CA2692866A1 - A method for analysing memantine, or a pharmaceutically acceptable salt thereof, and its impurities using gas chromatography - Google Patents
A method for analysing memantine, or a pharmaceutically acceptable salt thereof, and its impurities using gas chromatography Download PDFInfo
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- CA2692866A1 CA2692866A1 CA 2692866 CA2692866A CA2692866A1 CA 2692866 A1 CA2692866 A1 CA 2692866A1 CA 2692866 CA2692866 CA 2692866 CA 2692866 A CA2692866 A CA 2692866A CA 2692866 A1 CA2692866 A1 CA 2692866A1
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- memantine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/84—Purification
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/025—Gas chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
- G01N30/14—Preparation by elimination of some components
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
Abstract
The present invention relates to a novel assay for the analysis of memantine and related compounds.
Description
Novel Assay Methods Technical Field The present invention relates to a novel assay for the analysis of memantine and related compounds.
Background Art In order to secure marketing approval for a pharmaceutical product, a manufacturer must submit detailed evidence to the appropriate regulatory authorities to show that the product is suitable for release on to the market. The regulatory authority must be satisfied, inter alia, that the product is acceptable for administration to humans and that the particular pharmaceutical composition which is to be marketed is free from impurities at the time of release and that it has an acceptable storage stability (shelf-life).
Submissions made to regulatory authorities therefore must include analytical data which demonstrate that impurities are absent from the active pharmaceutical ingredient (API) at the time of manufacture, or are present only at a negligible level, and that the shelf-life of the pharmaceutical composition is acceptable.
Potential impurities in APIs and pharmaceutical compositions include residual amounts of synthetic precursors to the API, 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 API or in the preparation of the pharmaceutical composition, 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.
The health authorities have very stringent standards and manufacturers must demonstrate that their product is relatively free from impurities (within certain agreed limits) and that this standard is reproducible for each batch of pharmaceutical product that is produced.
Background Art In order to secure marketing approval for a pharmaceutical product, a manufacturer must submit detailed evidence to the appropriate regulatory authorities to show that the product is suitable for release on to the market. The regulatory authority must be satisfied, inter alia, that the product is acceptable for administration to humans and that the particular pharmaceutical composition which is to be marketed is free from impurities at the time of release and that it has an acceptable storage stability (shelf-life).
Submissions made to regulatory authorities therefore must include analytical data which demonstrate that impurities are absent from the active pharmaceutical ingredient (API) at the time of manufacture, or are present only at a negligible level, and that the shelf-life of the pharmaceutical composition is acceptable.
Potential impurities in APIs and pharmaceutical compositions include residual amounts of synthetic precursors to the API, 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 API or in the preparation of the pharmaceutical composition, 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.
The health authorities have very stringent standards and manufacturers must demonstrate that their product is relatively free from impurities (within certain agreed limits) and that this standard is reproducible for each batch of pharmaceutical product that is produced.
The tests that are required to satisfy the relevant health authorities that the API and pharmaceutical compositions are safe and effective include a purity assay, content uniformity test, dissolution testing and related substances test. The purity assay determines the purity of the test product (analyte) when compared to a standard of a known purity, while the related substances test is used to quantify all of the impurities present in the product. The content uniformity test ensures that batches of product (e.g. a tablet) contain a uniform amount of API and the dissolution testing ensures that each batch of product has a consistent dissolution and release of the API.
When developing these methods for the analysis of either the API or the pharmaceutical composition (e.g. the tablet or capsule), the technique of choice would usually be High Performance I.iquid Chromatography (HPLC) combined with a UV-Visible Spectrometer.
The API and any impurities that are present in the mixture are separated on the HPLC
stationary phase and they can be quantified by detection and measurement via the W-Visible spectrometer.
HPLC is a chromatographic separating technique in which high-pressure pumps force the substance or mixture being analysed (analyte) together with a liquid solvent -the mobile phase (also referred to as the eluent) - through a separating column containing the stationary phase. If a constituent substance interacts strongly with the stationary phase, it remains in the column for a relatively long time, whereas a substance that does not interact with the stationary phase as strongly leaves the column sooner. Depending on the strength of the interactions, the various constituents of the analyte appear at the end of the separating column at different times - retention times - where they can be identified by means of a suitable detector.
This method works well for compounds that have a chromophore, that is to say compounds that absorb energy in the UV-Visible range of the electromagnetic spectrum.
However, for other compounds which do not contain a chromophore, an alternative detection method must be found. This sometimes involves derivatising the subject compound with a reagent such that the resultant analyte contains a chromophore which can be detected using a UV-Visible detector.
When developing these methods for the analysis of either the API or the pharmaceutical composition (e.g. the tablet or capsule), the technique of choice would usually be High Performance I.iquid Chromatography (HPLC) combined with a UV-Visible Spectrometer.
The API and any impurities that are present in the mixture are separated on the HPLC
stationary phase and they can be quantified by detection and measurement via the W-Visible spectrometer.
HPLC is a chromatographic separating technique in which high-pressure pumps force the substance or mixture being analysed (analyte) together with a liquid solvent -the mobile phase (also referred to as the eluent) - through a separating column containing the stationary phase. If a constituent substance interacts strongly with the stationary phase, it remains in the column for a relatively long time, whereas a substance that does not interact with the stationary phase as strongly leaves the column sooner. Depending on the strength of the interactions, the various constituents of the analyte appear at the end of the separating column at different times - retention times - where they can be identified by means of a suitable detector.
This method works well for compounds that have a chromophore, that is to say compounds that absorb energy in the UV-Visible range of the electromagnetic spectrum.
However, for other compounds which do not contain a chromophore, an alternative detection method must be found. This sometimes involves derivatising the subject compound with a reagent such that the resultant analyte contains a chromophore which can be detected using a UV-Visible detector.
An alternative detection method is to replace the UV-Visible detector with a fluorescence detector. However, this technique requires the analyte to have a fluorophore but, as compounds which fluoresce are very rare, the subject compound must usually be derivatised with a chemical moiety which does fluoresce. This again involves derivatising the analyte, this time with a reagent to produce a fluorescent compound.
Derivatisation of the analyte is both time consuming and difficult to develop, particularly as some analytes will not have a functional group that is readily reacted with a derivatising reagent. In addition, some related substances may lose, on degradation, the functional group which can be derivatised and consequently these related substances will not be detected.
Another drawback of fluorescent derivatisation is that fluorescence detectors are not as common in the analytical laboratory of a pharmaceutical company as a UV-Visible detector.
Gas chromatography (GC) is regularly used by pharmaceutical companies to quantify residual solvents in both pharmaceutical compositions and APIs. The method generally involves dissolving the test sample in a quantity of one or more solvents, injecting the sample and volatilisation of the solvents using a headspace technique. The analytes are typically detected using a flame ionisation detector (FID) technique. These FID detectors can be used for almost all pharmaceutical products, as they are able to detect any analyte which contains a C-C or C-H bond. However, in order to analyse compounds using gas chromatography, the compounds must have a low enough vapour pressure to allow them to be volatilised prior to interaction with the chromatographic column.
Gas chromatography is a highly efficient, sensitive method, which is used to analyse complex mixtures of substances. It is a chromatographic technique that uses gas as the mobile phase and the gas is routed through a column of a defined diameter containing the stationary phase, a bighly viscous liquid. Most capillary columns are generally made of fused silica, have an internal diameter of between 0.1 and 0.5 mm and are between 5 and 60 m long. The inner column wall is coated with the stationary phase, whereby the film is 0.1 to 5 m thick. Hydrogen, helium or nitrogen is usually used as the carrier gas, whereby hydrogen offers significant advantages in terms of separating efficiency and analytical speed.
Derivatisation of the analyte is both time consuming and difficult to develop, particularly as some analytes will not have a functional group that is readily reacted with a derivatising reagent. In addition, some related substances may lose, on degradation, the functional group which can be derivatised and consequently these related substances will not be detected.
Another drawback of fluorescent derivatisation is that fluorescence detectors are not as common in the analytical laboratory of a pharmaceutical company as a UV-Visible detector.
Gas chromatography (GC) is regularly used by pharmaceutical companies to quantify residual solvents in both pharmaceutical compositions and APIs. The method generally involves dissolving the test sample in a quantity of one or more solvents, injecting the sample and volatilisation of the solvents using a headspace technique. The analytes are typically detected using a flame ionisation detector (FID) technique. These FID detectors can be used for almost all pharmaceutical products, as they are able to detect any analyte which contains a C-C or C-H bond. However, in order to analyse compounds using gas chromatography, the compounds must have a low enough vapour pressure to allow them to be volatilised prior to interaction with the chromatographic column.
Gas chromatography is a highly efficient, sensitive method, which is used to analyse complex mixtures of substances. It is a chromatographic technique that uses gas as the mobile phase and the gas is routed through a column of a defined diameter containing the stationary phase, a bighly viscous liquid. Most capillary columns are generally made of fused silica, have an internal diameter of between 0.1 and 0.5 mm and are between 5 and 60 m long. The inner column wall is coated with the stationary phase, whereby the film is 0.1 to 5 m thick. Hydrogen, helium or nitrogen is usually used as the carrier gas, whereby hydrogen offers significant advantages in terms of separating efficiency and analytical speed.
One basic prerequisite for gas chromatography is that the substance can be vaporised without decomposing - assuming that the substance is not available in gaseous form.
Substances with inadequate volatility can be derivatised selectively to produce more volatile substances, such as trimethylsilyl derivatives. The sample can be introduced into the capillary column by directly injecting a liquid sample or by extracting from the gas space of a sample vial. The latter method, referred to as headspace gas chromatography, is a special technique which offers a means of detecting low concentrations of highly volatile substances in liquid or solid samples.
An alternative detection method is to use mass spectrometry to detect the compounds separated by either gas chromatography (GC-MS) or liquid chromatography (LC-MS).
However, this method requires an expensive mass spectrometer which is not convenient for many analytical laboratories.
Memantine is the common chemical name for 3,5-dimethyltricyclo[3.3.1.13'7]decan-l-amine or 1-amino-3,5-dimethyladamantane. It is a moderate affinity N-methyl-D-aspartate (NMDA) receptor antagonist.
Bormann et al discloses in US patent 5061703 that memantine hydrochloride is useful for the prevention and treatment of cerebral ischemia after apoplexy, open-heart surgery, subarachnoidal hemorrhage, transient cerebro-ischemic attacks, perinatal asphyxia, anoxia, hypoglycemia, apnoea and Alzheimer's disease. In addition, a method of using memantine for reducing non-ischemic NMDA receptor mediated neuronal degeneration in a mammal is disclosed in US patent 5614560.
Memantine hydrochloride, represented by Formula I, is currently approved and marketed for the prevention and treatment of moderate to severe Alzheimer's disease.
NH2 HCl 4 CH3 (1) Methods for the preparation of memantine are known in the art and these methods include those disclosed in US patent 4122193 and by K Gerzon et al in J. Med. Chem., vol. 6, pages 760-763, 1963.
