CN103159636B

CN103159636B - Aminomethyl caproic acid derivative and use

Info

Publication number: CN103159636B
Application number: CN201310115531.0A
Authority: CN
Inventors: 李兴惠
Original assignee: Individual
Current assignee: Individual
Priority date: 2013-04-05
Filing date: 2013-04-05
Publication date: 2015-02-25
Anticipated expiration: 2033-04-05
Also published as: CN103159636A

Abstract

The invention discloses an aminomethyl caproic acid derivative and use, in particular a composition which comprises a compound shown by formula I and a compound shown by formula II as an impurity. The invention further discloses a medical preparation prepared by the composition and pharmaceutical use thereof. The compound provided by the invention has good pharmaceutical properties.

Description

Aminomethyl caproic acid derivative and purposes

Technical field

The present invention relates to Aminomethyl caproic acid derivative particularly (S)-3-(the aminomethyl)-5-methylhexanoic acid of assisting therapy that can be used for generalized anxiety disorder, diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia syndrome, epilepsy, with and uses thereof.

Background technology

(S)-3-(aminomethyl)-5-methylhexanoic acid, general Prey Bahrain (pregabalin) by name, be also often called lyrica, its molecular formula is C ₈h ₁₇nO ₂, molecular weight is 159.23.It is the same with gabapentin, and Prey Bahrain is that 3 of a kind of γ-aminobutyric acid (GABA) replace analogue, and their chemical structural formula is as follows:

Prey Bahrain GABA gabapentin

Prey Bahrain (the pregabalin developed by Pfizer, trade(brand)name Le Ruika, Lyrica) be 3 of a kind of γ-aminobutyric acid and replace analogues, it had obtained related compound and the expection adoption person thereof of the antiepileptic drug gabapentin (gabapentin) of huge business success already as the said firm.Prey Bahrain is neuralgia medicine of new generation, agents of calcium ion channel modulators.By the neurone of accommodative excess excitement, reduce the excessive release of excitatory neurotransmitter, be used for the treatment of the neurogenic pains such as postherpetic neuralgia, be recommended as first-line treatment medicine by numerous international guidelines.

Specifically, the Pharmacological Mechanism of Prey Bahrain is: in Prey Bahrain and central nervous system, there is high affinity in α 2-δ site (ancillary subunit of valtage-gated calcium channel).The mechanism of action of Prey Bahrain is still not clear, but the result of study of transgenic mice and structure related compound (such as gabapentin) is pointed out, the analgesia in animal model and anticonvulsant action may with Prey Bahrain and α 2-δ subunit in conjunction with relevant.In vitro study shows, and Prey Bahrain can reduce the Ca-dependent release of some neurotransmitters by regulating calcium channel function.Although Prey Bahrain is the structural derivative of inhibitory neurotransmitter γ-aminobutyric acid (GABA), but it is not directly and GABAA, GABAB or benzodiazepine receptors bind, do not increase the neuronic GABAA reaction of vitro culture, do not change GABA concentration in rat brain, GABA is absorbed or degrades without acute effect.But research finds, the neurone of vitro culture is exposed to Prey Bahrain for a long time, GABA translocator density and functional GABA transport velocity increase.Prey Bahrain not block sodium channels, to opioid receptor non-activity, does not change cyclooxygenase activity, to Dopamine HCL and 5-hydroxytryptamine receptor non-activity, does not suppress the re-uptake of Dopamine HCL, serotonin or norepinephrine.

Le Ruika (Prey Bahrain capsule) goes on the market in the U.S. for 2004, be used for postherpetic neuralgia, Diabetes Peripheral neurodynia, epilepsy, fibromyalgia by U.S. FDA approval, and more than 80 the countries and regions listing in the whole world, and having obtained SFDA approval in Discussion on Chinese Listed, first indication is postherpetic neuralgia.

Prey Bahrain is used for the treatment of peripheral nerve characteristic of disease pain in July, 2004 Yi Huo European Union approval and is used as the adjunctive therapy medicine of part insane carbuncle outbreak treatment.Prey Bahrain also obtains approval in U.S.A in by the end of December, 2004, for diabetes-alleviating peripheral neurophaty related neural characteristic of disease pain and postherpetic neuralgia, thus become the U.S.'s first medicine of formally getting permission simultaneously to treat these two kinds of neuropathic pains so far, within 2005, obtain again FDA approval and be used for adults with epilepsy partial seizures assisting therapy.U.S. FDA have approved Lyrica and was used for the treatment of fibromyalgia in June, 2007, and this is the medicine that first of FDA approval is used for the treatment of fibromyalgia.

