CN101155775A - Stable atomoxetine hydrochloride, a process for the preparation thereof, and an analytical control of its stability - Google Patents
Stable atomoxetine hydrochloride, a process for the preparation thereof, and an analytical control of its stability Download PDFInfo
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- CN101155775A CN101155775A CNA2006800113592A CN200680011359A CN101155775A CN 101155775 A CN101155775 A CN 101155775A CN A2006800113592 A CNA2006800113592 A CN A2006800113592A CN 200680011359 A CN200680011359 A CN 200680011359A CN 101155775 A CN101155775 A CN 101155775A
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Abstract
Stable Atomoxetine hydrochloride, a process for the manufacture thereof, the use of stable Atomoxetine Hydrochloride for making a pharmaceutical formulation, a process for the preparation of any form of Atomoxetine Hydrochloride, and an analytical method for analyzing the stability of Atomoxetine Hydrochloride are provided.
Description
The cross reference of related application
The application requires the U.S. Provisional Patent Application 60/668 of submission on April 5th, 2005,741, the U.S. Provisional Patent Application of submitting on May 31st, 2,005 60/686, the U.S. Provisional Patent Application 60/688 that on June 7th, 386 and 2005 submitted to, 406 rights and interests, its full content is incorporated into herein as a reference.
Invention field
The present invention relates to the stable atomoxetine hydrochloride that does not have impurity and degraded product basically (Atomoxetine hydrochloride), its preparation method, and the analytical procedure of prediction atomoxetine hydrochloride stability.
Background of invention
Atomoxetine (Atomoxetine ATM) is known as (R) (-)-n-methyl-3-(2-methylphenoxy)-3-amphetamine, has following structure:
With molecular formula C
17H
21NO, molecular weight are 255.35, and weight consists of: 79.96%C, 8.29%H, 5.49%N and 6.27%O.Atomoxetine is (R)-(-) enantiomer of tomoxetine (Tomoxetine).Atomoxetine is the competitive inhibitor at the norepinephrine uptake of the synaptosome of rat hypothalamus.Atomoxetine is used for the treatment of attention shortcoming/superfunction illness (ADHD).
The atomoxetine hydrochloride is with STRATTERA
Sell, its form with oral capsule with 10 milligrams, 18 milligrams, 25 milligrams, 40 milligrams and 60 milligrams dosage is prescribed.
The stability of atomoxetine hydrochloride is known as serious problems.The synthetic use excessive hydrogen chloride that relates to of atomoxetine hydrochloride.The existence of excessive free hydrogenchloride may cause degraded between last several steps of manufacturing processed and shelf lives.Therefore, for example Sigma-Aldrich suggestion 2 ℃ to 8 ℃ storages with avoid this degraded (referring to identification symbol T7947, (R)-tomoxetine hydrochloride, www.sigmaaldrich.com).
Known in the artly be, before active medicine component (API) product ommercialization,, need country and international control and management office to having differentiated, but the non-distinctive impurity of toxicology to be set up low-down limit based on security consideration for people's administration.These limits are usually less than about 0.15 weight % of each impurity.Obviously lower without limit that differentiate and/or non-distinctive impurity.Therefore in making API, for example the product of atomoxetine hydrochloride needs purifying before commercialization, and is same, and when making preparation medicine, promoting agent needs purifying equally.
This area it is also known that the impurity among the API may be produced by the degraded of API itself, between this and shelf lives, in the manufacturing processed, comprises that the stability of pure API is relevant during the chemosynthesis.Process impurity comprises chemical derivative, synthesising by-product and the degraded product of the impurity that contains in unreacted starting materials, the starting material.
Except the stability as API storage time factor, the purity of the API for preparing in the industrial manufacturing processed obviously also is business-like prerequisite.The impurity of introducing in the industry manufacturing processed must be limited in very little amount, and does not preferably have basically.For example API manufacturer's ICH Q7A handbook requires process impurity to remain on below the prescribed limit by stipulating raw material quality, control process parameters (for example temperature, pressure, time and stoichiometric ratio) and introduce purification step (for example crystallization, distillation and liquid-liquid extraction) in manufacturing processed.In the U.S., FDA's criterion requires the amount of some impurity to be limited in less than 0.1%.
As those skilled in the art were known, by understanding its chemical structure and synthesis path, and by determining to influence the parameter of impurity level in the final product, the control of process impurity improved greatly.Therefore the impurity among the API is mainly from one of two sources: (I) synthetic and (II) degraded of API of manufacturing processed or API itself.
In case obtain the pure atomoxetine hydrochloride, that is, the atomoxetine hydrochloride does not have process impurity basically, perhaps exists with very little, limited amount at the last impurity of manufacturing processed.As long as avoided pollution, the degradation impurity (II) relevant with memory period stability is the main source of impurity.Country and international regulations require manufacturer to provide suitable file to prove the stability of API and compounding pharmaceutical to control and management office.Therefore the stability of the API of being as known in the art itself is commercial prerequisite.For example referring to the ICH Q7A handbook of API manufacturers.
Other product (side products), by product and auxiliary reagent (being commonly referred to as impurity) utilize spectrographic technique usually and/or use other physical method to determine, then in conjunction with the peak position, the peak position in the chromatogram for example, perhaps the spot on the chromatographic sheet determines that (Strobel p.953, Strobel, H.A.; Heineman, W.R., Chemical Instrumentation:A Systematic Approach, 3rd dd. (Wiley ﹠amp; Sons:New York 1989)).This rear impurity can for example determine by the relative position in the chromatogram that wherein the position in the chromatogram is passed through between the detector with a minute measurement at sample injection tower and specific components wash-out usually.Relative position in the chromatogram is known as " retention time ".
