Chemistry: analytical and immunological testing – Heterocyclic carbon compound – Hetero-n
Reexamination Certificate
1999-03-10
2001-12-25
Soderquist, Arlen (Department: 1743)
Chemistry: analytical and immunological testing
Heterocyclic carbon compound
Hetero-n
C436S008000, C436S091000, C436S098000, C436S161000, C436S162000, C514S242000, C544S182000
Reexamination Certificate
active
06333198
ABSTRACT:
The present invention relates to compounds useful as reference markers for the analysis of lamotrigine and pharmaceutical formulations thereof.
In order to secure marketing approval for a new drug product, a drugs manufacturer must submit detailed evidence to the appropriate regulatory authority to show that the product is suitable for release on to the market. The regulatory authority must be satisfied, inter alia, that the active agent is acceptable for administration to humans and that the particular formulation which is to be marketed is free from impurities at the time of release and has an appropriate shelf-life.
Submissions made to regulatory authorities therefore typically include analytical data which demonstrate (a) that impurities are absent from the drug at the time of manufacture, or are present only at a negligible level, and (b) that the storage stability, i.e. shelf-life, of the drug is acceptable. These data are usually obtained by testing the drug 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, by-products which arise during synthesis of the active agent, residual solvent, isomers of the active agent, contaminants which were present in materials used in the synthesis of the active agent or in the preparation of the pharmaceutical formulation, and unidentified adventitious substances. Other impurities which may appear on storage include substances resulting from degradation of the active agent, for instance by oxidation or hydrolysis.
Lamotrigine is 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, of formula (IV)
It is a known compound which is useful in the treatment of disorders of the central nervous system (CNS), in particular epilepsy, as described for example in EP-A-0021121. Both lamotrigine per se and its pharmaceutical formulations are manufactured relatively free from impurities. In particular, lamotrigine remains stable during the manufacture of its pharmaceutical formulations.
It has now been appreciated that two compounds can be used as reference markers for the analysis of lamotrigine or of pharmaceutical dosage forms comprising lamotrigine. One of the compounds is a potential degradation product of lamotrigine and the other is a potential contaminant arising from side reactions during the synthesis of lamotrigine.
The present invention therefore provides a method of testing the purity or stability to degradation of a sample of lamotrigine or a pharmaceutical dosage form comprising lamotrigine, which method comprises assaying the said sample for 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. In the method of the invention the said compound is acting 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 is produced upon hydrolysis of the drug. The compound of formula A may therefore be produced by hydrolysing lamotrigine under basic conditions. The hydrolysis is suitably conducted by combining lamotrigine and a base with water, and then heating the resulting solution under reflux. The base is preferably a strong base, for instance an alkali metal hydroxide. Sodium hydroxide is particularly preferred. The basic solution in water may be heated under reflux for a period of from 1 hour to 48 hours, for instance from 10 hours to 36 hours, preferably for 24 hours.
The other compound used as a reference marker is novel. 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) may be produced directly by treating lamotrigine with 2,3-dichlorobenzoyl chloride in pyridine. However, it has utility as a reference marker for lamotrigine because it is a potential contaminant arising from side reactions which can occur during the synthesis of the drug. In practice the level of this contaminant is controlled at a maximum of 0.5% in the crude lamotrigine by thin-layer chromatography (TLC). Recrystallisation of crude drug of this quality then results in the production of lamotrigine meeting the required purity level for commercial production of not more than 2% total impurities.
The synthesis of lamotrigine is illustrated in Reference Example 1. 2,3-Dichlorobenzoyl cyanide, which is intermediate 1.4 in that synthesis, may 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 sulphuric acid, which is step (d) in Reference Example 1, the adduct (Z)-2-(2,3-dichlorophenyl)-2-(guanidinoimino)acetonitrile (intermediate 1.5) is produced. The anhydride contaminant can then react with the latter adduct to form (Z)-2-(2,3-dichlorophenyl)-2-[N′-(2,3-dichlorobenzoyl)guanidinoimino]acetonitrile, which is the direct precursor to compound B. Cyclisation of the precursor in propan-1-ol under reflux yields compound B.
The present invention therefore further provides a process for producing compound B, which 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) cyclising a compound of formula (I):
in propan-1-ol under reflux.
In step (ii), the compound of formula (I) is produced by reacting together compounds of formulae (II) and (Ill):
in the presence of a mineral acid, for instance sulphuric acid.
The compound of formula (II) is produced by treatment of 2,3-dichlorobenzoyl cyanide with a solution of aminoguanidine bicarbonate in sulphuric acid.
When compounds A and B are used as reference markers they must be in a suitably pure form. Compounds A and B produced as described above may be purified if necessary to achieve the desired purity level. The process of the invention for producing compound B as described above may therefore include the additional step of purifying the resulting compound.
Purification may be carried out by conventional methods which are routine in organic synthesis. For instance, the compound may be heated in an organic solvent such as a C
1
-C
6
alkanol, filtered and dried under vacuum. Heating is typically carried out at the reflux temperature of the solvent. A C
1
-C
6
alkanol is preferably propanol. Alternatively the compound may be recrystallised from a hot C
1
-C
6
alkanol solvent, preferably hot propanol.
Compounds A and B are preferably finally recovered in substantially pure form. The purity level of a final sample of either compound is typically at least 80%, for example at least 85%, more preferably at least 90%. Purity levels above 90% may be desirable but are not essential. The purity level may be, for instance, at least 92%, at least 95% or at least 98%. Even more desirably the purity level is 99% or 99.5%.
Either lamotrigine itself (also referred to as drug substance) or a pharmaceutical dosage form comprising lamotrigine (also referred to as drug product) may be analysed for purity or stability to degradation. For instance, it is necessary to ensure that lamotrigine is pure following its manufacture. The drug substance is therefore typically assayed for both the degradation product (compound A) and the process impurity (compound B). Pharmaceutical dosage forms of lamotrigine need to be analysed to check that the active agent remains stable to degradation both during manufacture of the drug product and after several years' storage. Pharmaceutical dosage forms, which include conventional oral tablets and dispersible tablets, are therefore typically assayed for compound A only.
The test sample of drug substance or dr
Edmeades Lorraine Mary
Griffith-Skinner Nigel Arthur
Hill Derek Anthony
Hill Graham Thronton
Packham Terence William
Glaxo Wellcome Inc.
Nixon & Vanderhye
Soderquist Arlen
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