Alliance of European neurological association (EFNS) Guidelines recommend Le Ruika in 2006 is a line medication of pain property polyneuropathy, postherpetic neuralgia, central pain.Within 2007, IASP (IASP) Consensus of experts recommends Le Ruika for treatment postherpetic neuralgia one line medicine.2007, Le Ruika (Prey Bahrain capsule) was chosen as one of year ten large medical science breakthrough by Time.Britain NICE Guidelines recommend Le Ruika in 2010 is the medicine uniquely simultaneously with maincenter, peripheral nerve pathologic pain indication.The action character of Le Ruika (Prey Bahrain capsule): the α 2-δ subunit that can suppress central nervous system voltage-dependent ca channel, reduce flow of calcium ions, reduce the release of the excitatory neurotransmitters such as glutaminate, norepinephrine, Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 thereupon, thus effectively control neurogenic pain, and there is anxiety, anticonvulsant effect.

The advantage of Prey Bahrain: quick, lasting, potent alleviation postherpetic neuralgia, significantly improve patients with post herpetic neuralgia somnopathy and pain general impression, serious adverse reaction is rare, do not find that drug pharmacokinetics interacts temporarily, take medicine conveniently, be beneficial to adjustment, absorb linearly relevant to dosage, and in dose dependent.

Prey Bahrain conventional formulation capsule recommended dose is each 75 or 150mg, every day 2 times; Or each 50mg or 100mg, every day 3 times.Initial dose can be each 75mg, every day 2 times; Or each 50mg, every day 3 times.Each 150mg can be increased to according to curative effect and tolerance, every day 2 times in 1 week.Because Prey Bahrain mainly removes through renal excretion, the patient of renal hypofunction should adjust dosage.Above recommended dose is applicable to the patient of CrCl >=60 ml/min.Take Prey Bahrain 300mg/ day, after 2-4 week, pain does not obtain the patient fully alleviated, and as tolerated this product, can increase to each 300mg, every day 2 times, or each 200mg, every day 3 times (600mg/ day).Because untoward reaction is dose-dependently, and untoward reaction can cause higher drug withdrawal rate, and dosage is suffered from more than the rest pain being only applied to tolerance 300mg/ per daily dose 300mg/ day.

Prey Bahrain clinical indication granted in the whole world comprises: the assisting therapy of generalized anxiety disorder, diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia syndrome, epilepsy.

The basic demand of medicine is safe, effective, controlled, and it is the basic demand of clinical application that the run-of-the-mill wherein meeting medicine requires such as to require medicine stable in its validity period, and the controllability of this drug quality is again for the security of medicine provides guarantee.Typically, as a kind of medicine, impurity is wherein necessary to do special stipulation, such as, usually require that a certain impurity of regulation is lower than 5%, or such as lower than 1%, or such as lower than 0.5%, or such as lower than 0.1%, or such as lower than 0.05%.For same medicine, wherein plurality of impurities may be contained, the most high-content upper limit of these impurity may identical also may be different, typically in the Long-term Storage process of medicine in the validity period of such as 2 ~ 3 years, foreign matter content wherein should be that metastable, qualified medicine does not allow its foreign matter content in Long-term Storage process significantly to increase.Prey Bahrain needs to control impurity wherein equally, such as CN102869350A (Ai Jisi, CN2011800195930) the background technology part elaboration GABA class medicine of specification sheets easily goes out out undesirable lactam impurity in molecule, such as wherein explicitly point out, with regard to gabapentin, in molecule, lactan 4-cyclohexyl pyrrolidone is regarded as having more toxicity than gabapentin, and the cyclic lactam of Prey Bahrain is also less desirable by product, controlling and monitor undesirable lactam impurity in GABA class medicament research and development and storage is important parameter.

Therefore, those skilled in the art expect have a kind of stay-in-grade Prey Bahrain to be applied to clinical.

Summary of the invention

The object of this invention is to provide a kind of have good stability can Prey Bahrain clinical to be applied to.The present invention is achieved in the following ways.

First aspect present invention provides a kind of composition, and it comprises with compounds of Formula I:

and as impurity with Formula Il compound:

Composition according to a first aspect of the present invention, it is Prey Bahrain bulk drug, and it can be described as in the present invention " present composition ", " composition of first aspect present invention " etc.In one embodiment, described formula II compound also can be described as " lactan ", " undesirable lactam impurity ", " Prey Bahrain lactan ", " Prey Bahrain undesirable lactam impurity " etc.

Composition according to a first aspect of the present invention, its compounds of formula I content is greater than 98%, such as, be usually greater than 99%, such as, be greater than 99.5%.

Composition according to a first aspect of the present invention, its compounds of formula I content is more than 100 times of formula II compounds content, such as said composition compounds of formula I content is 100 ~ 20000 times of formula II compounds content, be such as 150 ~ 15000 times, be such as 200 ~ 10000 times, be such as 250 ~ 10000 times, be such as 500 ~ 10000 times.