As those skilled in the art were known, by understanding its chemical structure and synthesis path, and by determining to influence the parameter of impurity level in the final product, the control of process impurity improved greatly.
Therefore, it will be favourable having the atomoxetine hydrochloride that improves stability.The invention provides this atomoxetine hydrochloride.
Summary of the invention
One aspect of the present invention provides stable atomoxetine hydrochloride.The free hydrogenchloride that contains the reduction amount in the stable atomoxetine hydrochloride of the present invention is so that the aqueous solution of stable atomoxetine hydrochloride has the pH at least about 4.Stable atomoxetine hydrochloride preferably has the pH of about 4-about 7.
The present invention provides the method for preparing stable atomoxetine hydrochloride on the other hand.
Another aspect of the invention provides the method for analyzing atomoxetine hydrochloride stability, comprises the pH that determines atomoxetine hydrochloride aqueous sample.
One aspect of the invention provides the method for analyzing atomoxetine hydrochloride stability, comprises the chloride content of determining in the atomoxetine hydrochloride.
Another aspect of the present invention provides preparation to contain the method for the pharmaceutical preparation of stable atomoxetine hydrochloride, may further comprise the steps:
A) obtain one or more samples of one or more atomoxetine hydrochloride batch of materials;
B) a) content of arbitrary impurity in each sample of measuring process:
(c)
C), select impurity (a) doped level to be lower than about 0.15% w/w, and arbitrary content is lower than the atomoxetine hydrochloride batch of material of about 0.10% w/w (passing through HPLC) in impurity (b) and the impurity (c) based on the measurement of carrying out in the step b); With
D) use the batch of material of selecting in the step c) to contain the pharmaceutical preparation of stable atomoxetine hydrochloride with preparation.
The present invention provides the method for preparing crystallization or amorphous atomoxetine hydrochloride on the other hand, may further comprise the steps:
A) obtain one or more samples of one or more atomoxetine hydrochloride batch of materials;
B) a) the impurity (a) and (b) and (c) content of arbitrary impurity in each sample of measuring process;
C), select impurity (a) doped level to be lower than 0.15% w/w, and arbitrary content is lower than the atomoxetine hydrochloride batch of material of about 0.10% w/w (passing through HPLC) in impurity (b) and the impurity (c) based on the measurement of carrying out in the step b); With
D) batch of material of selecting in the use step c) is to prepare described crystallization or amorphous atomoxetine hydrochloride.
One aspect of the invention provides arbitrary impurity (a) and (b) or HPLC method (c) in the mensuration atomoxetine hydrochloride, may further comprise the steps:
A) sample that will contain 1 milligram of atomoxetine hydrochloride joins in the mixture that 1 milliliter of pH is phosphate buffered saline buffer/acetonitrile (60/40) of about 3;
B) mixture with step a) is injected in 250 millimeters * 4.6 millimeters * 5.0 microns YMC-filling ADS-AQ (or similar) posts;
C) use acetonitrile as elutriant: water (90: 10) is about 2.8 mg/ml NaH with containing concentration
2PO
4The aqueous solution of monohydrate and 85% (w/w) H
3PO
4With the mixture of the damping fluid of regulating pH about 3 elution samples gradually from post; With
D) use arbitrary impurity (a) and (b) or content (c) in the UV detectors measure sample.
The present invention provides on the other hand and has contained the stable atomoxetine hydrochloride of the present invention and the pharmaceutical preparation of pharmaceutically acceptable vehicle.
The present invention provides the preparation method of the pharmaceutical preparation that contains stable atomoxetine hydrochloride of the present invention and pharmaceutically acceptable vehicle on the other hand.
One aspect of the invention provides the stable atomoxetine hydrochloride of the present invention to be used for the application of pharmaceutical compositions.
Detailed Description Of The Invention
The term of Shi Yonging " free hydrogenchloride " refers to the hydrogenchloride molecule that is not attached to atomoxetine herein, and hydrogenchloride surpasses 1: 1 amount existence with the ratio with atomoxetine in the atomoxetine hydrochloride thus.
The term of Shi Yonging " high vacuum " refers to the pressure of about 0 mmhg to about 50 mmhg herein.
The term of Shi Yonging " low temperature " refers to and is lower than 40 ℃ temperature herein, more preferably less than 30 ℃ temperature.
Atomoxetine hydrochloride three kinds of major impurities that degraded produces in the presence of free HCl are:
Impurity (a): N-methyl-3-hydroxyl-3-amphetamine, it has following structure:
Be the starting material of synthetic atomoxetine, and from atomoxetine, detect and analyze with 0.2 RRt by HPLC;
Impurity (b): N-methyl-3-phenyl-2,3-propenyl amine, it has following structure:
From atomoxetine, detect and analyze with 0.4 RRt by HPLC; With
Impurity (c): ortho-cresol (2-cresols), it has following structure:
And from atomoxetine, detect and analyze with 0.9 RRt by HPLC.
The term relevant with the atomoxetine hydrochloride of Shi Yonging " stablized " and referred in about 70 ℃ of storages during at least about 58 hours herein, perhaps the impurity (a) in the atomoxetine hydrochloride can not be increased to more than about 0.15% w/w, perhaps the impurity (b) in the atomoxetine hydrochloride or (c) can not be increased to more than about 0.10% w/w.
The invention provides stable atomoxetine hydrochloride.
The atomoxetine hydrochloride that the present invention is stable contains the free hydrogenchloride of reduction amount, makes the aqueous solution of stable atomoxetine hydrochloride have the pH at least about 4.Stable atomoxetine hydrochloride preferably has the pH of about 4-about 7.
