 and 0.05% w / w, respectively). The intensity of any of the secondary spots obtained in the chromatogram of solution 1 against the spots due to lamotrigine obtained in the chromatograms of solutions 5,6,7 and 8 was estimated.
(equivalent to 0.2, 0.15, 0.1 and 0.05%, respectively). The Rf values obtained were: lamotrigine: 0.20 compound B: 0.60
Test 2 Compound A The following standard solutions and tests were prepared in a mixture of equal volume of methanol and 2-methoxyethanol. solution 1: solution 1 of the test .1 up solution 2: 0.05% w / v of the solution of the compound A.
The following TLC operating conditions were made:
plate: 20 x 20 cm plate covered with a 0.25 mm layer of silica gel 60 F 254
mobile phase: chloroform / methanol / glacial acetic acid / butan-1-ol (80: 10: 10: 5 v / v)
charged spot: 10 μl of solution 1, 1 μl and 2 μl of solution 2
Length of the run: 15 cm
the TLC plate was allowed to dry in air and then checked under ultraviolet light at 254 nm. The intensity of any of the secondary spots of the corresponding Rf value in the chromatogram of solution 1 against the spots was estimated due to compound A in solution 2 (equivalent to 0.1 and 0.2% w / w). The Rf values obtained were: lamotrigine: 0.25- compound A: 0.37 Example 5: Determination of compound A in a medical product (100 mg lamotripine tablets) by TLC.
Preparation of "sample solutions and standards
A standard solution was prepared by accurately weighing approximately 10 mg of compound A into a 100-ml volumetric flask. The compound was dissolved in, and diluted to volume with, methanol. A sample of solution was prepared by transferring a quantity of powdered tablets, equivalent to 500 mg of lamotrigine in a 50 ml volumetric flask. The powder was dispersed in 15 ml of hydrochloric acid (0.1 M) and a mixture of methanol: 2-methoxyethanol (15/15 v / v, 30 ml) was added. The flask was placed in an ultrasonic bath for 15 minutes. The solution was then allowed to cool to room temperature and diluted to the volume with the solvent mixture methanol: 2-methoxyethanol. The solution was mixed well and filtered through filter paper (Whatman No.l). The clear filtrate was the test solution.
Test method The following operating conditions of TLC were used.
license plate; . 20 x 20 cm plate covered with a 0.25 mm layer of silica gel 60 F 254
mobile phase, chloroform / methanol / glacial acetic acid / butan-1-ol (80: 10: 10: 5 v / v)
charged spot: 10 μl of test solution, 3 μl and 5 μl of the standard solution
Length of the run: 15 cm
The plate was allowed to dry in a stream of air and was checked under ultra violet light at 254 nm. The intensity of any of the other spots was estimated instead of the main spot obtained in the chromatogram of the sample solution against the spot obtained with 3 μl of the standard solution (corresponding to 0.3% w / w of impurity). The combined intensity of all secondary spots does not. was greater than 5 μl loaded with the standard solution (corresponding to 0.3% w / w of impurities). The Rf values were as follows: Lamotrigine: 0.20 compound A: 0.34
Through this specification and the appended claims, it is understood that the words "comprises" and "includes" and variations such as "comprise" "comprising", "include" "including" are also interpreted inclusive, unless the context requires otherwise. That is, the use of these words may involve the inclusion of an element or elements not specifically related. The present invention has been described by way of example only, and it is recognized that modifications thereto which are within the scope and spirit of the appended claims, and which may be obvious to an expert based on the description herein, are also considered to be included within the invention.
Claims (11)
1. A method of titrating the purity or stability to degradation of a lamotrigine sample or a pharmaceutical dosage form comprising lamotrigine, characterized in that the method comprises the titration of said sample by the presence of a compound selected from 3-amino -6- (2,3-dichlorophenyl) -1,2,4-triazine-5- (4H) -one and N- [5-amino-6- (2,3-dichlorophenyl) -1, 2, 4- triazine-3-yl] -2, 3-dichlorobenzamide.