As everyone knows, as the bulk drug of pharmaceutical chemicals, wherein can contain trace impurity more or less, for the present invention, the content of the composition compounds of formula I provided is greater than 98% usually, such as usually be greater than 99%, such as be greater than 99.5%, and for bulk drug, wherein the total content of various impurity is less than 2% usually, such as usually be less than 1%, such as, be less than 0.5%.Above-mentioned phrase " said composition compounds of formula I content is 100 ~ 20000 times of formula II compounds content " represents, such as in 100g Prey Bahrain bulk drug, if wherein containing 98g formula I, then the amount of formula II compound is 0.0049 ~ 0.98g, and remaining may be other impurity (comprising such as moisture), make formula I amount+formula II compound amount+other total impurities=100g.Specifically, the implication that such as phrase " said composition compounds of formula I content is 1000 times of formula II compounds content " represents is, in 100g Prey Bahrain bulk drug, if wherein containing 98g formula I, then the amount of formula II compound is 0.098g, and other total impurities is 1.902g, like this, the content of formula I is the content of 98%, formula II compound is in the composition 0.098%.And for the pharmaceutical preparation comprising pharmaceutical excipient, when mentioning the content as the formula II compound of impurity, refer to the percentage ratio of the absolute magnitude of pharmaceutical preparation compound of formula H divided by this pharmaceutical preparation compounds of formula I absolute magnitude, namely, in a pharmaceutical preparation, content=(weight of weight ÷ this part of pharmaceutical preparation compounds of formula I of this part of pharmaceutical preparation compound of formula H) × 100% of formula II compound.

The amount of present composition compounds of formula I and the amount of formula II compound can by well known to a person skilled in the art that method measures, such as by using reference substance to carry out quantitatively in HPLC method, such as hereafter described in [HPLC method A], these methods easily can measure the content of present composition compounds of formula I and the content of formula II compound.

Composition according to a first aspect of the present invention, wherein also optionally comprises other impurity.Composition according to a first aspect of the present invention, wherein also optionally comprises the RRT1.45 impurity determined by this paper [HPLC method A].Composition according to a first aspect of the present invention, wherein also optionally comprises the RRT1.73 impurity determined by this paper [HPLC method A].Composition according to a first aspect of the present invention, wherein also optionally comprises the RRT1.94 impurity determined by this paper [HPLC method A].Composition according to a first aspect of the present invention, wherein also optionally comprises the RRT2.15 impurity determined by this paper [HPLC method A].

Composition according to a first aspect of the present invention, wherein also optionally comprise determined by herein [HPLC method A] be selected from one or more following other impurity: RRT1.45 impurity, RRT1.73 impurity, RRT1.94 impurity, RRT2.15 impurity.

Composition according to a first aspect of the present invention, it is under the high performance liquid chromatography chromatographic condition (such as the present invention [HPLC method A]) that the resolution between formula I and formula II compound can be made to be greater than 8, in said composition gained HPLC collection of illustrative plates, described formula I peak area is more than 50 times of formula II compound peaks area, and such as formula I peak area is 100 ~ 20000 times or 100 ~ 15000 times or 100 ~ 10000 times or 100 ~ 5000 times of formula II compound peaks area.Or, composition according to a first aspect of the present invention, it is under the high performance liquid chromatography chromatographic condition (such as the present invention [HPLC method A]) that the resolution between formula I and formula II compound can be made to be greater than 8, in said composition gained HPLC collection of illustrative plates, the peak area ratio of described formula I and formula II compound is greater than 50, such as this peak area ratio is 100 ~ 20000, be such as 100 ~ 15000, be such as 100 ~ 10000, be such as 100 ~ 5000.

Composition according to a first aspect of the present invention, it is under the high performance liquid chromatography chromatographic condition (such as the present invention [HPLC method A]) that the resolution between formula I and formula II compound can be made to be greater than 8, in said composition gained HPLC collection of illustrative plates, the peak area ratio of described formula I and RRT1.45 impurity is greater than 100, such as this peak area ratio is 100 ~ 20000, be such as 100 ~ 15000, be such as 100 ~ 10000, be such as 150 ~ 10000, be such as 200 ~ 10000.Above-mentioned " peak area ratio of formula I and RRT1.45 impurity is greater than 100 " also can be described as " formula I peak area is more than 100 times of RRT1.45 impurity peak area "; Or phrase " peak area ratio of formula I and RRT1.45 impurity is 100 ~ 20000 " also can be described as " formula I peak area is 100 ~ 20000 times of formula II compound peaks area ", also has identical implication under other similar linguistic context of the present invention.

Composition according to a first aspect of the present invention, it is under the high performance liquid chromatography chromatographic condition (such as the present invention [HPLC method A]) that the resolution between formula I and formula II compound can be made to be greater than 8, in said composition gained HPLC collection of illustrative plates, the peak area ratio of described formula I and RRT1.73 impurity is greater than 100, such as this peak area ratio is 100 ~ 20000, be such as 100 ~ 15000, be such as 100 ~ 10000, be such as 150 ~ 10000, be such as 200 ~ 10000.

Composition according to a first aspect of the present invention, it is under the high performance liquid chromatography chromatographic condition (such as the present invention [HPLC method A]) that the resolution between formula I and formula II compound can be made to be greater than 8, in said composition gained HPLC collection of illustrative plates, the peak area ratio of described formula I and RRT1.94 impurity is greater than 100, such as this peak area ratio is 100 ~ 20000, be such as 100 ~ 15000, be such as 100 ~ 10000, be such as 150 ~ 10000, be such as 200 ~ 10000.