A kind of method for preparing stable atomoxetine hydrochloride comprises by the low temperature high vacuum removes excessive free hydrogenchloride arbitrarily from isolating thick atomoxetine hydrochloride product.Vacuum is removed needs high-vacuum pump and the acid hydrogenchloride steam of neutralization.And, because the high metallic corrosion level of hydrochloric acid needs anhydrous evaporation conditions to avoid destroying the stainless steel industry vacuum apparatus.
The invention provides the method for the stable atomoxetine hydrochloride of preparation, comprise by being suspended at least a water, the C of being selected from
3-C
8Ketone and C
3-C
8The solvent of alcohol and/or from atomoxetine hydrochloride product, remove any excessive free hydrogenchloride with at least a described solvent wash.Remove any production process that de-chlorine hydride is very suitable for the atomoxetine hydrochloride of synthesizing stable by being suspended in the described solvent and/or with solvent wash.When washing and/or suspended solvents dissolving hydrogenchloride and can not dissolve the atomoxetine hydrochloride time, this method is the most effective.Preferably, C
3-C
8Ketone is C
3-C
5Ketone.More preferably, C
3-C
5Ketone is selected from acetone, methylethylketone.Most preferably, C
3-C
5Ketone is acetone.Preferably, C
3-C
8Alcohol is C
3-C
5Alcohol.More preferably, C
3-C
5Alcohol is selected from propyl alcohol, Virahol and butanols.Most preferably, C
3-C
5Alcohol is butanols.
When using suspension, recovery comprises filtering suspension liquid, washing and drying.The preferred solvent that suspends and use that uses of washing.Preferably, when using aqueous suspension, temperature is about 0 ℃ to about 10 ℃.
Preferably, work as C
3-C
8Ketone and C
3-C
8When alcohol was used to wash, temperature was about 10 ℃ to about 30 ℃.Preferably, when water was used to wash, temperature was about 0 ℃ to about 30 ℃.Preferably, when acetone was used to wash, temperature was about 30 ℃.Wet atomoxetine hydrochloride is preferred further dry.Dry preferably carry out to about 70 ℃ temperature vacuum at about 60 ℃.
As those skilled in the art are known, to compare with chemical solvents, water provides bigger economy and environmental advantage.
When doing or wet atomoxetine hydrochloride in not exist free HCl or pH to surpass about 4.0 the time, the thermally-stabilised experiment of pressure shows and obtains highly stable atomoxetine hydrochloride.Yet the existence of HCl in the atomoxetine hydrochloride as described below, it can easily detect by pH test in the atomoxetine hydrochloride aqueous solution, can cause the remarkable degraded of atomoxetine hydrochloride.
Atomoxetine hydrochloride sample analytical characteristic:
| The pH of 2% (weight/volume) aqueous solution | Estimate free HCl content (weight %) | Water ratio (weight %) | |
| Sample 1 sample 2 samples 3 samples 4 | 2.4 5.8 6.0 5.9 | 2％ 0％ 0％ 0％ | 10％ 11％ 0.5％ 0.0％ |
Atomoxetine hydrochloride sample stability test (70 ℃ 58 hours) result
| Time zero | Impurity (a) (HPLC A%) | Impurity (b) (HPLC A%) | Impurity (c) (HPLC A%) |
| Sample 1 sample 2 samples 3 samples 4 | Do not detect | Do not detect | Do not detect |
Impurity (a): N-methyl-3-hydroxyl-3-amphetamine
Impurity (b): N-methyl-3-phenyl-2,3-propenyl amine and
Impurity (c): ortho-cresol (2-cresols)
| The test duration terminal point | Impurity (a) (HPLC A%) | Impurity (b) (HPLC A%) | Impurity (c) (HPLC A%) |
| Sample 1 sample 2 samples 3 samples 4 | 10.5% does not detect | 14.2% does not detect | 26.2% does not detect |
Heating under vacuum is generally used for desolvating commercial synthesizing to remove from wet solid., contain in two samples of the wet atomoxetine hydrochloride of discovery for example as the n-butyl acetate of solvent with as after filtering the hydrochloric acid of reactant from crystallization medium:
| The atomoxetine hydrochloride | Water | N-butyl acetate | Free HCl | PH (in the water 2%) | |
| Sample 5 | 80.44％ | 9.7％ | 8.25％ | 1.61％ | 2.4 |
| Sample 6 | 83.54％ | 10.5％ | 4.77％ | 1.19％ | 2.4 |
Show that pH is not the existence of insignificant free HCl less than 4 simple pH aqueous solution evidence in the atomoxetine hydrochloride.This combination that can pass through the quantitative assay of the quantitative assay of weight loss on drying, water ratio and chloride ion content confirms.