Memantine is very unusual as a pharmaceutical compound, because the molecule does not contain a chromophore. As discussed above, this means that the usual choice of HPLC
with UV-Visible detector is not feasible as a method for analysing memantine and its impurities. Memantine also contains very few functional groups, which means that derivatisation to form a compound containing a suitable chromophore or fluorophore would be difficult in addition to the general disadvantages of such a method.
Several methods have been published in the literature to analyse memantine, but these various methods are all encumbered with the problems described above as they involve derivatisation and/or specialist detection equipment.
Examples of more recent publications disclosing these methods include the following:
HPLC methods using fluorescent reagents to derivatise memantine in articles by T-H Duh et al in J. Chromatography A, vol. 987, pages 205-209, 2003, and J.
Chromatography A, vol.
1088, pages 175-181, 2005. An HPLC method using derivatisation and UV
detection by C
Shuangjin in J. Pharm. & Biomed. Analysis (in press). A liquid chromatography-mass spectrometry (LC-MS) method by MJ Koeberle et al in J. Chromatography B, vol.
787, pages 313-322, 2003. A specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method by AA Almeida et al in J. Chromatography B, vol. 848, pages 311-316, 2007. An electrophoretic method by N Reichova et al in Electrophoresis, vol.
23, pages 259-262, 2002.
Consequently, although several methods have been disclosed for the analysis of memantine and its impurities, there is still a need for an alternative method which avoids the problems associated with the known methods as discussed above.
Studies by the inventors have surprisingly shown that memantine is volatile enough to be used in GC without derivatisation and without decomposition. This enables analysis of the product using GC and a sample of memantine can be injected directly onto the column without the need for the headspace sampling described above. It is also possible to quantify the organic impurities of inemantine using this GC method. The inventors have also developed novel, efficient and reproducible methods of sample preparation for the GC
method.
Object of the Invention It is therefore an object of the present invention to provide a novel, alternative method for analysing memantine and its impurities whilst avoiding the typical prior art problems associated with derivatisation and the use of specialist detection methods.
Summary of the Invention Therefore, a first aspect of the present invention provides a method for analysing memantine, or a pharmaceutically acceptable salt thereof, and its impurities using gas chromatography. The method preferably involves a test sample of memantine being injected directly onto the GC column without headspace sampling. The method preferably uses flame ionisation detection. Memantine is preferably in the form of the free base, the hydrochloride salt or another acid addition salt.
The method of the first aspect of the invention can be used to analyse memantine API or memantine when prepared as a pharmaceutical composition. Preferably the memantine is prepared as a pharmaceutical composition.
The pharmaceutical compositions that can be analysed by the method of the first aspect of the invention include solid and liquid compositions and optionally comprise one or more pharmaceutically acceptable carriers or excipients. Solid form compositions include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid compositions include solutions or suspensions which can be administered by oral, injectable or infusion routes.
Substances with inadequate volatility can be derivatised selectively to produce more volatile substances, such as trimethylsilyl derivatives. The sample can be introduced into the capillary column by directly injecting a liquid sample or by extracting from the gas space of a sample vial. The latter method, referred to as headspace gas chromatography, is a special technique which offers a means of detecting low concentrations of highly volatile substances in liquid or solid samples.
An alternative detection method is to use mass spectrometry to detect the compounds separated by either gas chromatography (GC-MS) or liquid chromatography (LC-MS).
However, this method requires an expensive mass spectrometer which is not convenient for many analytical laboratories.
Memantine is the common chemical name for 3,5-dimethyltricyclo[3.3.1.13'7]decan-l-amine or 1-amino-3,5-dimethyladamantane. It is a moderate affinity N-methyl-D-aspartate (NMDA) receptor antagonist.
Bormann et al discloses in US patent 5061703 that memantine hydrochloride is useful for the prevention and treatment of cerebral ischemia after apoplexy, open-heart surgery, subarachnoidal hemorrhage, transient cerebro-ischemic attacks, perinatal asphyxia, anoxia, hypoglycemia, apnoea and Alzheimer's disease. In addition, a method of using memantine for reducing non-ischemic NMDA receptor mediated neuronal degeneration in a mammal is disclosed in US patent 5614560.
Memantine hydrochloride, represented by Formula I, is currently approved and marketed for the prevention and treatment of moderate to severe Alzheimer's disease.
NH2 HCl 4 CH3 (1) Methods for the preparation of memantine are known in the art and these methods include those disclosed in US patent 4122193 and by K Gerzon et al in J. Med. Chem., vol. 6, pages 760-763, 1963.
Memantine is very unusual as a pharmaceutical compound, because the molecule does not contain a chromophore. As discussed above, this means that the usual choice of HPLC
with UV-Visible detector is not feasible as a method for analysing memantine and its impurities. Memantine also contains very few functional groups, which means that derivatisation to form a compound containing a suitable chromophore or fluorophore would be difficult in addition to the general disadvantages of such a method.
Several methods have been published in the literature to analyse memantine, but these various methods are all encumbered with the problems described above as they involve derivatisation and/or specialist detection equipment.
Examples of more recent publications disclosing these methods include the following:
HPLC methods using fluorescent reagents to derivatise memantine in articles by T-H Duh et al in J. Chromatography A, vol. 987, pages 205-209, 2003, and J.
Chromatography A, vol.
1088, pages 175-181, 2005. An HPLC method using derivatisation and UV
detection by C
Shuangjin in J. Pharm. & Biomed. Analysis (in press). A liquid chromatography-mass spectrometry (LC-MS) method by MJ Koeberle et al in J. Chromatography B, vol.
787, pages 313-322, 2003. A specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method by AA Almeida et al in J. Chromatography B, vol. 848, pages 311-316, 2007. An electrophoretic method by N Reichova et al in Electrophoresis, vol.
23, pages 259-262, 2002.
Consequently, although several methods have been disclosed for the analysis of memantine and its impurities, there is still a need for an alternative method which avoids the problems associated with the known methods as discussed above.
Studies by the inventors have surprisingly shown that memantine is volatile enough to be used in GC without derivatisation and without decomposition. This enables analysis of the product using GC and a sample of memantine can be injected directly onto the column without the need for the headspace sampling described above. It is also possible to quantify the organic impurities of inemantine using this GC method. The inventors have also developed novel, efficient and reproducible methods of sample preparation for the GC
method.
Object of the Invention It is therefore an object of the present invention to provide a novel, alternative method for analysing memantine and its impurities whilst avoiding the typical prior art problems associated with derivatisation and the use of specialist detection methods.
Summary of the Invention Therefore, a first aspect of the present invention provides a method for analysing memantine, or a pharmaceutically acceptable salt thereof, and its impurities using gas chromatography. The method preferably involves a test sample of memantine being injected directly onto the GC column without headspace sampling. The method preferably uses flame ionisation detection. Memantine is preferably in the form of the free base, the hydrochloride salt or another acid addition salt.
The method of the first aspect of the invention can be used to analyse memantine API or memantine when prepared as a pharmaceutical composition. Preferably the memantine is prepared as a pharmaceutical composition.
The pharmaceutical compositions that can be analysed by the method of the first aspect of the invention include solid and liquid compositions and optionally comprise one or more pharmaceutically acceptable carriers or excipients. Solid form compositions include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid compositions include solutions or suspensions which can be administered by oral, injectable or infusion routes.
The term "impurities" as used herein throughout the specification can mean either impurities formed in the manufacture of the API or the pharmaceutical composition and/or impurities (or related substances) formed by degradation in the pharmaceutical composition on storage.
As described above, memantine is usually present as a hydrochloride salt for pharmaceutical use. This introduces an additional problem for analysis by gas chromatography, because the salt is very acidic and can corrode the column used for separation. Therefore, the salt must typically be neutralised before analysis to form memantine free base. A typical sample preparation technique in such cases would be to neutralise the memantine hydrochloride, present as the API or when present in a pharmaceutical composition, by reaction with an aqueous solution of an alkali, such as sodium hydroxide. The memantine free base thus formed and the corresponding impurities are then extracted using an organic solvent such as chloroform.
However, this extraction technique can be very unreliable for several reasons including variable extraction rates into the organic layer and incomplete separation of the aqueous and organic solvent layers. The inventors have found that the quantity of memantine that is recovered following this type of extraction process is not consistently reproducible and this leads to additional problems in quantitation of the related substances.
Consequently a second aspect of the invention affords a method for analysing memantine hydrochloride, or another pharmaceutically acceptable acid addition salt thereof, and its impurities using gas chromatography, wherein a test sample is prepared by mixing memantine hydrochloride or another pharmaceutically acceptable acid addition salt thereof, or a pharmaceutical composition comprising memantine hydrochloride or another pharmaceutically acceptable acid addition salt thereof, with one or more solvent(s) and a non-aqueous alkaline reagent, wherein the solvent(s) is capable of dissolving the memantine and the alkaline reagent.
The method of the second aspect of the invention preferably involves the test sample of memantine being injected directly onto the GC column without headspace sampling. The method preferably uses flame ionisation detection.
As described above, memantine is usually present as a hydrochloride salt for pharmaceutical use. This introduces an additional problem for analysis by gas chromatography, because the salt is very acidic and can corrode the column used for separation. Therefore, the salt must typically be neutralised before analysis to form memantine free base. A typical sample preparation technique in such cases would be to neutralise the memantine hydrochloride, present as the API or when present in a pharmaceutical composition, by reaction with an aqueous solution of an alkali, such as sodium hydroxide. The memantine free base thus formed and the corresponding impurities are then extracted using an organic solvent such as chloroform.
However, this extraction technique can be very unreliable for several reasons including variable extraction rates into the organic layer and incomplete separation of the aqueous and organic solvent layers. The inventors have found that the quantity of memantine that is recovered following this type of extraction process is not consistently reproducible and this leads to additional problems in quantitation of the related substances.
Consequently a second aspect of the invention affords a method for analysing memantine hydrochloride, or another pharmaceutically acceptable acid addition salt thereof, and its impurities using gas chromatography, wherein a test sample is prepared by mixing memantine hydrochloride or another pharmaceutically acceptable acid addition salt thereof, or a pharmaceutical composition comprising memantine hydrochloride or another pharmaceutically acceptable acid addition salt thereof, with one or more solvent(s) and a non-aqueous alkaline reagent, wherein the solvent(s) is capable of dissolving the memantine and the alkaline reagent.
The method of the second aspect of the invention preferably involves the test sample of memantine being injected directly onto the GC column without headspace sampling. The method preferably uses flame ionisation detection.
The method of the second aspect of the invention can be used to analyse memantine API
or memantine when prepared as a pharmaceutical composition. Preferably the memantine is prepared as a pharmaceutical composition.
The pharmaceutical compositions that can be analysed by the method of the second aspect of the invention include solid and liquid compositions and optionally comprise one or more pharmaceutically acceptable carriers or excipients. Solid form compositions include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid compositions include solutions or suspensions which can be administered by oral, injectable or infusion routes.