Composition according to a first aspect of the present invention, it is under the high performance liquid chromatography chromatographic condition (such as the present invention [HPLC method A]) that the resolution between formula I and formula II compound can be made to be greater than 8, in said composition gained HPLC collection of illustrative plates, the peak area ratio of described formula I and RRT2.15 impurity is greater than 100, such as this peak area ratio is 100 ~ 20000, be such as 100 ~ 15000, be such as 100 ~ 10000, be such as 150 ~ 10000, be such as 200 ~ 10000.

Composition according to a first aspect of the present invention, the high performance liquid chromatography that wherein parameter such as the content of Measurement and Computation present composition compounds of formula I, formula II compound and other impurity and the ratio between described formula I peak area and formula II compound (or and other impurity) peak area is used, can carry out according to [HPLC method A] shown below:

[HPLC method A]

Step 1, the high performance liquid chromatography described in Chinese Pharmacopoeia version in 2010 two annex VD is adopted to measure;

Step 2, chromatographic condition and system suitability: be weighting agent with octadecylsilane chemically bonded silica, the mixed solution of water-methanol-acetonitrile-phosphate buffered saline buffer volume ratio 550:350:100:1 is moving phase, determined wavelength is 210nm, number of theoretical plate calculates by Prey Bahrain peak and is not less than 1800, the resolution at Prey Bahrain and undesirable lactam impurity peak should be greater than 8, and (compound method of wherein said phosphate buffered saline buffer is: get potassium primary phosphate 3.5g and Sodium phosphate dibasic dodecahydrate 14.62g, be dissolved in water and be diluted to 1000ml, by phosphoric acid or potassium hydroxide solution adjust ph to 7.0, obtain),

Prepared by step 3, need testing solution: (it can be Prey Bahrain bulk drug to get the sample to be tested being about equivalent to Prey Bahrain 50mg, it can also be the pharmaceutical composition such as pharmaceutical preparation comprising Prey Bahrain and pharmaceutical excipient, such as commercially available capsule, 50mg is about containing Prey Bahrain) in this sample to be tested of taking, accurately weighed, put in 50ml measuring bottle, add moving phase to dissolve, stirring or acutely jolting 15 minutes, shake up, be diluted to scale by moving phase, shake up, as need testing solution (wherein the concentration of Prey Bahrain is about 1000 μ g/ml);

Step 4, reference substance solution (it can be used for the content measuring Prey Bahrain in trial-product) preparation: (this term " reference substance " has the usually known implication of those skilled in the art to get Prey Bahrain reference substance, particularly can be used for the content measuring principal constituent in sample to be tested, it obtains by commercial sources usually, such as by buying to the government organs such as National Institute for Food and Drugs Control or other commercial undertaking, also reach more than 99.9% by being purified to such as content and obtaining, in the present invention, if not otherwise indicated, the reference substance mentioned is all content/purity reference substances more than 99.9% of involved material) about 50mg, accurately weighed, put in 50ml measuring bottle, add moving phase to dissolve, stirring or acutely jolting 15 minutes, shake up, scale is diluted to by moving phase, shake up, product solution (wherein the concentration of Prey Bahrain is about 1000 μ g/ml) in contrast,

The preparation of step 5,1 ‰ contrast solutions: precision measures above-mentioned need testing solution 5ml, puts in 250ml measuring bottle, is diluted to scale by moving phase, shake up; Precision measures this diluent 5ml, puts in 100ml measuring bottle, is diluted to scale by moving phase, shake up, as 1 ‰ contrast solutions (this 1 ‰ contrast solution concentration is the thousandth of above need testing solution concentration, and concentration is about 1 μ g/ml);

The preparation of step 6, undesirable lactam impurity solution: modus ponens II undesirable lactam impurity reference substance is about 10mg, accurately weighed, puts in 250ml measuring bottle, adds moving phase and dissolves, be diluted to scale, shake up by moving phase; Accurate this solution of amount 5ml, puts in 200ml measuring bottle, is diluted to scale by moving phase, shake up, as undesirable lactam impurity reference substance solution (this undesirable lactam impurity reference substance solution is about 1 μ g/ml) again;

Step 7, assay method:

Step 71, precision measure 1 ‰ contrast solution 50 μ l injection liquid chromatographies, regulate detection sensitivity, make the peak height of principal constituent chromatographic peak be about 10% of full range;

Step 72, precision measure 1 ‰ contrast solution 50 μ l injection liquid chromatographies, record color atlas to principal constituent (in the present invention, if not otherwise indicated, mention principal constituent Jun Zhi Prey Bahrain) 8 times of chromatographic peak retention time, this color atlas is designated as color atlas A, reads retention time and the peak area at the principal constituent peak in this color atlas A;

Step 73, precision measure undesirable lactam impurity reference substance solution 50 μ l injection liquid chromatography, record color atlas is to 3 times of undesirable lactam impurity peak retention time, this color atlas is designated as color atlas B, reads retention time and the peak area at the undesirable lactam impurity peak in this color atlas B;