Experiment shows, the wet atomoxetine hydrochloride that 70 ℃ of dryings contain free HCl more than 2% in vacuum drying oven seriously reduces product purity (HPLC result, weight percentage).These experimental results are consistent with previous described stability data.
| Sample 5 | Impurity (a) | Impurity (b) | Impurity (c) |
| Before the drying | Do not detect | Do not detect | Do not detect |
| After the drying | 0.31％ | 0.04％ | 0.12％ |
Under 40 ℃ lesser temps for example, aqueous solution pH test reduces less than the stability of 4 atomoxetine hydrochloride sample, and aqueous solution pH test is stable greater than the stability of 4 atomoxetine hydrochloride sample.The data of collecting are listed in following:
Atomoxetine hydrochloride sample analytical characteristic:
| Moisture pH test result | Water ratio (weight %) | |
| Sample 7 samples 8 samples 9 samples 10 | 2.4 4.4 4.8 6.1 | 9.0％ 3.8％ 3.6％ 0.5％ |
Sample 7: stability test (40 ℃, 5 days) result:
| Impurity (a) (HPLC A%) | Impurity (b) (HPLC A%) | Impurity (c) (HPLC A%) | |
| Time zero test duration terminal point | 0.014％ 0.633％ | Do not detect 0.0482% | 0.018％ 0.689％ |
Sample 8: stability test (40 ℃, 5 days) result:
| Impurity (a) (HPLC A%) | Impurity (b) (HPLC A%) | Impurity (c) (HPLC A%) | |
| Time zero test duration terminal point | Do not detect | Do not detect | Do not detect |
Sample 9: stability test (40 ℃, 5 days) result:
| Impurity (a) (HPLC A%) | Impurity (b) (HPLC A%) | Impurity (c) (HPLC A%) | |
| Time zero | Do not detect | Do not detect | Do not detect |
| The test duration terminal point | Do not detect | Do not detect | Do not detect |
Sample 10: stability test (40 ℃, 5 days) result:
| Impurity (a) (HPLC A%) | Impurity (b) (HPLC A%) | Impurity (c) (HPLC A%) | |
| Time zero | Do not detect | Do not detect | Do not detect |
| The test duration terminal point | Do not detect | Do not detect | Do not detect |
Sample 11: stability test (40 ℃, 75%RH) result:
| Impurity (a) (HPLC A%) | Impurity (b) (HPLC A%) | Impurity (c) (HPLC A%) | |
| Time zero 1 month 2 months 3 months 6 months | 0.01 0.02 0.02 0.02 0.01 | Not detecting 0.006 0.007 0.003 does not detect | Do not detect |
And as described below, even if when at room temperature simply contacting with the HCl air-flow in shorter exposure duration, dry atomoxetine hydrochloride is degraded:
| Before the HCl air-flow contacts | Moisture pH test result | Water ratio (weight %) |
| (sample 12) | 6.1 | 0.04％ |
| After the HCl air-flow contacts | Moisture pH test result | Water ratio (weight %) |
| (sample 12) | 2.8 | 0.06％ |
Sample 12 HPLC A% results:
| Impurity (a) | Impurity (b) | Impurity (c) | |
| Before the HCl air-flow contacts | Do not detect | Do not detect | Do not detect |
| After the HCl air-flow contacts | 0.10％ | 0.032％ | 1.54％ |
Free hydrogenchloride in the wet atomoxetine hydrochloride can for example be determined by the combine detection of quantitative analysis tech: chlorine ion concentration, total acid content, water ratio, or the loss when dry.
The invention provides the method for analyzing atomoxetine hydrochloride stability, comprise and determine the pH of atomoxetine hydrochloride sample in the aqueous solution.Described method is included in about 20 ℃ to about 30 ℃ the atomoxetine hydrochloride is dissolved in the water to obtain the aqueous solution and to measure pH.The dissolving of atomoxetine hydrochloride preferably promotes by supersound process.PH preferably uses glass electrode to measure.Have been found that the effective predictor that is defined as atomoxetine hydrochloride sample stability of atomoxetine hydrochloride pH in water.
The invention provides the other method of analyzing atomoxetine hydrochloride stability, comprise the chloride content of determining in the atomoxetine hydrochloride.Muriate is preferably by using AgNO
3Titration is determined.
The invention provides the method that preparation contains the pharmaceutical preparation of stable atomoxetine hydrochloride, may further comprise the steps:
A) obtain one or more samples of one or more atomoxetine hydrochloride batch of materials;
B) a) arbitrary impurity (a) and (b) and content (c) in each sample of measuring process;
C), select impurity (a) doped level to be lower than about 0.15% w/w, and arbitrary content is lower than the atomoxetine hydrochloride batch of material of about 0.10% w/w (passing through HPLC) in impurity (b) and the impurity (c) based on the measurement of carrying out in the step b); With
D) use the batch of material of selecting in the step c) to contain the pharmaceutical preparation of stable atomoxetine hydrochloride with preparation.
The atomoxetine hydrochloride sample of step a) preferably includes the impurity (a) and (b) of enough low levelss and (c).More preferably, measure by HPLC, the atomoxetine hydrochloride sample of step a) contains and is lower than about 0.15% w/w impurity (a), and impurity (b) and (c) arbitrary content be lower than about 0.10% w/w.
The invention provides the method for preparing crystallization or amorphous atomoxetine hydrochloride, may further comprise the steps:
A) obtain one or more samples of one or more atomoxetine hydrochloride batch of materials;
B) a) the impurity (a) and (b) and (c) content of arbitrary impurity in each sample of measuring process;
C), select impurity (a) doped level to be lower than about 0.15% w/w, and arbitrary content is lower than the atomoxetine hydrochloride batch of material of about 0.10% w/w (passing through HPLC) in impurity (b) and the impurity (c) based on the measurement of carrying out in the step b); With
D) batch of material of selecting in the use step c) is to prepare described crystallization or amorphous atomoxetine hydrochloride.
The atomoxetine hydrochloride sample of step a) preferably includes the impurity (a) and (b) of enough low levelss and (c).More preferably, measure by HPLC, the atomoxetine hydrochloride sample of step a) contains and is lower than about 0.15% w/w impurity (a), and impurity (b) and (c) arbitrary content be lower than about 0.10% w/w.
