WO2023069040A1 - Use of reticulin impurity as purity and stability specification in morphine and morphine extracts - Google Patents
Use of reticulin impurity as purity and stability specification in morphine and morphine extracts Download PDFInfo
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- WO2023069040A1 WO2023069040A1 PCT/TR2022/050286 TR2022050286W WO2023069040A1 WO 2023069040 A1 WO2023069040 A1 WO 2023069040A1 TR 2022050286 W TR2022050286 W TR 2022050286W WO 2023069040 A1 WO2023069040 A1 WO 2023069040A1
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- morphine
- reticulin
- purity
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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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
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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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds
-
- 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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/8872—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample impurities
Definitions
- Morphine is a very effective analgesic active ingredient. It is the typical active ingredient of opioids and is the prototype of this group. It is present in crude opium at a rate of 10-12%. Morphine is included in the World Health Organization's List of Essential Medicines as a medicine.
- Morphine is a very powerful drug in the group of narcotic pain relievers. Heavenly operations, It is used in the treatment of cancer pain, heart attack, long-lasting chronic pain.
- Opium is a drug obtained from the capsules of the poppy plant. Although the amount of opium in the capsule varies between 0.2-0.8%, it is stated that this rate has reached 1% as a result of the improvement studies. The production of opium, which is used for medicinal purposes in the world, is made from the poppy (Papaver somniferum L.) plant.
- Opium contains approximately 10% morphine, 5% codeine, and 6% narcotine. Obtaining morphine from opium in solution requires evaporation and re-dissolving with calcium chloride solution.
- Codeine is obtained by methylating the phenolic group.
- Morphine is used as an active ingredient in medicine as hydrochloride, sulfate, acetate, tartrate salts.
- Fast-acting tablets containing 10 mg, 20 mg or 50 mg of morphine; Slow-release and extended- release tablets containing 5 mg, 10 mg, 15 mg, 30 mg, 60 mg, 100 mg, or 200 mg of morphine; Slow-acting capsules containing 10 mg, 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, or 200 mg of morphin; granules containing 30 mg, 60 mg, 100 mg or 200 mg of morphine in a sachet; There is a liquid form containing 10 mg of morphine in 5 ml or 20 mg of morphine in 1 ml and a suppository form containing 10 mg of morphine.
- the present application relates to an improved method for the use of a compound named Reticulin, an impurity present in Morphine, morphine salts and morphine extracts, as impurity determination, shelf-life indicator and stability specification in Morphine, morphine salts and morphine extracts.
- reticulin can range from 0.001% to 2% w/w.
- Reticulin is one of the opium alkaloids (Formula II). It has a toxic effect on dopaminergic neurons, causing atypical parkinsonism known as Guadeloupean Parkinsonism.
- Reticulin is a precursor of morphine and some other alkaloids with a phenanthrene ring. Morphine biosynthesis from reticulin is shown below (Novak B, Hudlicky T, Reed J, Mulzer J, Trauner D (March 2000). "Morphine Synthesis and Biosynthesis-An Update” (POF). Current Organic Chemistry. 4 (3): 343-362; https://en.wikipedia.org/wiki/Morphine)
- morphine In this application, from the term morphine; It should be understood that by morphine, morphine salts, hydrates and solvates it is meant morphine extracts, morphine intermediates and semi-finished products.
- the present application is an HPLC method for the determination of purity, stability or shelf life in morphine, morphine salts, hydrates and solvates and morphine extracts, morphine preparation intermediates and semi-finished products, and its feature covers the determination of the amount of reticulin in the material under investigation.
- the present application relates to an improved method for the use of a compound named Reticulin, an impurity present in morphine, morphine salts, hydrate or solvates, and morphine extracts, as an impurity determination, shelf-life indicator, and stability specification.
- the present application contains a compound called Reticulin, an impurity present in morphine extracts.
- the present application contains a compound called Reticulin, an impurity present in morphine semi-finished products developed for use as impurity determination, shelf life determination and stability specification
- HPLC method in which the amount of reticulin is determined, which is the subject of the present application, It is applied for determination of shelf life.
- HPLC method in which the amount of reticulin is determined, which is the subject of the present application,
- HPLC method in which the amount of reticulin is determined, which is the subject of the present application,
- the impurity of retucillin is the specification of purity, stability. It can be used in tests and determination of shelf life.
- the material examined in the HPLC method in which the amount of reticulin, which is the subject of the current application, is determined morphine salts of which are morphine hydrochloride, morphine sulfate, morphine tartrate, morphine citrate and these salts hydrates and solvates.