Step 74, precision measure the reference substance solution 50 μ l injection liquid chromatography that step 4 is prepared, record color atlas is to 3 times of principal constituent chromatographic peak retention time, this color atlas is designated as color atlas C, reads retention time and the peak area at the principal constituent peak in this color atlas C;

Step 75, precision measures need testing solution 50 μ l injection liquid chromatography, record color atlas is to 8 times of principal constituent chromatographic peak retention time, this color atlas is designated as color atlas D, in this color atlas D, ignore in solvent peak and optional pharmaceutical excipient peak, with the relative retention time of principal constituent chromatographic peak for 1, read relative retention time in this color atlas D respectively and be about the impurity of 1.35 ~ 1.55 (in the present invention, this impurity is called RRT1.45 impurity), relative retention time is about the impurity of 1.63 ~ 1.83 (in the present invention, this impurity is called RRT1.73 impurity), relative retention time is about the impurity of 1.84 ~ 2.04 (in the present invention, this impurity is called RRT1.94 impurity), relative retention time is about the impurity of 2.05 ~ 2.25 (in the present invention, this impurity is called RRT2.15 impurity) retention time and peak area, and the peak area of the impurity peaks (it be undesirable lactam impurity peak) corresponding to undesirable lactam impurity retention time in color atlas B in this color atlas D,

Step 8, calculating:

In the sample tested,

The content of formula I: the sample weighting amount using dosing in principal constituent peak-to-peak area in color atlas C and color atlas D and step 3 and step 4, by external standard method with calculated by peak area sample to be tested (i.e. trial-product, the such as present composition or the pharmaceutical preparation that prepared by it) content of compounds of formula I, this content can represent (in the present invention with % (w/w), the phrase " by external standard method with calculated by peak area " mentioned well known to a person skilled in the art, such as Chinese Pharmacopoeia describes a large amount of HPLC of use method and measures the content of material medicine and adopt this kind by external standard method with the method for calculated by peak area),

The content of formula II compound: the sample weighting amount using dosing in the peak area at the undesirable lactam impurity peak in color atlas B and color atlas D and step 3 and step 6, by external standard method with calculated by peak area sample to be tested (i.e. trial-product, the such as present composition or the pharmaceutical preparation that prepared by it) content of compound of formula H, this content can represent with % (w/w)

The each long-pending ratio of formula I and the peak between formula II compound, RRT1.45 impurity, RRT1.73 impurity, RRT1.94 impurity, RRT2.15 impurity or other impurity, respectively as pressed formulae discovery:

In the present invention, the phraseology relating to " ratio " or " ratio " well known to a person skilled in the art.Such as, when relating to " peak area ratio of formula I and RRT1.45 impurity ", if the peak area of formula I is 100, the peak area of RRT1.45 impurity is 1, then " peak area ratio of formula I and RRT1.45 impurity " directly should can be designated as 100, and also can be designated as 100:1.

In the present invention, the chromatographic purity of pharmaceutical preparation that also can calculate the present composition and be prepared by it, this chromatographic purity can adopt color atlas D in [HPLC method A] described herein to calculate, ignore in deduction solvent peak wherein, optional pharmaceutical excipient peak, any peak being less than 1 ‰ contrast solution main peak area 0.005 times, calculate with area normalization method, principal constituent peak area is the chromatographic purity of this material divided by whole peak area summation.In the present invention, also can calculate the content of total impurities in the present composition and the pharmaceutical preparation that prepared by it, it is the summation of the content in composition or medicine system of formula II compound and RRT1.45 impurity, RRT1.73 impurity, RRT1.94 impurity, RRT2.15 impurity and other impurity detected.

Composition according to a first aspect of the present invention, wherein in [HPLC method A], in step 2, octadecylsilane chemically bonded silica used is the chromatographic column of weighting agent, the octadecylsilane chemically bonded silica that easily can obtain various brand is from the market the chromatographic column of weighting agent, its column length can be selected as required, it can be typically the column length of 10 ~ 30cm, chromatographic column internal diameter can be 4.6mm usually, flow rate of mobile phase and column temperature also can adjust as required, typically flow velocity is 0.8 ~ 1.5min, and column temperature selects the steady temperature between 20 ~ 40 ° of C; Especially, in chromatographic condition described in step 2 of the present invention and system suitability, can suitably select column's length, flow rate of mobile phase, column temperature etc., control in the scope of 3 ~ 5min to make the retention time at Prey Bahrain peak, such as control in the scope of 3 ~ 4.5min, such as, to control in the scope of 3 ~ 4min.Like this, such as, when the retention time at Prey Bahrain peak is 3.5min, color atlas D is at least recorded to 28min in step 64; And relative retention time being about to the RRT1.45 impurity of 1.35 ~ 1.55, its retention time is generally 4.7 ~ 5.4min.Such as, but just for the ease of measuring within the scope of above-mentioned adjustment Prey Bahrain peak to 3 ~ 5min, the unlikely long recording time making color atlas D under each chromatographic peak of guarantee is separated satisfactory situation, completes test within the rational time.In addition, as everyone knows, after above-mentioned such as chromatographic column brand, column length, flow velocity, column temperature etc. appropriately adjust, typically each impurity peaks does not have large change relative to the relative retention time at principal constituent peak, and this is the ABC in liquid phase chromatography.