The invention provides and measure arbitrary impurity (a) and (b) or HPLC method (c) in the atomoxetine hydrochloride, may further comprise the steps:
A) sample that will contain 1 milligram of atomoxetine hydrochloride joins in the mixture that 1 milliliter of pH is phosphate buffered saline buffer/acetonitrile (60/40) of about 3;
B) mixture with step a) is injected in 250 millimeters * 4.6 millimeters * 5.0 microns YMC-filling ADS-AQ (or similar) posts;
C) use acetonitrile as elutriant: water (90: 10) with contain NaH
2PO
4The mixture of the damping fluid of monohydrate aqueous solution elution samples gradually from post; With
D) use arbitrary impurity (a) and (b) or content (c) in the UV detectors measure sample.
NaH
2PO
4The monohydrate aqueous solution is preferably concentration and 85% (w/w) H of about 2.8 mg/ml
3PO
4Be adjusted to about 3 pH.
Preferably about 30 minutes of elution time in the step c).
Preferably about 215 nanometers of UV wavelength.
The present invention also comprises and contains the stable atomoxetine hydrochloride of the present invention and the pharmaceutical preparation of pharmaceutically acceptable vehicle.
The present invention also comprises the method that is used to prepare the pharmaceutical preparation that contains stable atomoxetine hydrochloride of the present invention and pharmaceutically acceptable vehicle.
The present invention comprises that also the stable atomoxetine hydrochloride of the present invention is used for the application of pharmaceutical compositions.
According to patient's age, sex and symptom, the medication of pharmaceutical composition of the present invention can different preparation administrations.For example, pharmaceutical composition can tablet, pill, pulvis, liquid, suspension, emulsion, granule, capsule, suppository, injection formulations form administrations such as (solution and suspension).
Pharmaceutical composition of the present invention can be chosen wantonly with atomoxetine hydrochloride and/or other active ingredient of other form and mix.In addition, pharmaceutical composition of the present invention can contain inert component, for example thinner, carrier, filler, weighting agent, tackiness agent, disintegrating agent, disintegration inhibitor, absorption enhancer, wetting agent, lubricant, glidant, tensio-active agent, seasonings or the like.
Thinner increases the volume of solid composite medicament, and can make a kind of pharmaceutical dosage form that makes patient and care-giver be easier to use that comprises composition.The thinner that is used for solids composition for example comprises Microcrystalline Cellulose (AVICEL for example
), fine cellulose, lactose, starch, pregelatinized starch, lime carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, two hydration Bibasic Calcium Phosphates, three alkali calcium phosphates, kaolin, magnesiumcarbonate, magnesium oxide, Star Dri 5, N.F,USP MANNITOL, polymethacrylate (EUDRAGIT for example
), Repone K, Solka-floc, sodium-chlor, Sorbitol Powder and talcum.
For example be compressed into that the solid composite medicament of the formulation of tablet can comprise vehicle, its function helps active ingredient and other vehicle are bonded together after being included in compression.The tackiness agent that is used for solid composite medicament comprises gum arabic, alginic acid, carbomer (for example carbopol), Xylo-Mucine, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, Natvosol, hydroxypropylcellulose (KLUCEL for example
), Vltra tears (METHOCEL for example
), Liquid Glucose, neusilin, Star Dri 5, methylcellulose gum, polymethacrylate, polyvidone (KOLLIDON for example
, PLASDONE
), pregelatinized starch, sodiun alginate and starch.
The dissolution rate of compacted solid pharmaceutical composition in patient's stomach can increase by add disintegrating agent in composition.Disintegrating agent comprises alginic acid, calcium carboxymethylcellulose, Xylo-Mucine (AC-DI-SOL for example
, PRIMELLOSE
), colloid silica, cross-linked carboxymethyl cellulose sodium, Crospovidone (KOLLIDON for example
, POLYPLASDONE
), guar gum, neusilin, methylcellulose gum, Microcrystalline Cellulose, Polacrilin potassium, cellulose powder, pregelatinized starch, sodiun alginate, sodium starch glycolate (EXPLOTAB for example
) and starch.
Can add glidant to improve the mobile of non-compacted solid composition and to improve precision in drug administration.The vehicle that can be used as glidant comprises colloid silica, Magnesium Trisilicate, cellulose powder, starch, talcum and three alkali calcium phosphates.
If for example the formulation of tablet is made by the compacting powder composition, said composition stands the pressure from drift and punch die.Some vehicle and active ingredient are tended to be adhered on the surface of drift and punch die, can cause product to have indenture and other surface imperfection.Lubricant can be joined in the composition to reduce bonding and product is discharged from punch die easily.Lubricant comprises Magnesium Stearate, calcium stearate, glyceryl monostearate, palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyoxyethylene glycol, Sodium Benzoate, Sodium Lauryl Sulphate BP/USP, stearyl fumarate, stearic acid, talcum and Zinic stearas.
Seasonings and sweetener make formulation better to eat to the patient.The seasonings and the sweetener that are usually used in the medicament production that can be included in the present composition comprise voitol, Vanillin, vanillal, menthol, citric acid, fumaric acid, veltol plus and tartrate.
Solid and liquid composition also can use any pharmaceutically acceptable tinting material dyeing to improve its outward appearance and/or to help the patient to discern this product and unit dosage level.
In composition of liquid medicine of the present invention, stable atomoxetine hydrochloride and any other solid excipient are dissolved or suspended in the liquid vehicle of for example water, vegetables oil, alcohol, polyoxyethylene glycol, propylene glycol or glycerine.