Alkaline reagents that can be used in the method of the second aspect of the invention include inorganic alkaline reagents such as sodium carbonate; sodium bicarbonate;
potassium carbonate; potassium bicarbonate; calcium carbonate; calcium bicarbonate;
magnesium carbonate; magnesium bicarbonate; sodium hydroxide; potassium hydroxide;
calcium hydroxide; lithium hydroxide; ammonium hydroxide; aluminium hydroxide;
magnesium oxide; magnesium hydroxide; magnesium aluminium hydroxide; magnesium aluminium silicate; phosphate salts (e.g. sodium, potassium or calcium dibasic phosphate, tribasic calcium phosphate or trisodium phosphate); and mixtures thereof. The alkaline reagent is preferably an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide. Most preferably, the alkaline reagent is potassium hydroxide.
The organic solvent(s) used in the method of the second aspect of the invention are preferably lower alkyl alcohols, such as methanol, ethanol, propanol, butanol or isopropanol or mixtures thereof. Alternatively, the organic solvent(s) may be tetrahydrofuran, ethyl acetate or acetonitrile or any suitable organic solvent(s) which allow complete dissolution of the alkaline reagent and the liberated memantine free base.
Preferably the organic solvent is methanol or ethanol and, most preferably, it is methanol.
If required, the test sample solution formed can be separated from any residual solids from the remaining pharmaceutical composition by standard methods in the art such as filtration or centrifugation. Preferably, the test sample solution is separated by centrifugation.
or memantine when prepared as a pharmaceutical composition. Preferably the memantine is prepared as a pharmaceutical composition.
The pharmaceutical compositions that can be analysed by the method of the second aspect of the invention include solid and liquid compositions and optionally comprise one or more pharmaceutically acceptable carriers or excipients. Solid form compositions include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid compositions include solutions or suspensions which can be administered by oral, injectable or infusion routes.
Alkaline reagents that can be used in the method of the second aspect of the invention include inorganic alkaline reagents such as sodium carbonate; sodium bicarbonate;
potassium carbonate; potassium bicarbonate; calcium carbonate; calcium bicarbonate;
magnesium carbonate; magnesium bicarbonate; sodium hydroxide; potassium hydroxide;
calcium hydroxide; lithium hydroxide; ammonium hydroxide; aluminium hydroxide;
magnesium oxide; magnesium hydroxide; magnesium aluminium hydroxide; magnesium aluminium silicate; phosphate salts (e.g. sodium, potassium or calcium dibasic phosphate, tribasic calcium phosphate or trisodium phosphate); and mixtures thereof. The alkaline reagent is preferably an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide. Most preferably, the alkaline reagent is potassium hydroxide.
The organic solvent(s) used in the method of the second aspect of the invention are preferably lower alkyl alcohols, such as methanol, ethanol, propanol, butanol or isopropanol or mixtures thereof. Alternatively, the organic solvent(s) may be tetrahydrofuran, ethyl acetate or acetonitrile or any suitable organic solvent(s) which allow complete dissolution of the alkaline reagent and the liberated memantine free base.
Preferably the organic solvent is methanol or ethanol and, most preferably, it is methanol.
If required, the test sample solution formed can be separated from any residual solids from the remaining pharmaceutical composition by standard methods in the art such as filtration or centrifugation. Preferably, the test sample solution is separated by centrifugation.
A standard reference compound is a sample of an analyte that has a well established purity and a solution of the standard is usually prepared in parallel to the sample solution and used as a so called "external reference standard". The purity of the major compound or its impurities can then be calculated based on their response relative to the standard.
However, this method has been found to be unsuitable for the analysis of memantine due to the poor reproducibility of the sample preparation process.
An internal reference standard is a known amount of a compound which is added to the sample solution prior to analysis. In most cases, a cheap and simple hydrocarbon with a similar structure to the analyte would be chosen. This ensures that it has a similar retention time to the analyte and that highly pure standards can be obtained.
The inventors have developed an alternative technique using an internal reference standard, which does not require extraction of an aqueous layer with an organic solvent such as chloroform.
The methods that the inventors have developed use amantadine hydrochloride as the internal reference standard. The inventors have found that, surprisingly, amantadine and its salts behave in a similar way to memantine and its salts during the sample preparation process and that the ratio of memantine : amantadine that is recovered from the sample preparation process matches the ratio of inemantine hydrochloride : amantadine hydrochloride that was present in the samples prior to the sample preparation process.
Using this approach, the problems with sample extraction are completely overcome to afford a simple, reliable and cost effective method for the analysis of memantine, or a pharmaceutically acceptable salt thereof, and its related substances using gas chromatography.
The inventors have tested the methods extensively to show that they are reproducible, accurate, precise, linear with respect to concentration, and robust. The limits of detection and quantification have also been determined.
However, this method has been found to be unsuitable for the analysis of memantine due to the poor reproducibility of the sample preparation process.
An internal reference standard is a known amount of a compound which is added to the sample solution prior to analysis. In most cases, a cheap and simple hydrocarbon with a similar structure to the analyte would be chosen. This ensures that it has a similar retention time to the analyte and that highly pure standards can be obtained.
The inventors have developed an alternative technique using an internal reference standard, which does not require extraction of an aqueous layer with an organic solvent such as chloroform.
The methods that the inventors have developed use amantadine hydrochloride as the internal reference standard. The inventors have found that, surprisingly, amantadine and its salts behave in a similar way to memantine and its salts during the sample preparation process and that the ratio of memantine : amantadine that is recovered from the sample preparation process matches the ratio of inemantine hydrochloride : amantadine hydrochloride that was present in the samples prior to the sample preparation process.
Using this approach, the problems with sample extraction are completely overcome to afford a simple, reliable and cost effective method for the analysis of memantine, or a pharmaceutically acceptable salt thereof, and its related substances using gas chromatography.
The inventors have tested the methods extensively to show that they are reproducible, accurate, precise, linear with respect to concentration, and robust. The limits of detection and quantification have also been determined.
The first and second aspects of the invention may include the use of an internal reference standard. Preferably, the internal standard reference compound is amantadine or rimantadine. Most preferably, the internal standard reference compound is amantadine.
A third aspect of the invention provides a method for the analysis of inemantine hydrochloride and its impurities using gas chromatography, comprising:
(a) preparing a solution of an internal standard reference compound in a first organic solvent;
(b) mixing the internal standard reference compound solution with memantine hydrochloride or a pharmaceutical composition comprising memantine hydrochloride, a second organic solvent, and a non-aqueous alkaline reagent to liberate memantine free base in solution; and (c) analysing the supernatant solution.
The first and second organic solvents used in the method of the third aspect of the invention may or may not be the same and are preferably lower alkyl alcohols, such as methanol, ethanol, propanol, butanol or isopropanol. Alternatively, the first and second organic solvents may be tetrahydrofuran, ethyl acetate or acetonitrile or any suitable organic solvent which allows complete dissolution of the alkaline reagent and the liberated memantine free base. Preferably the organic solvent is methanol or ethanol and, most preferably, it is methanol.
A suitable alkaline reagent for use in the method of the third aspect of the invention can be an inorganic alkaline reagent such as sodium carbonate; sodium bicarbonate;
potassium carbonate; potassium bicarbonate; calcium carbonate; calcium bicarbonate;
magnesium carbonate; magnesium bicarbonate; sodium hydroxide; potassium hydroxide;
calcium hydroxide; lithium hydroxide; ammonium hydroxide; aluminium hydroxide;
magnesium oxide; magnesium hydroxide; magnesium aluminium hydroxide; magnesium aluminium silicate; phosphate salts (e.g. sodium, potassium or calcium dibasic phosphate, tribasic calcium phosphate or trisodium phosphate); and mixtures thereof. Preferably, the alkaline reagent is a hydroxide salt such as sodium hydroxide or potassium hydroxide.
Most preferably, the alkaline reagent is potassium hydroxide.
A third aspect of the invention provides a method for the analysis of inemantine hydrochloride and its impurities using gas chromatography, comprising:
(a) preparing a solution of an internal standard reference compound in a first organic solvent;
(b) mixing the internal standard reference compound solution with memantine hydrochloride or a pharmaceutical composition comprising memantine hydrochloride, a second organic solvent, and a non-aqueous alkaline reagent to liberate memantine free base in solution; and (c) analysing the supernatant solution.
The first and second organic solvents used in the method of the third aspect of the invention may or may not be the same and are preferably lower alkyl alcohols, such as methanol, ethanol, propanol, butanol or isopropanol. Alternatively, the first and second organic solvents may be tetrahydrofuran, ethyl acetate or acetonitrile or any suitable organic solvent which allows complete dissolution of the alkaline reagent and the liberated memantine free base. Preferably the organic solvent is methanol or ethanol and, most preferably, it is methanol.
A suitable alkaline reagent for use in the method of the third aspect of the invention can be an inorganic alkaline reagent such as sodium carbonate; sodium bicarbonate;
potassium carbonate; potassium bicarbonate; calcium carbonate; calcium bicarbonate;
magnesium carbonate; magnesium bicarbonate; sodium hydroxide; potassium hydroxide;
calcium hydroxide; lithium hydroxide; ammonium hydroxide; aluminium hydroxide;
magnesium oxide; magnesium hydroxide; magnesium aluminium hydroxide; magnesium aluminium silicate; phosphate salts (e.g. sodium, potassium or calcium dibasic phosphate, tribasic calcium phosphate or trisodium phosphate); and mixtures thereof. Preferably, the alkaline reagent is a hydroxide salt such as sodium hydroxide or potassium hydroxide.
Most preferably, the alkaline reagent is potassium hydroxide.
Usually the alkaline reagent is added to the solution in step (b).
Alternatively, the alkaline reagent can be added to the solution in step (a) instead of in step (b).
Preferably, the internal standard reference compound is amantadine or rimantadine. Most preferably, the internal standard reference compound is amantadine.
If required, the supernatant solution in step (c) can be separated from any residual solids from the pharmaceutical composition by standard methods in the art such as filtration or centrifugation. Preferably, the supernatant solution is separated by centrifugation.
The term "non-aqueous" as used in the second and third aspects of the invention means that there is not enough water present to form a distinct aqueous layer which separates from the organic solvent layer. Accordingly, the term "non-aqueous alkaline reagent"
means that, even though the alkaline reagent may be soluble in water, the alkaline reagent is dissolved in one or more organic solvents, since there is not enough water present to form a distinct aqueous layer which separates from the organic solvent layer.
The second and third aspects of the invention involve methods of analysing memantine free base using a monophasic solvent extraction. Consequently an organic/aqueous biphasic solvent extraction is avoided and no separation of an aqueous and organic layer is required, thus avoiding the problems associated with the prior art processes described above.