In addition, as well known to those skilled in the art, from color atlas D, directly can obtain the peak area ratio of formula I and each impurity equally, namely use the peak area at Prey Bahrain peak in chromatographic peak D directly divided by the peak area of the impurity peaks of institute's compute, described peak area ratio can be obtained.But because the area discrepancy of main peak and impurity peaks is comparatively large, people usually adopt and compare, to reduce measuring error with the solution of such as 1%, 0.5% or 0.1% concentration.In the present invention, unless otherwise noted, all as above, use 1 ‰ contrast solution as described in [HPLC method A] calculates.

The present invention have been surprisingly found that, when the RRT1.94 foreign matter content in the present composition is controlled within the specific limits, the composition that the present invention can be used as bulk drug and the pharmaceutical preparation prepared thereof have obviously better stability, particularly when the peak area ratio of formula I and RRT1.94 impurity is greater than 100, such as this peak area ratio is 100 ~ 20000, be such as 100 ~ 15000, be such as 100 ~ 10000, be such as 150 ~ 10000, such as, when being 200 ~ 10000, lactan in the present composition can control with in the scope of initial value no significant difference effectively.

Therefore, composition according to a first aspect of the present invention, it comprises with compounds of Formula I:

and as impurity with Formula Il compound:

Its compounds of formula I content be formula II compounds content more than 100 times (such as said composition compounds of formula I content is 100 ~ 20000 times of formula II compounds content, be such as 150 ~ 15000 times, be such as 200 ~ 10000 times, be such as 250 ~ 10000 times, be such as 500 ~ 10000 times)

The peak area ratio of the RRT1.94 impurity that formula I and [HPLC method A] determine be greater than 100 (such as this peak area ratio is 100 ~ 20000, be such as 100 ~ 15000, be such as 100 ~ 10000, be such as 150 ~ 10000, be such as 200 ~ 10000).

In the present invention, if not otherwise indicated, the RRT1.45 impurity mentioned, RRT1.73 impurity, RRT1.94 impurity, RRT2.15 impurity all as in herein [HPLC method A] define, namely, RRT1.45 impurity refers to that using [HPLC method A] herein to measure relative retention time compared with formula I is about the impurity of 1.35 ~ 1.55, RRT1.73 impurity refers to that using [HPLC method A] herein to measure relative retention time compared with formula I is about the impurity of 1.63 ~ 1.83, RRT1.94 impurity refers to that using [HPLC method A] herein to measure relative retention time compared with formula I is about the impurity of 1.84 ~ 2.04, RRT2.15 impurity refers to that using [HPLC method A] herein to measure relative retention time compared with formula I is about the impurity of 2.05 ~ 2.25.

In the present invention, retention time can represent with RT; Relative retention time can represent with RRT, and it is the ratio of retention time divided by the retention time gained at Prey Bahrain peak of mentioned chromatographic peak.

In addition, second aspect present invention additionally provides a kind of pharmaceutical preparation, wherein comprises composition described in first aspect present invention either a program, and the acceptable auxiliary material of pharmacy.

Pharmaceutical preparation according to a second aspect of the present invention, it is in liquid preparation or the form of solid preparation.

Pharmaceutical preparation according to a second aspect of the present invention, wherein said liquid preparation is the form of oral liquid or injection liquid.

Pharmaceutical preparation according to a second aspect of the present invention, wherein said solid preparation is the form of tablet or capsule.

Pharmaceutical preparation according to a second aspect of the present invention, it is in quick-release (be also called and often release) or the tablet of slowly-releasing or the form of capsule.

Pharmaceutical preparation according to a second aspect of the present invention, wherein comprises the formula I of 5 ~ 500mg in each tablet or capsule.In Prey Bahrain capsule of known listing, comprise the specification that every capsules contains 25,50,75,100,150,200,225 and 300mg formula I, and known Prey Bahrain is to being proposed its sustained release preparation clinically, its unit formulation content of dispersion will be larger, and therefore in pharmaceutical preparation of the present invention, the amount of activeconstituents formula I can change in a big way.

Pharmaceutical preparation according to a second aspect of the present invention, wherein contained I, and as the formula II compound of impurity.

Pharmaceutical preparation according to a second aspect of the present invention, its compounds of formula I content is more than 100 times of formula II compounds content, such as this pharmaceutical preparation compounds of formula I content is 100 ~ 20000 times of formula II compounds content, be such as 150 ~ 15000 times, be such as 200 ~ 10000 times, be such as 250 ~ 10000 times, be such as 500 ~ 10000 times.Although with the addition of pharmaceutical excipient in pharmaceutical preparation of the present invention, but formula I wherein, as the content in pharmaceutical preparation of the present invention of the formula II compound of impurity and the RRT1.45 impurity mentioned herein, RRT1.73 impurity, RRT1.94 impurity, RRT2.15 impurity and proportionlity each other, easily can be measured by [HPLC method A] of the present invention and obtain.