Composition of liquid medicine can contain emulsifying agent so that be insoluble to active ingredient or other vehicle of liquid vehicle and be evenly dispersed in the whole composition.The emulsifying agent that can be used in the liquid composition of the present invention for example comprises gelatin, yolk, casein, cholesterol, gum arabic, tragacanth, Chondrus, pectin, methylcellulose gum, carbomer, the pure and mild hexadecanol of cetearyl alcohol.
Liquid composition of the present invention also can comprise viscosity increasing agent with the mouthfeel of raising product and/or the coating of gi tract internal layer.These viscosity enahncers comprise gum arabic, alginic acid bentonite, carbomer, calcium carboxymethylcellulose or sodium, cetostearyl alcohol, methylcellulose gum, ethyl cellulose, gelatin guar gum, Natvosol, hydroxypropylcellulose, Vltra tears, Star Dri 5, polyvinyl alcohol, polyvidone, propylene carbonate, Protanal Ester SD-LB, sodiun alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
The sweeting agent that can add for example Sorbitol Powder, asccharin, soluble saccharin, sucrose, aspartame, fructose, N.F,USP MANNITOL and Nulomoline is to improve the sense of taste.
Safe amount be can take in and the sanitas of for example alcohol, Sodium Benzoate, Yoshinox BHT, butylated hydroxyanisol and ethylenediamine tetraacetic acid (EDTA) and sequestrant added with the raising stability in storage.
According to the present invention.Liquid composition also can contain buffer reagent for example glyconic acid, lactic acid, citric acid or acetate, gluconic acid sodium salt, Sodium.alpha.-hydroxypropionate, Trisodium Citrate or sodium acetate.Formulation science worker can rule of thumb easily determine the selection to vehicle and consumption with considering this area standard step and reference.
When preparation injectable (parenteral) pharmaceutical composition, solution and suspension are by sterilization and preferably blood etc. is oozed.Injection formulations can use the common known carrier in this area.The carrier that for example is used for injection formulations includes but not limited to the fatty acid ester of water, ethanol, propylene glycol, ethoxylation isooctadecanol, polyoxy isooctadecanol and polyoxyethylene sorbitol acid anhydride.Those skilled in the art can be seldom or the experience that does not almost have determine easily to make that injection formulations etc. oozes the amount of required sodium-chlor, glucose or glycerine.Also can add for example other component of solvent, buffer reagent and the agent that relieves the pain.
Solids composition of the present invention comprises powder, particle, aggregate and compacted compositions.Dosage comprises the amount that is applicable to oral, oral cavity, rectum, parenteral (comprising subcutaneous, intramuscular and intravenously), inhalation and dosing eyes.Although the character and the severity of the illness of being treated depended in only administration under any given situation, the most preferred route of administration of the present invention is oral.What dosage can suit provides and makes by any method that pharmaceutical field is known with unit dosage form.
Formulation comprises for example solid dosage of tablet, pulvis, capsule, suppository, bag agent (sachet), lozenge and dragee, and liquid sugar sirup, suspension agent and elixir.
Formulation of the present invention can be the capsule that contains the present composition that is included in hard or the soft shell, preferred powder of described composition or granular solids composition.Shell can be made and optional contained for example softening agent of glycerine and Sorbitol Powder by gelatin, and opacifying agent or tinting material.
Active ingredient and vehicle can enter composition and formulation according to the methods known in the art preparation.
The composition that is used for the filling of tablet or capsule can be made by wet granulation.In wet granulation, with the part or all of active ingredient of powder type and mixed with excipients and subsequently at liquid, be generally water, existence further mix down, make powder form particle.To granulate screening and/or pulverize, drying, and sieve subsequently and/or pulverize into required particle size.Particle can perhaps can be added other vehicle by compressing tablet subsequently before compressing tablet, for example glidant and/or lubricant.
Tablet composition can prepare by dry blending routinely.For example, the blend compositions of active ingredient and vehicle can be compacted into bulk or sheet and be ground into dense granule subsequently.Dense granule can be pressed into tablet subsequently.
As a kind of selection scheme of dry granulation, blend compositions can use direct compact technique directly to be compressed into the compacting formulation.Directly compacting produces does not have the more even tablet of particulate.The vehicle that is particularly suitable for direct compressed tablets comprises Microcrystalline Cellulose, spray-dried lactose, Tri-Compress and colloid silica.These or other vehicle in direct compressed tablets use to those skilled in the art and to challenge the skilled person of direct compressed tablets known.
Capsule filling of the present invention can comprise any aforementioned blend and granulation of describing when tablet, yet it does not carry out final compressing tablet step.
Solids composition of the present invention comprises powder, particle, aggregate and compacted compositions.Dosage comprises the amount that is applicable to oral, oral cavity, rectum, parenteral (comprising subcutaneous, intramuscular and intravenously), inhalation and dosing eyes.Although the character and the severity of the illness of being treated depended in only administration under any given situation, the most preferred route of administration of the present invention is oral.What dosage can suit provides and makes by any method that pharmaceutical field is known with unit dosage form.
Analytical procedure
Atomoxetine hydrochloride sample the determining of pH in the aqueous solution
2 gram atomoxetine hydrochlorides are dissolved in 100 ml deionized water to about 30 ℃ temperature at about 20 ℃, carry out supersound process if necessary to reach dissolving fully.PH uses glass electrode in about 20 ℃ of extremely about 30 ℃ temperature surveys.
Determine muriate in the atomoxetine hydrochloride by titration
250 milligrams of accurate weighings of atomoxetine hydrochloride are dissolved in 50 ml deionized water, and add the HNO of 5 milliliter of 4% weight/volume
3Solution.The gained mixture uses 0.1 N AgNO
3Potentiometric titration.