- reticulin In the HPLC method, in which the amount of reticulin, which is the subject of the present application, is determined, reticulin is referenced. standard may be R-reticulin, S-reticulin, racemic reticulin, or a mixture of R- and S-reticulin.
- the specified reticulin reference standard must be at least 98% pure.
- the HPLC method includes the following steps:
- the process parameters of the HPLC method are as follows:
- Injection volume 8 pL.
- Collusion cell parameters were set as follows.
- Morphine HCL Morphine Sulphate
- Morphine other forms morphine extracts It is possible to monitor stability by analysis of reticulin (peak at 19 minutes in HPLC).
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
It is based on the determination of the amount of reticulin by HPLC method for the determination of purity, stability or shelf life in morphine, morphine salts, hydrates and solvates and morphine extracts, semi-finished products and intermediates.
Description
USE OF RETICULIN IMPURITY AS PURITY AND STABILITY SPECIFICATION IN MORPHINE AND MORPHINE EXTRACT
Morphine is a very effective analgesic active ingredient. It is the typical active ingredient of opioids and is the prototype of this group. It is present in crude opium at a rate of 10-12%. Morphine is included in the World Health Organization's List of Essential Medicines as a medicine.
Morphine is a very powerful drug in the group of narcotic pain relievers. Heavenly operations, It is used in the treatment of cancer pain, heart attack, long-lasting chronic pain.
Opium (Opium) is a drug obtained from the capsules of the poppy plant. Although the amount of opium in the capsule varies between 0.2-0.8%, it is stated that this rate has reached 1% as a result of the improvement studies. The production of opium, which is used for medicinal purposes in the world, is made from the poppy (Papaver somniferum L.) plant.
Opium contains approximately 10% morphine, 5% codeine, and 6% narcotine. Obtaining morphine from opium in solution requires evaporation and re-dissolving with calcium chloride solution.
After separation of this solution, the liquid portion is evaporated several times and the remaining morphine and codeine crystals are collected. These are recrystallized after dissolving with the aid of ammonia. Thus, morphine was separated from the codeine remaining in solution.
Morphine crystallizes as acicular crystals with one molecule of water.
The morphine compound (Formula I), whose IUPAC name is 3,6-dihydroxy-4,S-epoxy-17- methylmorphinan-7-ene, has 2 hydroxyl groups, one phenolic and the other alcohol group.
Codeine is obtained by methylating the phenolic group.
Morphine is used as an active ingredient in medicine as hydrochloride, sulfate, acetate, tartrate salts.
Formula I
Morphine hydrochloride or sulfate injection as dosage forms used in medicine and pharmacy;
Fast-acting tablets containing 10 mg, 20 mg or 50 mg of morphine; Slow-release and extended- release tablets containing 5 mg, 10 mg, 15 mg, 30 mg, 60 mg, 100 mg, or 200 mg of morphine; Slow-acting capsules containing 10 mg, 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, or 200 mg of morphin; granules containing 30 mg, 60 mg, 100 mg or 200 mg of morphine in a sachet; There is a liquid form containing 10 mg of morphine in 5 ml or 20 mg of morphine in 1 ml and a suppository form containing 10 mg of morphine.
Disclosure of the invention
According to EMA and FDA guidelines, critically important peaks seen in chromatographic tests of chemical compounds need to be identified and characterized.
The present application relates to an improved method for the use of a compound named Reticulin, an impurity present in Morphine, morphine salts and morphine extracts, as impurity determination, shelf-life indicator and stability specification in Morphine, morphine salts and morphine extracts.
Impurity determination by reticulin analysis, stability has not been observed in morphine, morphine salts and morphine extracts as a shelf life indicator before. In samples, reticulin can range from 0.001% to 2% w/w.
Reticulin is one of the opium alkaloids (Formula II). It has a toxic effect on dopaminergic neurons, causing atypical parkinsonism known as Guadeloupean Parkinsonism.
Formula II
Reticulin is a precursor of morphine and some other alkaloids with a phenanthrene ring. Morphine biosynthesis from reticulin is shown below (Novak B, Hudlicky T, Reed J, Mulzer J, Trauner D (March 2000). "Morphine Synthesis and Biosynthesis-An Update" (POF). Current Organic Chemistry. 4 (3): 343-362; https://en.wikipedia.org/wiki/Morphine)
In this application, from the term morphine; It should be understood that by morphine, morphine salts, hydrates and solvates it is meant morphine extracts, morphine intermediates and semi-finished products.