Pharmaceutical preparation according to a second aspect of the present invention, wherein also optionally comprise determined by herein [HPLC method A] be selected from one or more following other impurity: RRT1.45 impurity, RRT1.73 impurity, RRT1.94 impurity, RRT2.15 impurity.

Pharmaceutical preparation according to a second aspect of the present invention, it is under the high performance liquid chromatography chromatographic condition (such as the present invention [HPLC method A]) that the resolution between formula I and formula II compound can be made to be greater than 8, in this pharmaceutical preparation gained HPLC collection of illustrative plates, described formula I peak area is more than 50 times of formula II compound peaks area, and such as formula I peak area is 100 ~ 20000 times or 100 ~ 15000 times or 100 ~ 10000 times or 100 ~ 5000 times of formula II compound peaks area.Or, pharmaceutical preparation according to a second aspect of the present invention, it is under the high performance liquid chromatography chromatographic condition (such as the present invention [HPLC method A]) that the resolution between formula I and formula II compound can be made to be greater than 8, in this pharmaceutical preparation gained HPLC collection of illustrative plates, the peak area ratio of described formula I and formula II compound is greater than 50, such as this peak area ratio is 100 ~ 20000, be such as 100 ~ 15000, be such as 100 ~ 10000, be such as 100 ~ 5000.

Pharmaceutical preparation according to a second aspect of the present invention, it is under the high performance liquid chromatography chromatographic condition (such as the present invention [HPLC method A]) that the resolution between formula I and formula II compound can be made to be greater than 8, in this pharmaceutical preparation gained HPLC collection of illustrative plates, the peak area ratio of described formula I and RRT1.45 impurity is greater than 100, such as this peak area ratio is 100 ~ 20000, be such as 100 ~ 15000, be such as 100 ~ 10000, be such as 150 ~ 10000, be such as 200 ~ 10000.Above-mentioned " peak area ratio of formula I and RRT1.45 impurity is greater than 100 " also can be described as " formula I peak area is more than 100 times of RRT1.45 impurity peak area "; Or phrase " peak area ratio of formula I and RRT1.45 impurity is 100 ~ 20000 " also can be described as " formula I peak area is 100 ~ 20000 times of formula II compound peaks area ", also has identical implication under other similar linguistic context of the present invention.

Pharmaceutical preparation according to a second aspect of the present invention, it is under the high performance liquid chromatography chromatographic condition (such as the present invention [HPLC method A]) that the resolution between formula I and formula II compound can be made to be greater than 8, in this pharmaceutical preparation gained HPLC collection of illustrative plates, the peak area ratio of described formula I and RRT1.73 impurity is greater than 100, such as this peak area ratio is 100 ~ 20000, be such as 100 ~ 15000, be such as 100 ~ 10000, be such as 150 ~ 10000, be such as 200 ~ 10000.

Pharmaceutical preparation according to a second aspect of the present invention, it is under the high performance liquid chromatography chromatographic condition (such as the present invention [HPLC method A]) that the resolution between formula I and formula II compound can be made to be greater than 8, in this pharmaceutical preparation gained HPLC collection of illustrative plates, the peak area ratio of described formula I and RRT1.94 impurity is greater than 100, such as this peak area ratio is 100 ~ 20000, be such as 100 ~ 15000, be such as 100 ~ 10000, be such as 150 ~ 10000, be such as 200 ~ 10000.

Pharmaceutical preparation according to a second aspect of the present invention, it is under the high performance liquid chromatography chromatographic condition (such as the present invention [HPLC method A]) that the resolution between formula I and formula II compound can be made to be greater than 8, in this pharmaceutical preparation gained HPLC collection of illustrative plates, the peak area ratio of described formula I and RRT2.15 impurity is greater than 100, such as this peak area ratio is 100 ~ 20000, be such as 100 ~ 15000, be such as 100 ~ 10000, be such as 150 ~ 10000, be such as 200 ~ 10000.

Pharmaceutical preparation according to a second aspect of the present invention, the high performance liquid chromatography that wherein parameter such as the content of Measurement and Computation pharmaceutical preparation of the present invention compounds of formula I, formula II compound and other impurity and the ratio between described formula I peak area and formula II compound (or and other impurity) peak area is used, can carry out according to [the HPLC method A] that the present invention is mentioned above.