2. A method according to claim 1, for the assessment of the purity of a lamotrigine sample, characterized in that it includes the steps of: (i) dissolving a sample of lamotrigine in a solvent to produce a solution sample; (ii) dissolving a sample of 3-amino-6- (2,3-dichlorophenyl) -1,2-triazine-5- (4H) -one or N- (5-amino-6- (2, 3- dichlorophenyl) -1,2-triazine-3-yl] -2,3-dichlorobenzamide in a solvent to produce a standard solution of the reference marker (iii) subjecting the sample solution and standard solution to thin-layer chromatography to obtain a TLC chromatogram for each one, and (iv) to estimate the intensity of any secondary spot obtained in the chromatogram of the sample solution, which corresponds in Rf value to the reference marker, against the spot due to the reference marker in the chromatogram of the standard solution.
3. A method according to claim 1, for the assessment of the degradation stability of a pharmaceutical dosage form comprising lamotrigine, characterized in that it includes the steps of: (i) dissolving a sample of the dosage form in a solvent for produce a sample solution; (ii) dissolving a sample of 3-amino-6- (2,3-dichlorophenyl) -1,2,4-triazine-5- (4H) -one in a solvent to produce a standard reference marker solution; (iii) submit the sample solution and standard solution to thin layer chromatography to obtain a TLC chromatogram for each; and (iv) estimate the intensity of any secondary spot obtained in the chromatogram of the sample solution, which corresponds in value to the reference marker against the spot due to the reference marker in the chromatogram of the standard solution.
4. A method according to claim 1, for the assessment of the degradation stability of a pharmaceutical dosage form comprising lamotrigine, characterized in that it includes the steps of: (i) dissolving a sample of the dosage form in a solvent for produce one or more sample solutions; (ii) dissolving a standard reference lamotrigine sample in a solvent to produce a standard solution; (iii) injecting the sample and the standard solutions into or onto an HPLC column, and (iv) determining the areas of the main peak of each solution and calculating from these, the reference marker of the compound 3-amino-6- (2 , 3-dichlorophenyl) -1,2-triazine-5- (4H) -one in the or each of the sample solutions.
5. A compound characterized in that it is N- [5-amino-6- (2,3-dichlorophenyl) -1,2,4-triazine-3-yl] -2,3-dichlorobenzamide of formula (B)
6. A sample of a compound according to claim 6, characterized in that it is in a substantially pure form.
7. A sample according to claim 6, characterized in that it has a purity level of 90% or more.
8. A process for producing a compound as defined in claim 5, characterized in that the process comprises: (il) reacting 2 equivalents of 2,3-dichlorobenzoyl chloride with 1 equivalent of lamotrigine dissolved in pyridine at a temperature of less than 35 ° C; or (ii) cycling a compound of formula (I): in propan-1-ol under reflux conditions.
9. A process according to claim 8, characterized in that, in step (ii), the compound of formula (I) is produced by reacting it together with compounds of formulas (II) and (III): < «) (Lll) in the presence of a mineral acid,
10. A process according to claim 9, characterized in that the compound of formula (II) is produced by the treatment of 2,3-dichlorobenzoyl cyanide with a solution of aminoguanidine bicarbonate in sulfuric acid.
11. The use of a compound selected from 3-amino-6- (2,3-dichlorophenyl) -1,2,4-triazine-5- (4H) -one and N- [5-amino-6- (2 , 3-dichlorophenyl) -1,2,4-triazine-3-yl] -2,3-dichlorobenzamide as a reference marker in the assessment of the purity or stability to degradation of a lamotrigine sample or a dosage form Pharmaceutical comprising lamotrigine.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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GB9812413.4 | 1998-06-10 |
Publications (1)
Publication Number | Publication Date |
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MXPA99002202A true MXPA99002202A (en) | 2000-08-01 |
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