However, if a biphasic solvent extraction is preferred, the inventors have found that the use of chlorinated solvents such as chloroform is not very suitable for sample preparation, since results are not reproducible, and since the chloroform layer is below the aqueous layer and is consequently more difficult to separate for assay purposes. The inventors have surprisingly found that an aqueous alkaline/organic solvent biphasic extraction works very well, when lower alkyl hydrocarbon organic solvents such as pentane, hexane, heptane and octane or aromatic hydrocarbons such as benzene or toluene are used. The inventors have tested this method extensively to show that it is reproducible, accurate, precise, linear with respect to concentration, and robust.
Alternatively, the alkaline reagent can be added to the solution in step (a) instead of in step (b).
Preferably, the internal standard reference compound is amantadine or rimantadine. Most preferably, the internal standard reference compound is amantadine.
If required, the supernatant solution in step (c) can be separated from any residual solids from the pharmaceutical composition by standard methods in the art such as filtration or centrifugation. Preferably, the supernatant solution is separated by centrifugation.
The term "non-aqueous" as used in the second and third aspects of the invention means that there is not enough water present to form a distinct aqueous layer which separates from the organic solvent layer. Accordingly, the term "non-aqueous alkaline reagent"
means that, even though the alkaline reagent may be soluble in water, the alkaline reagent is dissolved in one or more organic solvents, since there is not enough water present to form a distinct aqueous layer which separates from the organic solvent layer.
The second and third aspects of the invention involve methods of analysing memantine free base using a monophasic solvent extraction. Consequently an organic/aqueous biphasic solvent extraction is avoided and no separation of an aqueous and organic layer is required, thus avoiding the problems associated with the prior art processes described above.
However, if a biphasic solvent extraction is preferred, the inventors have found that the use of chlorinated solvents such as chloroform is not very suitable for sample preparation, since results are not reproducible, and since the chloroform layer is below the aqueous layer and is consequently more difficult to separate for assay purposes. The inventors have surprisingly found that an aqueous alkaline/organic solvent biphasic extraction works very well, when lower alkyl hydrocarbon organic solvents such as pentane, hexane, heptane and octane or aromatic hydrocarbons such as benzene or toluene are used. The inventors have tested this method extensively to show that it is reproducible, accurate, precise, linear with respect to concentration, and robust.
Consequently a fourth aspect of the invention provides a method for the analysis of memantine hydrochloride, or another pharmaceutically acceptable acid addition salt thereof, and its impurities using gas chromatography, comprising mixing memantine hydrochloride or another pharmaceutically acceptable acid addition salt thereof, or a pharmaceutical composition comprising memantine hydrochloride or another pharmaceutically acceptable acid addition salt thereof, with one or more organic solvent(s) and an aqueous alkaline reagent to liberate memantine free base in solution in the organic solvent(s), separating the biphasic mixture to afford an organic solvent layer, and analysing the organic solvent solution.
The fourth aspect of the invention may involve the use of an internal standard reference compound. Preferably, the internal standard reference compound is amantadine or rimantadine. Most preferably, the internal standard reference compound is amantadine.
The organic solvent(s) used in the fourth aspect of the invention is preferably a hydrocarbon solvent selected from one or more of the following solvents:
pentane, hexane, heptane, octane, benzene or toluene. Preferably the hydrocarbon solvent is n-hexane.
A suitable atkaline reagent for use in the method of the fourth aspect of the invention can be an inorganic alkaline reagent such as sodium carbonate; sodium bicarbonate;
potassium carbonate; potassium bicarbonate; calcium carbonate; calcium bicarbonate;
magnesium carbonate; magnesium bicarbonate; sodium hydroxide; potassium hydroxide;
calcium hydroxide; lithium hydroxide; ammonium hydroxide; aluminium hydroxide;
magnesium oxide; magnesium hydroxide; magnesium aluminium hydroxide; magnesium aluminium silicate; phosphate salts (e.g. sodium, potassium or calcium dibasic phosphate, tribasic calcium phosphate or trisodium phosphate); and mixtures thereof. Preferably, the alkaline reagent is a hydroxide salt such as sodium hydroxide or potassium hydroxide.
Most preferably, the alkaline reagent is potassium hydroxide.
If required, the organic solvent solution can be separated from any residual solids from the pharmaceutical composition by standard methods in the art such as filtration or centrifugation. Preferably, the organic solvent solution is separated by centrifugation.
The fourth aspect of the invention may involve the use of an internal standard reference compound. Preferably, the internal standard reference compound is amantadine or rimantadine. Most preferably, the internal standard reference compound is amantadine.
The organic solvent(s) used in the fourth aspect of the invention is preferably a hydrocarbon solvent selected from one or more of the following solvents:
pentane, hexane, heptane, octane, benzene or toluene. Preferably the hydrocarbon solvent is n-hexane.
A suitable atkaline reagent for use in the method of the fourth aspect of the invention can be an inorganic alkaline reagent such as sodium carbonate; sodium bicarbonate;
potassium carbonate; potassium bicarbonate; calcium carbonate; calcium bicarbonate;
magnesium carbonate; magnesium bicarbonate; sodium hydroxide; potassium hydroxide;
calcium hydroxide; lithium hydroxide; ammonium hydroxide; aluminium hydroxide;
magnesium oxide; magnesium hydroxide; magnesium aluminium hydroxide; magnesium aluminium silicate; phosphate salts (e.g. sodium, potassium or calcium dibasic phosphate, tribasic calcium phosphate or trisodium phosphate); and mixtures thereof. Preferably, the alkaline reagent is a hydroxide salt such as sodium hydroxide or potassium hydroxide.
Most preferably, the alkaline reagent is potassium hydroxide.
If required, the organic solvent solution can be separated from any residual solids from the pharmaceutical composition by standard methods in the art such as filtration or centrifugation. Preferably, the organic solvent solution is separated by centrifugation.
The term "aqueous" as used in the fourth aspect of the invention means that there is enough water present to form a distinct aqueous layer which separates from the organic solvent layer. Accordingly, the term "aqueous alkaline reagent" means that at least some of the alkaline reagent is dissolved in the aqueous layer.
Alternatively to the hydrochloride salt, the four aspects of the invention may be used to analyse other acid addition salts of inemantine such as the hydrobromide, hydroiodide, maleate, mesylate, besylate, tosylate, oxalate, acetate, propionate or formate salts. However, the inventive method is preferably used to analyse the hydrochloride salt of inemantine.
The pharmaceutical compositions that can be analysed by all four aspects of the invention include solid and liquid compositions which optionally comprise one or more pharmaceutically acceptable carriers or excipients. Solid form compositions include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Typical excipients used in the solid dosage forms comprise additives conventional in the dosage form in question. Tableting aids commonly used in tablet formulation can be used and reference is made to the extensive literature on the subject, see in particular Fiedler's "Lexikon der Hilfsstoffe", 4th edition, ECV Aulendorf, 1996, which is incorporated herein in its entirety by reference. Typical excipients include but are not limited to fillers, binders, disintegrants, glidants, lubricants, stabilising agents, diluents, surfactants and the like.
Consequently, the pharmaceutical composition to be analysed typically comprises: one or more fillers, such as microcrystalline cellulose, lactose, lactose monohydrate, sugars, starches, modified starch, mannitol, sorbitol and other polyols, dextrin, dextran or maltodextrin; one or more binders, such as lactose, starches, modified starch, maize starch, dextrin, dextran, maltodextrin, microcrystalline cellulose (e.g. Avicel ), sugars, polyethylene glycols, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, gelatin, acacia gum, tragacanth, polyvinylpyrrolidone or crospovidone; one or more disintegrants, such as croscarmellose sodium, cross-linked polyvinylpyrrolidone, crospovidone, cross-linked carboxymethyl starch, starches, microcrystalline cellulose, polyacrylin potassium; one or more different glidants or lubricants, such as magnesium stearate, calcium stearate, zinc stearate, calcium behenate, sodium stearyl fumarate, talc, magnesium trisilicate, stearic acid, palmitic acid, carnauba wax or silicon dioxide (e.g. colloidal silicon dioxide).
If required, the pharmaceutical compositions to be analysed may also include surfactants and other conventional excipients. Typical surfactants that may be used are ionic surfactants, such as sodium lauryl sulphate, or non-ionic surfactants, such as different poloxamers (polyoxyethylene and polyoxypropylene copolymers), natural or synthesized lecithins, esters of sorbitan and fatty acids (such as Spano ), esters of polyoxyethylene-sorbitan and fatty acids (such as Tween ), polyoxyethylated hydrogenated castor oil (such as Cremophor~, polyoxyethylene stearates (such as Brij~, dimethylpolysiloxane, or any combination of the above mentioned surfactants.
If the solid pharmaceutical composition is in the form of coated tablets, the coating may be prepared from at least one film-former, such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose or methacrylate polymers, which optionally may contain at least one plasticizer, such as polyethylene glycols, dibutyl sebacate, triethyl citrate, and other pharmaceutical auxiliary substances conventional for film coatings, such as pigments, fillers and others.
One or more of these excipients can be selected and used by the skilled person having regard to the particular desired properties of the solid oral dosage form by routine experimentation and without any undue burden.
The absolute amounts of each excipient and the amounts relative to other additives is similarly dependent on the desired properties of the solid oral dosage form and may also be chosen by the skilled person by routine experimentation without undue burden.
For example, the solid oral dosage form may be chosen to exhibit accelerated and/or delayed release of the active agent with or without quantitative control of the release of active agent.
In powders, the carrier is a finely divided solid that is in a mixture with the finely divided API. In tablets, the API is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
Alternatively to the hydrochloride salt, the four aspects of the invention may be used to analyse other acid addition salts of inemantine such as the hydrobromide, hydroiodide, maleate, mesylate, besylate, tosylate, oxalate, acetate, propionate or formate salts. However, the inventive method is preferably used to analyse the hydrochloride salt of inemantine.
The pharmaceutical compositions that can be analysed by all four aspects of the invention include solid and liquid compositions which optionally comprise one or more pharmaceutically acceptable carriers or excipients. Solid form compositions include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Typical excipients used in the solid dosage forms comprise additives conventional in the dosage form in question. Tableting aids commonly used in tablet formulation can be used and reference is made to the extensive literature on the subject, see in particular Fiedler's "Lexikon der Hilfsstoffe", 4th edition, ECV Aulendorf, 1996, which is incorporated herein in its entirety by reference. Typical excipients include but are not limited to fillers, binders, disintegrants, glidants, lubricants, stabilising agents, diluents, surfactants and the like.
Consequently, the pharmaceutical composition to be analysed typically comprises: one or more fillers, such as microcrystalline cellulose, lactose, lactose monohydrate, sugars, starches, modified starch, mannitol, sorbitol and other polyols, dextrin, dextran or maltodextrin; one or more binders, such as lactose, starches, modified starch, maize starch, dextrin, dextran, maltodextrin, microcrystalline cellulose (e.g. Avicel ), sugars, polyethylene glycols, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, gelatin, acacia gum, tragacanth, polyvinylpyrrolidone or crospovidone; one or more disintegrants, such as croscarmellose sodium, cross-linked polyvinylpyrrolidone, crospovidone, cross-linked carboxymethyl starch, starches, microcrystalline cellulose, polyacrylin potassium; one or more different glidants or lubricants, such as magnesium stearate, calcium stearate, zinc stearate, calcium behenate, sodium stearyl fumarate, talc, magnesium trisilicate, stearic acid, palmitic acid, carnauba wax or silicon dioxide (e.g. colloidal silicon dioxide).