Detailed description of the invention
The present application is an HPLC method for the determination of purity, stability or shelf life in morphine, morphine salts, hydrates and solvates and morphine extracts, morphine preparation intermediates and semi-finished products, and its feature covers the determination of the amount of reticulin in the material under investigation.
The present application relates to an improved method for the use of a compound named Reticulin, an impurity present in morphine, morphine salts, hydrate or solvates, and morphine extracts, as an impurity determination, shelf-life indicator, and stability specification.
The present application contains a compound called Reticulin, an impurity present in morphine extracts.
Developed for use as impurity determination, shelf life determination and stability specification It's about a method.
The present application contains a compound called Reticulin, an impurity present in morphine semi-finished products developed for use as impurity determination, shelf life determination and stability specification
It's about a method.
The HPLC method, in which the amount of reticulin is determined, which is the subject of the present application,
It is applied for determination of shelf life.
The HPLC method, in which the amount of reticulin is determined, which is the subject of the present application,
Applied for stability tests.
The HPLC method, in which the amount of reticulin is determined, which is the subject of the present application,
It is applied for purity test. Thus, the impurity of retucillin is the specification of purity, stability. It can be used in tests and determination of shelf life.
The material examined in the HPLC method, in which the amount of reticulin, which is the subject of the current application, is determined morphine salts of which are morphine hydrochloride, morphine sulfate, morphine tartrate, morphine citrate and these salts hydrates and solvates.
In the HPLC method, in which the amount of reticulin, which is the subject of the present application, is determined, reticulin is referenced. standard may be R-reticulin, S-reticulin, racemic reticulin, or a mixture of R- and S-reticulin.
The specified reticulin reference standard must be at least 98% pure.
The HPLC method includes the following steps:
(i) dissolve a suitable weighed amount of a morphine test material in the solvent to obtain a sample solution;
(ii) a suitable weighed amount of the Reticulin reference standard to obtain the standard solution solvent dissolves in it;
(iii) samples and standard solutions are injected into an HPLC column; and
(iv) the main peak areas of each solution are determined and the amount of reticulin in the test material is calculated.
As the stationary phase in the HPLC method in which the amount of reticulin is determined, which is the subject of the present application. C18 column (2.1 x 100 mm, 1.8 pm) acetonitrile containing 0.1% formic acid in water as mobile phase used.
The process parameters of the HPLC method are as follows:
Stationary phase: C18 column (2.1 x 100 mm, 1.8 pm)
Mobile Phase: acetonitrile (B) and 0.1% formic acid (FA) in water (A).
Flow rate: 0.4 ml/min
Injection volume: 8 pL.
Column temperature: 45C .
Sample room temperature: 4C.
Gradient conditions:
Minutes/B%: 0/1, 12/100, 14/100, 14.5/0, 16.5/100
Test method in morphine, morphine salts, hydrate and solvates, and morphine extracts and intermediates products and semi-finished products, feature stability, insecurity, shelf life criteria the use of reticulin.
With this method, the stability of morphine according to the amount of reticulin, insecurity, the design of the shelves is not of great importance.
Evaluations critical peak in morphine raw material in previous methods has been researched. For this purpose, the UPLC-QTOF-MS method was applied, as in Figure 1.
Agilent RRHD Zorbax C18 (2.1 x 100 mm, 1.8 pm) column as stationary phase, mobile phase acetonitrile (B) and 0.1% formic acid in water are shown as peaks with a shooting time of 5.2 minutes. The liquid eluted from liquid chromatography directly into a to be analyzed in electrospray (Electros spray = ESi) ionization spectrometry fractions were collected. More like after mass spectrometry in Figures 2 and 3 The unknown peak belonged to reticulin with a mass of 330.168 g/mol.
MS Parameters are given below:
• Mode: ESi Positive
• Nitrogen nebulizer gas pressure: 3 bar
• Drying gas flow rate: 12 E/min
• End plate offset: 500 V
• Capillary voltage: +4500 V
• Dry temperature: 200 C
• Funnel 1 RF and funnel 2 RF: 200, 175 Vpp
• CID energy: that house
• Hexapol RF: 50 Vpp
• Ion energy: 5 eV
• Low mass filtration: 50 m/z
Collusion cell parameters were set as follows.
• Collusion energy 10 eV; collusion RF 500 Vpp; transfer time 60 pS and pre-pulse storage 6 ps.