Calculate:
Wherein V is that titration volume and F are the titration correction factor.
HPLC analyzes
| Zhu ﹠amp; Fill: | YMC-Pack ODS-AQ, the S-5 micron, 12 nanometers, 250 millimeters * 4.6 millimeters * 5.0 microns, cat is (W) or equivalent n.042574458 | ||
| Buffer reagent: | NaH in 1000 ml deionized water 2PO 43.0: 2.8 grams of monohydrate pH use H 3PO 485% (w/w) regulated pH to 3.0.Use 0.45 micron filter to filter. | ||
| Elutriant A: | Acetonitrile: water 90: 10 | ||
| Gradient | Time (minute) | The % buffer reagent | % elutriant A |
| 0 | 85 | 15 | |
| 20 | 48 | 52 | |
| 30 | 48 | 52 | |
| Starting time: | 8 minutes | ||
| Flow velocity: | 1.5 ml/min | ||
| Detect: | 215 nanometer UV | ||
| Column temperature: | 40 ℃ | ||
| Thinner | Damping fluid: acetonitrile (60: 40) | ||
| Inject | 5 microlitres | ||
Typical case's relative retention time is:
Impurity (a): N-methyl-3-hydroxyl-3-amphetamine RRt=0.2;
Impurity (b): N-methyl-3-phenyl-2,3-propenyl amine RRt=0.4
Impurity (c): ortho-cresol (2-cresols) RRt=0.9; And
Atomoxetine hydrochloride RRt=1.0
Embodiment
Embodiment 1: the preparation of atomoxetine hydrochloride
Under agitation, use water-bath that temperature is maintained at about 22 ℃ to about 25 ℃, 286 gram (2.825 moles) hydrochloride aqueous solutions (36%) are added drop-wise to as 5063 of preparation as described in U.S. Provisional Application 60/583643,60/583644 and 60/622065 restrain (2.379 moles) atomoxetine alkali in the solution of n-butyl acetate.Crystal of hydrochloride.Gained suspension is about 25 ℃ of stir abouts 1 hour, and by solid collected by filtration, uses 900 milliliters of n-butyl acetates to wash 3 times.Obtain the wet atomoxetine hydrochloride of about 850 grams.After twice separation preparation, with the wet solid sample of gained water-soluble (2 grams in 100 milliliters).The pH of each sample is defined as 2.39 and 2.40 respectively.
Embodiment 2: remove free HCl by aqeous suspension
To mix 30 minutes to obtain suspension with 100 ml waters at 5 ℃ based on the wet product of about 100 grams that weight loss on drying contains as the estimation 83.5 gram atomoxetine hydrochlorides of preparation as described in the embodiment 1, collect by filtering, and with 30 ml waters washings (200 milligrams of samples are dissolved in 10 ml waters, find to have 4.4 pH).
Wet solid mixed 30 minutes at 5 ℃ with 100 ml waters once more, collected by filtering, and washed with 30 ml waters.Obtain the wet atomoxetine hydrochloride of 90.1 grams (2 gram samples are dissolved in 100 ml waters, and discovery has 5.9 pH).Wet product provides 79.9 grams dry atomoxetine hydrochloride in about 60 ℃ of extremely about 70 ℃ of vacuum-dryings, and yield is 95.7%.Purity:＞99.8%.
Embodiment 3: remove free HCl by washing with acetone
The wet atomoxetine of 70 grams as embodiment 1 preparation uses 62.5 milliliters of acetone room temperature (promptly about 20 ℃ to about 25 ℃) washed twice on B.Obtain the wet atomoxetine hydrochloride of about 65 grams.Wet product obtains the dry atomoxetine hydrochloride of 62.4 grams 65 ℃ of vacuum-dryings, and yield is about 94%.Sample is water-soluble with the concentration of about 2% weight/volume, and pH is defined as 4.6.Purity:＞99.8%.
Claims (38)
1. stable atomoxetine hydrochloride.
2. the stable atomoxetine hydrochloride of claim 1, wherein the aqueous solution of atomoxetine hydrochloride has the pH at least about 4.
3. the stable atomoxetine hydrochloride of claim 2, wherein the aqueous solution of atomoxetine hydrochloride has about 4 to about 7 pH.
4. the method for any one stable atomoxetine hydrochloride among the preparation claim 1-3 comprises that the atomoxetine hydrochloride that will contain excessive hydrogen chloride is with at least a water, the C of being selected from
3-C
8Ketone and C
3-C
8The solvent suspension and/or the washing of alcohol.
5. the method for claim 4, wherein C
3-C
8Ketone is C
3-C
5Ketone.
6. the method for claim 5, wherein C
3-C
5Ketone is selected from acetone and methylethylketone.
7. the method for claim 6, wherein C
3-C
5Ketone is acetone.
8. any one method, wherein C among the claim 4-7
3-C
8Alcohol is C
3-C
5Alcohol.
9. the method for claim 8, wherein C
3-C
5Alcohol is selected from propyl alcohol, Virahol and butanols.
10. the method for claim 9, wherein C
3-C
5Alcohol is butanols.
11. the method for claim 4, wherein solvent is a water.
12. any one method among the claim 4-11, wherein the atomoxetine hydrochloride is suspended in the solvent.
13. the method for claim 12 comprises in addition by filtering, wash and the dry stable atomoxetine hydrochloride of atomoxetine hydrochloride recovery that suspends.
14. arbitrary method in claim 12 and 13, wherein the atomoxetine hydrochloride uses the solvent wash that in suspension uses.
15. any one method among the claim 12-14, wherein solvent is a water.