If required, the pharmaceutical compositions to be analysed may also include surfactants and other conventional excipients. Typical surfactants that may be used are ionic surfactants, such as sodium lauryl sulphate, or non-ionic surfactants, such as different poloxamers (polyoxyethylene and polyoxypropylene copolymers), natural or synthesized lecithins, esters of sorbitan and fatty acids (such as Spano ), esters of polyoxyethylene-sorbitan and fatty acids (such as Tween ), polyoxyethylated hydrogenated castor oil (such as Cremophor~, polyoxyethylene stearates (such as Brij~, dimethylpolysiloxane, or any combination of the above mentioned surfactants.
If the solid pharmaceutical composition is in the form of coated tablets, the coating may be prepared from at least one film-former, such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose or methacrylate polymers, which optionally may contain at least one plasticizer, such as polyethylene glycols, dibutyl sebacate, triethyl citrate, and other pharmaceutical auxiliary substances conventional for film coatings, such as pigments, fillers and others.
One or more of these excipients can be selected and used by the skilled person having regard to the particular desired properties of the solid oral dosage form by routine experimentation and without any undue burden.
The absolute amounts of each excipient and the amounts relative to other additives is similarly dependent on the desired properties of the solid oral dosage form and may also be chosen by the skilled person by routine experimentation without undue burden.
For example, the solid oral dosage form may be chosen to exhibit accelerated and/or delayed release of the active agent with or without quantitative control of the release of active agent.
In powders, the carrier is a finely divided solid that is in a mixture with the finely divided API. In tablets, the API is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
I.iquid form preparations include solutions, suspensions and emulsions, for example water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
Aqueous solutions suitable for oral use can be prepared by dissolving the API
in water and adding suitable colorants, flavours, stabilizing and thickening agents as desired.
The quantity of active component in a unit dose preparation may be varied or adjusted from 0.5 mg to 50 mg, preferably 2 mg to 30 mg, and most preferably 5 mg to 20 mg. A
daily dose range of about 5 mg to about 20 mg is preferred. The composition can, if desired, also contain other compatible therapeutic agents.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
The methods of the invention disclosed herein can also be used for the analysis of compounds with similar chemical structures and/or similar chemical or physical properties to memantine, e.g. rimantadine and pharmaceutically acceptable salts thereof.
The present invention is illustrated but in no way limited by the following examples.
Aqueous solutions suitable for oral use can be prepared by dissolving the API
in water and adding suitable colorants, flavours, stabilizing and thickening agents as desired.
The quantity of active component in a unit dose preparation may be varied or adjusted from 0.5 mg to 50 mg, preferably 2 mg to 30 mg, and most preferably 5 mg to 20 mg. A
daily dose range of about 5 mg to about 20 mg is preferred. The composition can, if desired, also contain other compatible therapeutic agents.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
The methods of the invention disclosed herein can also be used for the analysis of compounds with similar chemical structures and/or similar chemical or physical properties to memantine, e.g. rimantadine and pharmaceutically acceptable salts thereof.
The present invention is illustrated but in no way limited by the following examples.
Examples Example 1: Content Uniformity Test GC SYSTEM: Agilent 6890 or equivalent INLET LINER: Agilent Split/Splitless Liner Part No. 5183-4711 COLUMN: ZB-1, 30 m length, 0.32 mm internal diameter, 1.0 m film thickness PRE-COLUMN: de-activated fused silica tubing, 5 m length, 0.32 mm internal diameter CARRIER GAS FLOW: Helium, 2.5 mL/min (constant flow) INLET: Temperature: 340 C
Split Injection: Split Ratio: 20:1 Gas Saver: ON On Time: 2.0 min Flow: 20.0 OVEN TEMPERATURE: Initial Temperature 140 C
Initial Time 1 min Rate 1 10 C/min Temperature 1 200 C
Time 1 0 min Rate 2 40 C/min Temperature 2 340 C
Time 2 1 min DETECTOR: Flame Ionization Detector (FID) at 340 C
Hydrogen 30 mL/min Air 350 mL/min Helium (makeup) 22.5 mL/min INJECTION VOLUME: 1 L
Split Injection: Split Ratio: 20:1 Gas Saver: ON On Time: 2.0 min Flow: 20.0 OVEN TEMPERATURE: Initial Temperature 140 C
Initial Time 1 min Rate 1 10 C/min Temperature 1 200 C
Time 1 0 min Rate 2 40 C/min Temperature 2 340 C
Time 2 1 min DETECTOR: Flame Ionization Detector (FID) at 340 C
Hydrogen 30 mL/min Air 350 mL/min Helium (makeup) 22.5 mL/min INJECTION VOLUME: 1 L
INJECTOR: 5 pre-washes with Diluent post-washes with Methanol 5 sample washes 5 injector pumps DILUENT: 0.005M Methanolic Potassium Hydroxide RUN TIME: 12 minutes Internal Standard Working Solution (ISTD), Accurately weigh about 100 mg of Amantadine HC1 (C10H17N=HC1) and transfer into a 1000 mL volumetric flask. Add about 600 mL of Diluent and sonicate for about 2 minutes or until dissolved. Let cool to room temperature, dilute to volume with Diluent and mix well. (Conc. ;:z~ 100 gg/mL of Amantadine HCl).
Standard Working Solution (prepare in duplicate) Accurately weigh about 25.0 mg of Memantine HC1 RS (C12H21N=HC1) and transfer into a 250 mL volumetric flask. Add about 150 mL of ISTD and sonicate for about 2 minutes or until dissolved. Let cool to room temperature, dilute to volume with ISTD and mix well.
(Conc. ,z~ 100 g/mL of Memantine HC1 and ;t~ 100 g/mL of Amantadine HC1).
Sample Working Solution Transfer one tablet into a 100 mL volumetric flask. Add 70 mL of ISTD. Shake mechanically for 20 minutes or until the tablet is disintegrated completely.
Sonicate for 10 minutes with occasional swirling. Allow to stand at room temperature for 10 minutes.
Dilute to volume with ISTD. Mix well. Centrifuge a portion at 3000 rpm for 5 minutes.
Take supernatant for analysis.
(Conc. ;zz~ 100 g/mL of Memantine HCl and ;zz~ 100 g/mL of Amantadine HCI).
Standard Working Solution (prepare in duplicate) Accurately weigh about 25.0 mg of Memantine HC1 RS (C12H21N=HC1) and transfer into a 250 mL volumetric flask. Add about 150 mL of ISTD and sonicate for about 2 minutes or until dissolved. Let cool to room temperature, dilute to volume with ISTD and mix well.
(Conc. ,z~ 100 g/mL of Memantine HC1 and ;t~ 100 g/mL of Amantadine HC1).
Sample Working Solution Transfer one tablet into a 100 mL volumetric flask. Add 70 mL of ISTD. Shake mechanically for 20 minutes or until the tablet is disintegrated completely.
Sonicate for 10 minutes with occasional swirling. Allow to stand at room temperature for 10 minutes.
Dilute to volume with ISTD. Mix well. Centrifuge a portion at 3000 rpm for 5 minutes.
Take supernatant for analysis.
(Conc. ;zz~ 100 g/mL of Memantine HCl and ;zz~ 100 g/mL of Amantadine HCI).
Example 2: Dissolution Testing GC SYSTEM: Agilent 6890 or equivalent INLET LINER: Agilent Split/Splitless Liner Part No. 5183-4711 COLUMN: ZB-1, 30 m length, 0.32 mm internal diameter, 1.0 m film thickness CARRIER GAS FLOW: Helium, 2.5 mL/min (constant flow) INLET: Temperature: 250 C
Split Injection: Split Ratio: 10:1 Gas Saver: OFF
OVEN TEMPERATURE: Initial Temperature 140 C
Initial Time 1 min Rate 1 10 C/min Temperature 1 200 C
Time 1 0 min Rate 2 40 C/min Temperature 2 300 C
Time 2 2 min DETECTOR: Flame Ionization Detector (FID) at 300 C
Hydrogen 40 mL/min Air 400 mL/min Helium (makeup) 22.5 mL/min INJECTION VOLUME: 5 L
INJECTOR: 5 pre-washes with 0.01M NaOH in Ethanol*
5 post-washes with Ethanol 5 sample washes 5 injector pumps *0.01M Ethanolic NaOH: 100 L of 1.OM aqueous NaOH diluted to 10 mL with anhydrous ethanol RUN TIME: 12 minutes DISSOLUTION EOUIPMENT AND PARAMETERS
MEDIUM: 0.1N HCl with NaCI*
VOLUME: 900 mL
METHOD: Apparatus I (Basket) SPEED: 100 rpm RUN TIME: 30 minutes TEMPERATURE: 37 C 0.5 C
MEDIUM*: Weigh accurately 12 g of Sodium Chloride (NaCl) and dissolve in 5 L of water. Add 40 mL of Hydrochloric Acid (HCl). Dilute to 6 L with water. Mix well. Adjust pH to 1.2 0.05 with HCI.
INTERNAL STANDARD PREPARATION (ISTD), Stock Internal Standard Solution Weigh 27.8 mg of Amantadine HCl (C10H17N=HC1) and transfer into a 50 mL
volumetric flask. Add about 40 mL of Medium. Sonicate for 2 minutes or until dissolved.
Dilute to volume with Medium. Mix well.
Internal Standard Intermediate Solution Transfer 30.0 mL of Stock Internal Standard Solution into a 100 mL volumetric flask. Add 5.0 mL of 1.ON NaOH Solution. Swirl to mix. Add 20.0 mL of n-Hexane. Stopper tightly. Shake mechanically for 5 minutes. Allow to stand for 10 minutes.
Internal Standard Working Solution (IS=
Transfer 5.0 mL of upper layer from Internal Standard Intermediate Solution into a 250 mL volumetric flask. Dilute to volume with n-Hexane. Mix well.
(Conc. z 16.7 g/mL of Amantadine HCl).