• Data analysis 4.2 (Bruker Daltonics, Bremen, Germany)
Description of drawings:
Figure 1. Appearance of impurity with a retention time of 5.2 minutes in the UPLC chromatogram
Method: Agilent RRHD Zorbax C18 (2.1 x 100 mm, 1.8 pm) column, Mobile Phase was acetonitrile (B) and 0.1% formic acid (FA) in water (A)
Figure 2. Mass spectroscopy (MS) of unknown impurity
Figure 3. MS/MS (mole weight = 330.168) for the precursor ion of the unknown impurity
Advantages of the method
- Available in Morphine HCL, Morphine Sulphate, Morphine other forms and morphine extracts It is possible to monitor stability by analysis of reticulin (peak at 19 minutes in HPLC).
- Analytical traceability of morphine and morphine extracts as a natural product can be extended by impurity or by reticulin impurity of produced batches possible to be combined.
- Stability tests of morphine and morphine extracts of reticulin impurity, product information and analysis certificates, it will be possible to specify it as a specification.
Claims
1. HPLC method for the determination of purity, stability or shelf life in morphine, morphine salts, hydrates and solvates and morphine extracts, semi-finished products and intermediates, and wherein it includes the determination of the amount of reticulin in the material under investigation.
2. HPLC method according to claim 1, wherein it is applied to determine the shelf life of the examined material.
3. HPLC method according to claim 1, wherein the material examined is applied in the stability test.
4. HPLC method according to claim 1, wherein it is used in the purity test of the material under investigation is the implementation.
5. HPLC method according to claim 1, wherein a C18 column (2.1 x 100 mm, 1.8 pm) is used as the stationary phase and acetonitrile containing 0.1% formic acid in water as the mobile phase.
6. Morphine salts according to claim 1 are hydrochloride, sulfate, tartrate and citrate.
7. Use of Reticulin as a reference standard in the HPLC method for the determination of purity, stability or shelf life in morphine, morphine salts, hydrates and solvates and morphine extracts, semi-finished products and intermediates.
8. Reticulin reference standard according to claim 7, whereinthe reference standart is R- reticulin, S-reticulin, racemic reticulin or a mixture of R- and S-reticulin.
9. Reticulin reference standard according to claim 8, where it has at least 98% purity.
7
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2021/016490 | 2021-10-22 | ||
| TR2021/016490A TR2021016490A2 (en) | 2021-10-22 | 2021-10-22 | USE OF REticULIN IMPURITY AS PURITY AND STABILITY SPECIFICATION IN MORPHINE AND MORPHINE EXTRACTS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2023069040A1 true WO2023069040A1 (en) | 2023-04-27 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2022/050286 Ceased WO2023069040A1 (en) | 2021-10-22 | 2022-04-01 | Use of reticulin impurity as purity and stability specification in morphine and morphine extracts |
Country Status (2)
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| TR (1) | TR2021016490A2 (en) |
| WO (1) | WO2023069040A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080206883A1 (en) * | 2007-02-26 | 2008-08-28 | Cody Laboratories, Inc. | Hplc method for separation and detection of hydromorphone and related opioid pharmacophores |
-
2021
- 2021-10-22 TR TR2021/016490A patent/TR2021016490A2/en unknown
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2022
- 2022-04-01 WO PCT/TR2022/050286 patent/WO2023069040A1/en not_active Ceased
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080206883A1 (en) * | 2007-02-26 | 2008-08-28 | Cody Laboratories, Inc. | Hplc method for separation and detection of hydromorphone and related opioid pharmacophores |
Non-Patent Citations (3)
| Title |
|---|
| AL-AMRI A.M, SMITH R.M, EL-HAJ B.M, JUMA’A M.H: "The GC–MS detection and characterization of reticuline as a marker of opium use", FORENSIC SCIENCE INTERNATIONAL, ELSEVIER B.V., AMSTERDAM, NL, vol. 140, no. 2-3, 1 March 2004 (2004-03-01), AMSTERDAM, NL , pages 175 - 183, XP093064996, ISSN: 0379-0738, DOI: 10.1016/j.forsciint.2003.10.022 * |
| CHAN KAR-WENG: "Validation of a straightforward high performance liquid chromatographic method for morphine quantitation", EGYPTIAN JOURNAL OF FORENSIC SCIENCES, vol. 7, no. 1, 1 December 2017 (2017-12-01), XP093064997, DOI: 10.1186/s41935-017-0003-0 * |
| LURIE, I. S. ET AL.: "Applicability of ultra-performance liquid chromatography- tandem mass spectrometry for heroin profiling.", JOURNAL OF CHROMATOGRAPHY A, vol. 1188, no. 2, 2008, pages 322 - 326, XP022588657, DOI: 10.1016/j.chroma.2008.03.011 * |
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| TR2021016490A2 (en) | 2021-11-22 |
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