16. the method for claim 15, wherein the atomoxetine hydrochloride suspends in about 0 ℃ of extremely about 10 ℃ temperature.
17. the method for claim 4, wherein C is used in washing
3-C
8Ketone and C
3-C
8Alcohol.
18. the method for claim 17, wherein the atomoxetine hydrochloride is in about 10 ℃ of extremely about 30 ℃ temperature washings.
19. the method for claim 4, wherein the atomoxetine hydrochloride washes with water.
20. the method for claim 19, wherein the atomoxetine hydrochloride is in about 0 ℃ of extremely about 30 ℃ temperature washing.
21. the method for claim 4, wherein atomoxetine hydrochloride washing with acetone.
22. the method for claim 21, wherein the atomoxetine hydrochloride is in about 30 ℃ temperature washing.
23. any one method among the claim 4-22 comprises the atomoxetine hydrochloride of dry washing in addition.
24. the method for claim 23, wherein the atomoxetine hydrochloride is in about 60 ℃ of vacuum-dryings to about 70 ℃ temperature.
25. a right to analysis requires the method for stable atomoxetine hydrochloride any among the 1-3, comprises determining the stable pH of atomoxetine hydrochloride sample in the aqueous solution.
26. the method for claim 25, comprise in addition with the atomoxetine hydrochloride about 20 ℃ soluble in water obtaining solution to about 30 ℃ temperature, and measure pH.
27. the method for claim 26 comprises the dissolving of using supersound process to promote stable atomoxetine hydrochloride in addition.
28. arbitrary method in claim 26 and 27 comprises in addition and uses glass electrode to measure pH.
29. a right to analysis requires the method for stable atomoxetine hydrochloride any among the 1-3, comprises chloride determination.
30. the method for claim 29, wherein chloride determination comprises use AgNO
3Titration atomoxetine hydrochloride.
31. preparation contains the method for the pharmaceutical preparation of stable atomoxetine hydrochloride any among the claim 1-3, may further comprise the steps:
A) obtain one or more samples of one or more atomoxetine hydrochloride batch of materials;
B) a) content of arbitrary impurity in each sample of measuring process:
(c)
C), select impurity (a) doped level to be lower than about 0.15% w/w, and impurity (b) and impurity (c) content are lower than the atomoxetine hydrochloride batch of material of about 0.10% w/w (passing through HPLC) based on the measurement of carrying out in the step b); With
D) use the batch of material of selecting in the step c) to contain the pharmaceutical preparation of stable atomoxetine hydrochloride with preparation.
32. a method for preparing the atomoxetine hydrochloride may further comprise the steps:
A) obtain one or more samples of one or more atomoxetine hydrochloride batch of materials;
B) a) content of arbitrary impurity in each sample of measuring process:
(c)
C), select impurity (a) doped level to be lower than about 0.15% w/w, and arbitrary content is lower than the atomoxetine hydrochloride batch of material of about 0.10% w/w (passing through HPLC) in impurity (b) and the impurity (c) based on the measurement of carrying out in the step b); With
D) batch of material of selecting in the use step c) is to prepare described atomoxetine hydrochloride.
33. measure arbitrary impurity in the atomoxetine hydrochloride for one kind
Or (c)
The HPLC method, may further comprise the steps:
A) sample that will contain 1 milligram of atomoxetine hydrochloride joins in the mixture that 1 milliliter of pH is phosphate buffered saline buffer/acetonitrile (about 60/40) of 3;
B) mixture with step a) injects post;
C) use acetonitrile as elutriant: water (about 90: 10) with contain NaH
2PO
4The mixture of the damping fluid of monohydrate aqueous solution elution samples gradually from post; With
D) use arbitrary impurity (a) and (b) and content (c) in the UV detectors measure sample.
34. the method for claim 33, wherein NaH
2PO
4The aqueous solution of monohydrate is the H of concentration and about 85% (w/w) of about 2.8 mg/ml
3PO
4
35. arbitrary method in claim 33 and 34, wherein the UV wavelength is about 215 nanometers.
36. contain the stable atomoxetine hydrochloride any among the claim 1-3 and the pharmaceutical preparation of pharmaceutically acceptable vehicle.
37. the method for a useful in preparing drug formulations comprises stable atomoxetine hydrochloride and at least a pharmaceutically acceptable mixed with excipients with claim 1.
38. any one stable atomoxetine hydrochloride is used for the application of pharmaceutical compositions among the claim 1-3.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US66874105P | 2005-04-05 | 2005-04-05 | |
| US60/668,741 | 2005-04-05 | ||
| US60/686,386 | 2005-05-31 | ||
| US60/688,406 | 2005-06-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101155775A true CN101155775A (en) | 2008-04-02 |
Family
ID=39256877
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800113592A Pending CN101155775A (en) | 2005-04-05 | 2006-04-05 | Stable atomoxetine hydrochloride, a process for the preparation thereof, and an analytical control of its stability |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101155775A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105705135A (en) * | 2013-11-08 | 2016-06-22 | 伊莱利利公司 | Atomoxetine solution |
| CN108558684A (en) * | 2018-05-14 | 2018-09-21 | 威海贯标信息科技有限公司 | A kind of atomoxetine novel crystal forms |
-
2006
- 2006-04-05 CN CNA2006800113592A patent/CN101155775A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105705135A (en) * | 2013-11-08 | 2016-06-22 | 伊莱利利公司 | Atomoxetine solution |
| CN108558684A (en) * | 2018-05-14 | 2018-09-21 | 威海贯标信息科技有限公司 | A kind of atomoxetine novel crystal forms |
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