Split Injection: Split Ratio: 10:1 Gas Saver: OFF
OVEN TEMPERATURE: Initial Temperature 140 C
Initial Time 1 min Rate 1 10 C/min Temperature 1 200 C
Time 1 0 min Rate 2 40 C/min Temperature 2 300 C
Time 2 2 min DETECTOR: Flame Ionization Detector (FID) at 300 C
Hydrogen 40 mL/min Air 400 mL/min Helium (makeup) 22.5 mL/min INJECTION VOLUME: 5 L
INJECTOR: 5 pre-washes with 0.01M NaOH in Ethanol*
5 post-washes with Ethanol 5 sample washes 5 injector pumps *0.01M Ethanolic NaOH: 100 L of 1.OM aqueous NaOH diluted to 10 mL with anhydrous ethanol RUN TIME: 12 minutes DISSOLUTION EOUIPMENT AND PARAMETERS
MEDIUM: 0.1N HCl with NaCI*
VOLUME: 900 mL
METHOD: Apparatus I (Basket) SPEED: 100 rpm RUN TIME: 30 minutes TEMPERATURE: 37 C 0.5 C
MEDIUM*: Weigh accurately 12 g of Sodium Chloride (NaCl) and dissolve in 5 L of water. Add 40 mL of Hydrochloric Acid (HCl). Dilute to 6 L with water. Mix well. Adjust pH to 1.2 0.05 with HCI.
INTERNAL STANDARD PREPARATION (ISTD), Stock Internal Standard Solution Weigh 27.8 mg of Amantadine HCl (C10H17N=HC1) and transfer into a 50 mL
volumetric flask. Add about 40 mL of Medium. Sonicate for 2 minutes or until dissolved.
Dilute to volume with Medium. Mix well.
Internal Standard Intermediate Solution Transfer 30.0 mL of Stock Internal Standard Solution into a 100 mL volumetric flask. Add 5.0 mL of 1.ON NaOH Solution. Swirl to mix. Add 20.0 mL of n-Hexane. Stopper tightly. Shake mechanically for 5 minutes. Allow to stand for 10 minutes.
Internal Standard Working Solution (IS=
Transfer 5.0 mL of upper layer from Internal Standard Intermediate Solution into a 250 mL volumetric flask. Dilute to volume with n-Hexane. Mix well.
(Conc. z 16.7 g/mL of Amantadine HCl).
Standard Stock Solution Accurately weigh about 22.2 mg of Memantine HCl RS (C12H21N=HC1) and transfer into a 100 mL volumetric flask. Add about 30 mL of Medium and sonicate for about 2 minutes or until dissolved. Dilute to volume with Medium and mix well.
(Conc. ;t~ 222 g/mL of Memantine HCl).
For 10mg Tablets:
Pipette 5.0 mL of Standard Stock Solution into a 100 mL volumetric flask.
Dilute to volume with Medium and mix. (Conc. ;z~ 11.1 g/mL of Memantine HCl).
For 5mg Tablets:
Pipette 5.0 mL of Standard Stock Solution into a 200 mL volumetric flask.
Dilute to volume with Medium and rnix. (Conc. ;t; 5.56 g/mL of Memantine HCl).
For 10mg Tablets:
Pipette 6.0 mL of Standard Stock Solution into a 25 mL volumetric flask. Add 1.0 mL of 1.ON NaOH Solution. Mix by swirling. Add 4.0 mL of ISTD. Stopper tightly.
Shake mechanically for 5 minutes. Allow to stand for 10 minutes. Using a disposable glass pipette, carefully transfer the upper layer into a GC vial.
(Conc. ;t~ 16.7 g/mL of Memantine HCl and ;z:~ 16.7 g/mL of Amantadine HCl).
For 5mg Tablets:
Pipette 6.0 mL of Standard Stock Solution into a 25 mL volumetric flask. Add 1.0 mL of 1.ON NaOH Solution. Mix by swirling. Add 4.0 mL of ISTD. Stopper tightly.
Shake mechanically for 5 minutes. Allow to stand for 10 minutes. Using a disposable glass pipette, carefully transfer the upper layer into a GC vial.
(Conc. P~ 8.33 g/mL of Memantine HCl and ;z:~ 16.7 g/mL of Amantadine HCl).
Pipette 6.0 mL of Medium into a 25 mL volumetric flask. Add 1.0 mL of 1.ON
NaOH
Solution. Mix by swirling. Add 4.0 mL of ISTD. Stopper tightly. Shake mechanically for 5 minutes. Allow to stand for 10 minutes. Using a disposable glass pipette, carefully transfer the upper layer into a GC vial. (Conc. ;-- 16.7 g/mL of Amantadine HCl).
(Conc. ;t~ 222 g/mL of Memantine HCl).
For 10mg Tablets:
Pipette 5.0 mL of Standard Stock Solution into a 100 mL volumetric flask.
Dilute to volume with Medium and mix. (Conc. ;z~ 11.1 g/mL of Memantine HCl).
For 5mg Tablets:
Pipette 5.0 mL of Standard Stock Solution into a 200 mL volumetric flask.
Dilute to volume with Medium and rnix. (Conc. ;t; 5.56 g/mL of Memantine HCl).
For 10mg Tablets:
Pipette 6.0 mL of Standard Stock Solution into a 25 mL volumetric flask. Add 1.0 mL of 1.ON NaOH Solution. Mix by swirling. Add 4.0 mL of ISTD. Stopper tightly.
Shake mechanically for 5 minutes. Allow to stand for 10 minutes. Using a disposable glass pipette, carefully transfer the upper layer into a GC vial.
(Conc. ;t~ 16.7 g/mL of Memantine HCl and ;z:~ 16.7 g/mL of Amantadine HCl).
For 5mg Tablets:
Pipette 6.0 mL of Standard Stock Solution into a 25 mL volumetric flask. Add 1.0 mL of 1.ON NaOH Solution. Mix by swirling. Add 4.0 mL of ISTD. Stopper tightly.
Shake mechanically for 5 minutes. Allow to stand for 10 minutes. Using a disposable glass pipette, carefully transfer the upper layer into a GC vial.
(Conc. P~ 8.33 g/mL of Memantine HCl and ;z:~ 16.7 g/mL of Amantadine HCl).
Pipette 6.0 mL of Medium into a 25 mL volumetric flask. Add 1.0 mL of 1.ON
NaOH
Solution. Mix by swirling. Add 4.0 mL of ISTD. Stopper tightly. Shake mechanically for 5 minutes. Allow to stand for 10 minutes. Using a disposable glass pipette, carefully transfer the upper layer into a GC vial. (Conc. ;-- 16.7 g/mL of Amantadine HCl).
Sample Stock Solution Place 900 mL of Medium into each of six dissolution vessels and equilibrate the Medium to 37 C 0.5 C. Preset the baskets speed to 100 rpm. Place one tablet into each of the dry baskets. Lower the baskets into the Medium and start rotating the baskets.
After 30 minutes, withdraw 10 mL sample from each vessel using probes from a zone midway between the surface of the Medium and the top of the rotating basket, not less than 1 cm from the vessel wall. Filter the solutions immediately.
For 10mg Tablets:
Pipette 6.0 mL of Sample Stock Solution into a 25 mL volumetric flask. Add 1.0 mL of 1.ON NaOH Solution. Mix by swirling. Add 4.0 mL of ISTD. Stopper tightly.
Shake mechanically for 5 minutes. Allow to stand for 10 minutes. Using a disposable glass pipette, carefully transfer the upper layer into a GC vial.
(Conc. - 16.7 g/mL of Memantine HC1 and,& 16.7 g/mL of Amantadine HC1).
For 5mg Tablets:
Pipette 6.0 mL of Sample Stock Solution into a 25 mL volumetric flask. Add 1.0 mL of 1.ON NaOH Solution. Mix by swirling. Add 4.0 mL of ISTD. Stopper tightly.
Shake mechanically for 5 minutes. Allow to stand for 10 minutes. Using a disposable glass pipette, carefully transfer the upper layer into a GC vial.
(Conc. - 8.33 g/mL of Memantine HCI and ;:t~ 16.7 g/mL of Amantadine HCl).
After 30 minutes, withdraw 10 mL sample from each vessel using probes from a zone midway between the surface of the Medium and the top of the rotating basket, not less than 1 cm from the vessel wall. Filter the solutions immediately.
For 10mg Tablets:
Pipette 6.0 mL of Sample Stock Solution into a 25 mL volumetric flask. Add 1.0 mL of 1.ON NaOH Solution. Mix by swirling. Add 4.0 mL of ISTD. Stopper tightly.
Shake mechanically for 5 minutes. Allow to stand for 10 minutes. Using a disposable glass pipette, carefully transfer the upper layer into a GC vial.
(Conc. - 16.7 g/mL of Memantine HC1 and,& 16.7 g/mL of Amantadine HC1).
For 5mg Tablets:
Pipette 6.0 mL of Sample Stock Solution into a 25 mL volumetric flask. Add 1.0 mL of 1.ON NaOH Solution. Mix by swirling. Add 4.0 mL of ISTD. Stopper tightly.
Shake mechanically for 5 minutes. Allow to stand for 10 minutes. Using a disposable glass pipette, carefully transfer the upper layer into a GC vial.
(Conc. - 8.33 g/mL of Memantine HCI and ;:t~ 16.7 g/mL of Amantadine HCl).
Example 3: Related Substances Test GC SYSTEM: Agilent 6890 or equivalent INLET LINER: Agilent Split/Splitless Liner Part No. 5183-4711 COLUMN: ZB-1, 60 m length, 0.32 mm internal diameter, 1.0 m film thickness CARRIER GAS FLOW: Helium, 2.5 mL/min (constant flow) INLET: Temperature: 250 C
Split Injection: Split Ratio: 20:1 Gas Saver: ON On Time: 2.0 min Flow: 20.0 OVEN TEMPERATURE: Initial Temperature 140 C
Initial Time 1 min Rate 1 2 C/min Temperature 1 200 C
Time 1 0 min Rate 2 30 C/min Temperature 2 300 C
Time2 5min DETECTOR: Flame Ionization Detector (FID) at 250 C
Hydrogen 40 mL/min Air 400 mL/min Helium (makeup) 22.5 mL/min INJECTION VOLUME: 5 L
INJECTOR: 5 pre-washes with 0.01M Ethanolic NaOH*
5 post-washes with Ethanol 5 sample washes 5 injector pumps *0.01M Ethanolic NaOH: 100 L of 1.OM aqueous NaOH diluted to 10 mL with anhydrous ethanol RUN TIME: 40 minutes Standard Stock Solution:
Accurately weigh about 5.0 mg of Memantine HC1 RS (C12H21N=HC1) and transfer into a 100 mL volumetric flask. Add about 60 mL of H20, and sonicate for 30 seconds if necessary to clissolve. Dilute to volume with H20 and mix well.
(Conc. ;z~ 50 g/mL of Memantine HCI).
Standard Intermediate Solution:
Pipette 4.0 mL of Standard Stock Solution into a 100 mL volumetric flask.
Dilute to volume with H20 and mix well. (Conc. ;t~ 2 g/mL of Memantine HCl).
Standard Working Solution:
Pipette 5.0 mL of Standard Intermediate Solution into a 25 mL volumetric flask. Add 1.0 mL of 6M NaOH Solution and 5.0 mL of n-Hexane. Ensure the flask is capped tightly immediately after adding the n-Hexane to prevent any leaking and/or evaporation. Shake the flask by hand for 5 minutes. Let stand for 5 minutes to allow the layers to separate.
Transfer a portion of the upper organic layer to a GC vial and cap immediately.
(Conc. ;z~ 2 g/mL of Memantine HC1).
Sample Working Solution:
Accurately weigh 20 tablets and determine average tablet weight. Finely powder the tablets using mortar and pestle. Accurately weigh tablet powder equivalent to 20.0 mg of Memantine HCl and transfer into a 40 mL polycarbonate centrifuge tube with Nalgene screw cap. Add 10.0 mL of H20 and sonicate for 2 minutes with occasional shaking. Add 2.0 mL of 6M NaOH Solution and 10.0 mL of n-Hexane. Ensure the tube is capped tightly immediately after adding the n-Hexane to prevent any leaking and/or evaporation.
Shake the tube by hand for 5 minutes. Let stand for 10 minutes to allow the layers to separate. Transfer a portion of the upper organic layer to a GC vial and cap immediately.
(Conc. ;zt~ 2 mg/mL of Memantine HCI).
Split Injection: Split Ratio: 20:1 Gas Saver: ON On Time: 2.0 min Flow: 20.0 OVEN TEMPERATURE: Initial Temperature 140 C
Initial Time 1 min Rate 1 2 C/min Temperature 1 200 C
Time 1 0 min Rate 2 30 C/min Temperature 2 300 C
Time2 5min DETECTOR: Flame Ionization Detector (FID) at 250 C
Hydrogen 40 mL/min Air 400 mL/min Helium (makeup) 22.5 mL/min INJECTION VOLUME: 5 L
INJECTOR: 5 pre-washes with 0.01M Ethanolic NaOH*
5 post-washes with Ethanol 5 sample washes 5 injector pumps *0.01M Ethanolic NaOH: 100 L of 1.OM aqueous NaOH diluted to 10 mL with anhydrous ethanol RUN TIME: 40 minutes Standard Stock Solution:
Accurately weigh about 5.0 mg of Memantine HC1 RS (C12H21N=HC1) and transfer into a 100 mL volumetric flask. Add about 60 mL of H20, and sonicate for 30 seconds if necessary to clissolve. Dilute to volume with H20 and mix well.
(Conc. ;z~ 50 g/mL of Memantine HCI).
Standard Intermediate Solution:
Pipette 4.0 mL of Standard Stock Solution into a 100 mL volumetric flask.
Dilute to volume with H20 and mix well. (Conc. ;t~ 2 g/mL of Memantine HCl).
Standard Working Solution:
Pipette 5.0 mL of Standard Intermediate Solution into a 25 mL volumetric flask. Add 1.0 mL of 6M NaOH Solution and 5.0 mL of n-Hexane. Ensure the flask is capped tightly immediately after adding the n-Hexane to prevent any leaking and/or evaporation. Shake the flask by hand for 5 minutes. Let stand for 5 minutes to allow the layers to separate.
Transfer a portion of the upper organic layer to a GC vial and cap immediately.
(Conc. ;z~ 2 g/mL of Memantine HC1).
Sample Working Solution:
Accurately weigh 20 tablets and determine average tablet weight. Finely powder the tablets using mortar and pestle. Accurately weigh tablet powder equivalent to 20.0 mg of Memantine HCl and transfer into a 40 mL polycarbonate centrifuge tube with Nalgene screw cap. Add 10.0 mL of H20 and sonicate for 2 minutes with occasional shaking. Add 2.0 mL of 6M NaOH Solution and 10.0 mL of n-Hexane. Ensure the tube is capped tightly immediately after adding the n-Hexane to prevent any leaking and/or evaporation.
Shake the tube by hand for 5 minutes. Let stand for 10 minutes to allow the layers to separate. Transfer a portion of the upper organic layer to a GC vial and cap immediately.
(Conc. ;zt~ 2 mg/mL of Memantine HCI).
Example 4: Purity Assay GC SYSTEM: Agilent 6890 or equivalent INLET LINER: Agilent Split/Splitless Liner Part No. 5183-4711 COLUMN: ZB-1, 30 m length, 0.32 mm internal diameter, 1.0 m flm tbickness PRE-COLUMN: de-activated fused silica tubing, 5 m length, 0.32 mm internal diameter CARRIER GAS FLOW: Helium, 2.5 mL/min (constant flow) INLET: Temperature: 340 C
Split Injection: Split Ratio: 20:1 Gas Saver: ON On Time: 2.0 min Flow: 20.0 OVEN TEMPERATURE: Initial Temperature 140 C
Initial Time 1 min Rate 1 10 C/min Temperature 1 200 C
Time 1 0 min Rate 2 40 C/min Temperature 2 340 C
Time 2 1 min DETECTOR: Flame Ionization Detector (FID) at 340 C
Hydrogen 30 mL/min Air 350 mL/min Helium (makeup) 22.5 mL/min INJECTION VOLUME: 1 L
Split Injection: Split Ratio: 20:1 Gas Saver: ON On Time: 2.0 min Flow: 20.0 OVEN TEMPERATURE: Initial Temperature 140 C
Initial Time 1 min Rate 1 10 C/min Temperature 1 200 C
Time 1 0 min Rate 2 40 C/min Temperature 2 340 C
Time 2 1 min DETECTOR: Flame Ionization Detector (FID) at 340 C
Hydrogen 30 mL/min Air 350 mL/min Helium (makeup) 22.5 mL/min INJECTION VOLUME: 1 L
INJECTOR: 5 pre-washes with Diluent post-washes with Methanol 5 sample washes 5 injector pumps S
DILUENT: 0.005M Methanolic Potassium Hydroxide*
*Dilute 10 mL of 0.5M Methanolic Potassium Hydroxide to 1000 mL with Methanol RUN TIME: 12 minutes Internal Standard Working Solution (ISTD~
Accurately weigh about 125 mg of Amantadine HCl (C10H17N=HC1) and transfer into a 1000 mL volumetric flask. Add about 600 mL of Diluent and sonicate for about 2 minutes or until dissolved. Let cool to room temperature, dilute to volume with Diluent and mix well. (Conc. z 125 g/mL of Amantadine HCl).
Standard Working Solution (prepare in duplicate) Accurately weigh about 25.0 mg of Memantine HCl RS (C12H21N=HCl) and transfer into a 200 mL volumetric flask. Add about 150 mL of ISTD and sonicate for about 2 minutes or until dissolved. Let cool to room temperature, dilute to volume with ISTD and mix well.
(Conc. ;z~ 125 g/mL of Memantine HCl and,& 125 g/mL of Amantadine HCl).
Sample Working Solution (prepare in duplicate) Accurately weigh 20 tablets and determine average tablet weight. Finely powder the tablets using mortar and pestle. Accurately weigh tablet powder equivalent to 25.0 mg of Memantine HCl and transfer into a 200 mL volumetric flask. Add about 100 mL of ISTD.
Shake mechanically for 10 minutes. Sonicate for 5 minutes with occasional swirling. Allow to stand at room temperature for 10 minutes. Dilute to volume with ISTD and mix well.
Centrifuge a portion at 3000 rpm for 5 minutes. Transfer portion of clear supernatant into GC vial. (Conc. ge 125 g/mL of Memantine HCl and ;z~ 125 g/mL of Amantadine HCl).
DILUENT: 0.005M Methanolic Potassium Hydroxide*
*Dilute 10 mL of 0.5M Methanolic Potassium Hydroxide to 1000 mL with Methanol RUN TIME: 12 minutes Internal Standard Working Solution (ISTD~
Accurately weigh about 125 mg of Amantadine HCl (C10H17N=HC1) and transfer into a 1000 mL volumetric flask. Add about 600 mL of Diluent and sonicate for about 2 minutes or until dissolved. Let cool to room temperature, dilute to volume with Diluent and mix well. (Conc. z 125 g/mL of Amantadine HCl).
Standard Working Solution (prepare in duplicate) Accurately weigh about 25.0 mg of Memantine HCl RS (C12H21N=HCl) and transfer into a 200 mL volumetric flask. Add about 150 mL of ISTD and sonicate for about 2 minutes or until dissolved. Let cool to room temperature, dilute to volume with ISTD and mix well.
(Conc. ;z~ 125 g/mL of Memantine HCl and,& 125 g/mL of Amantadine HCl).
Sample Working Solution (prepare in duplicate) Accurately weigh 20 tablets and determine average tablet weight. Finely powder the tablets using mortar and pestle. Accurately weigh tablet powder equivalent to 25.0 mg of Memantine HCl and transfer into a 200 mL volumetric flask. Add about 100 mL of ISTD.
Shake mechanically for 10 minutes. Sonicate for 5 minutes with occasional swirling. Allow to stand at room temperature for 10 minutes. Dilute to volume with ISTD and mix well.
Centrifuge a portion at 3000 rpm for 5 minutes. Transfer portion of clear supernatant into GC vial. (Conc. ge 125 g/mL of Memantine HCl and ;z~ 125 g/mL of Amantadine HCl).
Inject Blank Solution (ISTD) and ensure the baseline is clean and stable.
Inject Standard Working Solution 1 five times.
Calculate the relative standard deviation (RSD) of peak area ratio of Memantine to ISTD.
The RSD is NMT 2.0%. Calculate the tailing factor (T) and column efficiency (N) for Memantine peak. T is within 0.8 and 1.2, and N is NLT 100000. The resolution (R) between ISTD and Memantine is NLT 3.5.
Inject Standard Working Solution 2, Blank Solution (ISTD), and Sample Working Solutions once.
Inject Standard Working Solution 1 once after every six samples.
Inject Standard Working Solution 1 once each at the end of the run.
Inject Standard Working Solution 1 five times.
Calculate the relative standard deviation (RSD) of peak area ratio of Memantine to ISTD.
The RSD is NMT 2.0%. Calculate the tailing factor (T) and column efficiency (N) for Memantine peak. T is within 0.8 and 1.2, and N is NLT 100000. The resolution (R) between ISTD and Memantine is NLT 3.5.
Inject Standard Working Solution 2, Blank Solution (ISTD), and Sample Working Solutions once.
Inject Standard Working Solution 1 once after every six samples.
Inject Standard Working Solution 1 once each at the end of the run.
Claims (37)
1. A method for analysing memantine, or a pharmaceutically acceptable salt thereof, and its impurities using gas chromatography.
2. The method according to claim 1, wherein the memantine is in the form of its hydrochloride salt or the free base.
3. The method according to claim 1 or 2, wherein a memantine containing sample prepared from a pharmaceutical composition is separated from any residual solids from the pharmaceutical composition by filtration or centrifugation.
4. The method according to claim 3, wherein the memantine containing sample is separated from any residual solids by centrifugation.
5. A method for analysing memantine hydrochloride, or another pharmaceutically acceptable acid addition salt thereof, and its impurities using gas chromatography, wherein a test sample is prepared by mixing memantine hydrochloride or another pharmaceutically acceptable acid addition salt thereof, or a pharmaceutical composition comprising memantine hydrochloride or another pharmaceutically acceptable acid addition salt thereof, with one or more organic solvent(s) and a non-aqueous alkaline reagent, wherein the solvent(s) is capable of dissolving the liberated memantine free base and the alkaline reagent.
6. The method according to claim 5, wherein the organic solvent(s) is a lower alkyl alcohol, tetrahydrofuran, ethyl acetate, acetonitrile, or a mixture thereof.
7. The method according to claim 6, wherein the lower alkyl alcohol is methanol, ethanol, propanol, butanol, isopropanol, or a mixture thereof.
8. The method according to claim 7, wherein the lower alkyl alcohol is methanol or ethanol.
9. The method according to any of claims 5 to 8, wherein a test sample solution prepared from a pharmaceutical composition is separated from any residual solids from the pharmaceutical composition by filtration or centrifugation.
10. The method according to claim 9, wherein the test sample solution is separated from any residual solids by centrifugation.
11. A method for analysing memantine hydrochloride and its impurities using gas chromatography, comprising:
(a) preparing a solution of an internal standard reference compound in a first organic solvent;
(b) mixing the internal standard reference compound solution with memantine hydrochloride or a pharmaceutical composition comprising memantine hydrochloride, a second organic solvent and a non-aqueous alkaline reagent to liberate memantine free base in solution; and (c) analysing the supernatant solution.
(a) preparing a solution of an internal standard reference compound in a first organic solvent;
(b) mixing the internal standard reference compound solution with memantine hydrochloride or a pharmaceutical composition comprising memantine hydrochloride, a second organic solvent and a non-aqueous alkaline reagent to liberate memantine free base in solution; and (c) analysing the supernatant solution.
12. The method according to claim 11, wherein the first and second organic solvents are the same or different.
13. The method according to claim 11 or 12, wherein the first and second organic solvents are a lower alkyl alcohol, tetrahydrofuran, ethyl acetate, acetonitrile, or any suitable organic solvent which allows complete dissolution of the liberated memantine free base and the alkaline reagent, or a mixture thereof.
14. The method according to claim 13, wherein the lower alkyl alcohol is methanol, ethanol, propanol, butanol, isopropanol, or a mixture thereof.
15. The method according to claim 14, wherein the lower alkyl alcohol is methanol or ethanol.
16. The method according to any of claims 11 to 15, wherein the alkaline reagent is added to the solution in step (a) instead of in step (b).
17. The method according to any of claims 11 to 16, wherein the supernatant solution in step (c) is separated from any residual solids from the pharmaceutical composition by filtration or centrifugation.
18. The method according to claim 17, wherein the supernatant solution is separated from any residual solids by centrifugation.
19. A method for analysing memantine hydrochloride, or another pharmaceutically acceptable acid addition salt thereof, and its impurities using gas chromatography, comprising mixing memantine hydrochloride or another pharmaceutically acceptable acid addition salt thereof, or a pharmaceutical composition comprising memantine hydrochloride or another pharmaceutically acceptable acid addition salt thereof, with one or more organic solvent(s) and an aqueous alkaline reagent to liberate memantine free base in solution in the organic solvent(s), separating the biphasic mixture to afford an organic solvent layer, and analysing the organic solvent solution.
20. The method according to claim 19, wherein the organic solvent(s) is a hydrocarbon solvent(s).
21. The method according to claim 20, wherein the hydrocarbon solvent(s) is pentane, hexane, heptane, octane, benzene or toluene.
22. The method according to claim 21, wherein the hydrocarbon solvent is n-hexane.
23. The method according to any of claims 19 to 22, wherein the organic solvent solution is separated from any residual solids from the pharmaceutical composition by filtration or centrifugation.
24. The method according to claim 23, wherein the organic solvent solution is separated from any residual solids by centrifugation.
25. The method according to any of claims 5 to 24, wherein the alkaline reagent is potassium hydroxide or sodium hydroxide.
26. The method according to claim 25, wherein the alkaline reagent is potassium hydroxide.
27. The method according to any preceding claim, wherein a memantine containing sample is injected directly onto the GC column without headspace sampling.
28. The method according to any preceding claim, wherein flame ionisation detection is used.
29. The method according to any preceding claim, wherein memantine API or memantine when prepared as a pharmaceutical composition or memantine salt API
or memantine salt when prepared as a pharmaceutical composition is analysed.
or memantine salt when prepared as a pharmaceutical composition is analysed.
30. The method according to claim 29, wherein memantine when prepared as a pharmaceutical composition or memantine salt when prepared as a pharmaceutical composition is analysed.
31. The method according to claim 30, wherein the pharmaceutical composition is a solid or liquid composition.
32. The method according to claim 31, wherein the pharmaceutical composition is a tablet.
33. The method according to claim 32, wherein the tablet comprises one or more pharmaceutically acceptable carriers or excipients.
34. The method according to any preceding claim, wherein an internal reference standard is used.
35. The method according to claim 34, wherein amantadine, amantadine hydrochloride, rimantadine or rimantadine hydrochloride is used as an internal reference standard.
36. The method according to claim 35, wherein amantadine or amantadine hydrochloride is used as an internal reference standard.
37. The method according to any preceding claim, wherein the method is used to analyse memantine hydrochloride, hydrobromide, hydroiodide, maleate, mesylate, besylate, tosylate, oxalate, acetate, propionate or formate.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0713930.6A GB0713930D0 (en) | 2007-07-18 | 2007-07-18 | Novel assay methods |
| GB0713930.6 | 2007-07-18 | ||
| PCT/GB2008/050592 WO2009010806A1 (en) | 2007-07-18 | 2008-07-18 | Assay methods for memantine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2692866A1 true CA2692866A1 (en) | 2009-01-22 |
Family
ID=38476489
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2692866 Abandoned CA2692866A1 (en) | 2007-07-18 | 2008-07-18 | A method for analysing memantine, or a pharmaceutically acceptable salt thereof, and its impurities using gas chromatography |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP2170806A1 (en) |
| JP (1) | JP2010533858A (en) |
| CN (1) | CN101801911A (en) |
| AU (1) | AU2008277379A1 (en) |
| CA (1) | CA2692866A1 (en) |
| GB (1) | GB0713930D0 (en) |
| WO (1) | WO2009010806A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105866311A (en) * | 2016-05-25 | 2016-08-17 | 福建出入境检验检疫局检验检疫技术中心 | UPLC-MS/MS method for measuring antiviral drug residuals in chicken |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103604876B (en) * | 2013-10-25 | 2015-07-08 | 烟台荣昌制药股份有限公司 | Detection method for related substances in memantine hydrochloride preparation |
| CN104950047A (en) * | 2014-03-31 | 2015-09-30 | 珠海联邦制药股份有限公司 | Method for detecting content, dissolution rate and releasing rate of memantine hydrochloride or analogues thereof in medicinal agent |
| CN104237407A (en) * | 2014-09-12 | 2014-12-24 | 山东省医药工业研究所 | Method for detecting releasing rate of amantadine hydrochloride sustained release tablets |
| CN107290375A (en) * | 2017-05-23 | 2017-10-24 | 兰州兰石检测技术有限公司 | The method for determining calcirm-fluoride in fluorite, calcium carbonate, sulphur, iron and dioxide-containing silica |
| CN109959731B (en) * | 2017-12-26 | 2022-07-08 | 广东东阳光药业有限公司 | Method for determining memantine derivative by using HPLC method |
| CN108152422A (en) * | 2018-01-30 | 2018-06-12 | 上海信谊万象药业股份有限公司 | The analysis method that drug content measures in a kind of amantadine hydrochloride solid pharmaceutical preparation |
| CN110487919A (en) * | 2018-05-14 | 2019-11-22 | 人福普克药业（武汉）有限公司 | A method of detection amantadine hydrochloride soft capsule cleans residual quantity |
| CN109507326A (en) * | 2018-12-24 | 2019-03-22 | 营口康辉石化有限公司 | The measuring method and its application of content of tetrahydrofuran in a kind of PBT |
| CN110320293B (en) * | 2019-06-28 | 2022-04-12 | 弘和制药有限公司 | Method for determining residual solvent in phthalide compound |
| CN111323520A (en) * | 2020-04-14 | 2020-06-23 | 郑州中检科测试技术有限公司 | Method for simultaneously detecting ribavirin and amantadine residues in livestock products |
| CN112162045A (en) * | 2020-09-24 | 2021-01-01 | 石药集团欧意药业有限公司 | Method for detecting 2-chloropropane in memantine hydrochloride |
| CN113109460B (en) * | 2020-11-05 | 2023-04-07 | 四川阿格瑞新材料有限公司 | Method for analyzing high-boiling-point solvent residue in OLED material |
| CN114199812A (en) * | 2021-12-28 | 2022-03-18 | 南通联亚药业有限公司 | Method for detecting memantine hydrochloride in memantine hydrochloride sustained-release preparation |
| CN115060830A (en) * | 2022-07-05 | 2022-09-16 | 云南大理天新包装材料有限公司 | Method for detecting VOCs solvent residues of paper |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL7305644A (en) | 1972-04-20 | 1973-10-23 | ||
| JP4807675B2 (en) * | 2001-02-26 | 2011-11-02 | 東レ・ファインケミカル株式会社 | Method for producing high purity piperazine derivative hydrochloride |
| TW200616608A (en) * | 2004-07-09 | 2006-06-01 | Forest Laboratories | Memantine as adjunctive treatment to atypical antipsychotics in schizophrenia patients |
| WO2006122238A1 (en) * | 2005-05-11 | 2006-11-16 | Dr. Reddy's Laboratories Ltd. | Process for preparing memantine |
| MX2007014913A (en) * | 2006-03-27 | 2008-10-24 | Teva Pharma | Process for preparing memantine hydrochloride substantially free of impurities. |
-
2007
- 2007-07-18 GB GBGB0713930.6A patent/GB0713930D0/en not_active Ceased
-
2008
- 2008-07-18 CN CN200880106761A patent/CN101801911A/en active Pending
- 2008-07-18 EP EP08776227A patent/EP2170806A1/en not_active Withdrawn
- 2008-07-18 JP JP2010516600A patent/JP2010533858A/en active Pending
- 2008-07-18 CA CA 2692866 patent/CA2692866A1/en not_active Abandoned
- 2008-07-18 AU AU2008277379A patent/AU2008277379A1/en not_active Abandoned
- 2008-07-18 WO PCT/GB2008/050592 patent/WO2009010806A1/en active Application Filing
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105866311A (en) * | 2016-05-25 | 2016-08-17 | 福建出入境检验检疫局检验检疫技术中心 | UPLC-MS/MS method for measuring antiviral drug residuals in chicken |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2008277379A1 (en) | 2009-01-22 |
| JP2010533858A (en) | 2010-10-28 |
| GB0713930D0 (en) | 2007-08-29 |
| EP2170806A1 (en) | 2010-04-07 |
| WO2009010806A1 (en) | 2009-01-22 |
| CN101801911A (en) | 2010-08-11 |
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