Pharmaceutical preparation according to a second aspect of the present invention, it comprises with compounds of Formula I:

and pharmaceutical excipient,

And as impurity with Formula Il compound:

Its compounds of formula I content be formula II compounds content more than 100 times (such as this pharmaceutical preparation compounds of formula I content is 100 ~ 20000 times of formula II compounds content, be such as 150 ~ 15000 times, be such as 200 ~ 10000 times, be such as 250 ~ 10000 times, be such as 500 ~ 10000 times)

In addition, for pharmaceutical preparation of the present invention, owing to which are added the composition of the various embodiment of the present invention as activeconstituents, thus also may there is the formula II compound that can be understood as impurity in these pharmaceutical preparations and other impurity such as includes but not limited to following impurity: RRT1.45 impurity, RRT1.73 impurity, RRT1.94 impurity, RRT2.15 impurity etc.Those skilled in the art know that, these pharmaceutical preparations are when [HPLC method A] measures example as described in the present invention, composition compounds of formula I can be reflected equally exactly and include but not limited to following impurity: formula II compound, RRT1.45 impurity, RRT1.73 impurity, RRT1.94 impurity, RRT2.15 impurity etc., and typically this to join in pharmaceutical preparation content ratio that measured content ratio or peak area ratio and the bulk drug i.e. composition described in the arbitrary embodiment of such as first aspect present invention of this pharmaceutical preparation of preparation be measured to or peak area ratio identical or close.

Further, third aspect present invention provides the method preparing the present composition, it comprises the steps: Prey Bahrain to add in the mixing solutions of Virahol and acetonitrile, heating (is such as heated to 40-60 ° of C, such as be heated to 45-55 ° of C, such as about 50 ° of C) make dissolving, 0.5-5% (v/v) (such as 0.5-2% is added in mixing solutions, such as 0.5-1%) lactic acid, stir, slowly be cooled to about 5 ° of C (2-10 hour can be left standstill at this temperature) to separate out precipitation, leach precipitation, by washed with isopropyl alcohol, 40 ° of C vacuum-dryings, obtain.

Method according to a third aspect of the present invention, wherein said Virahol and the volume ratio both acetonitrile are 100:(30 ~ 50), preferred volume ratio is 100:(35 ~ 45).

In one embodiment, have been found that, to the RRT1.94 impurity that can effectively reduce after the mixing solutions of above-mentioned Virahol and acetonitrile adds appropriate lactic acid in material, and the amount of RRT1.94 impurity in material can be made to drop to lower by repeating above-mentioned recrystallization process.

Known Prey Bahrain can be used for the assisting therapy for the treatment of or preventing generalized anxiety disorder, diabetic peripheral neuropathy, postherpetic neuralgia (such as postherpetic neuralgia), fibromyalgia syndrome, epilepsy.Therefore, again further, fourth aspect present invention provide composition of the present invention for the preparation for the treatment of or prevention generalized anxiety disorder, diabetic peripheral neuropathy, postherpetic neuralgia (such as postherpetic neuralgia), fibromyalgia syndrome, epilepsy assisting therapy medicine in purposes.

Arbitrary embodiment of either side of the present invention, can combine, as long as they there will not be contradiction with arbitrary embodiment of either side.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characteristic goes for this technical characteristic in other embodiment, as long as they there will not be contradiction.

In the present invention, when determining the content of Prey Bahrain or other impurity in various material (the such as present composition and bulk drug, pharmaceutical preparation etc.), and when determining in these materials chromatographic purity, the present invention [HPLC method A] mentioned above can be adopted to carry out.[HPLC method A] can be easily used to measure some preparation performance, such as dissolution rates etc. of pharmaceutical preparation in addition.In the present invention, although the present inventor not yet knows wherein RRT1.45 impurity, RRT1.73 impurity, RRT1.94 impurity, the chemical structure of RRT2.15 impurity, but the present invention [HPLC method A] can easily carry out qualitative to these impurity, [the HPLC method A] that particularly can be specified by the present invention is determined qualitatively with this parameter of relative retention time, even if chromatogram test condition does suitable change time particularly, or even in different laboratory measurements, or even measured by different testing crews, or even when using the hplc determination of different brands, this parameter is all relatively-stationary.In addition, such as, 1.84 ~ 2.04, the fluctuation of this ± 0.2 or ± 0.1 unit is that pharmaceutical analysis field particularly allows in efficient liquid phase chromatographic analysis field to the relative retention time of RRT1.94 impurity (be 1 calculating with the relative retention time of formula I).

" pharmaceutical excipient " or " pharmaceutically acceptable carrier " that use in pharmaceutical preparation of the present invention (it also can be described as pharmaceutical composition) can be carrier or the auxiliary material of any routine in field of pharmaceutical preparations.The selection of specific support or auxiliary material will depend on the administering mode or disease type and state that are used for the treatment of particular patient.For the preparation method of the said synthetic processes of specific administration pattern completely in the ken of pharmaceutical field technician.Such as, the thinner of pharmaceutical field routine, carrier, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier and lubricant etc. can be comprised as pharmaceutically acceptable carrier.If desired, flavouring agent, preservative and sweetener etc. can also be added in pharmaceutical composition.

Pharmaceutical composition of the present invention can make the various ways such as tablet, pulvis, granule, capsule, oral liquid, paste, creme, injectable emulsion (aseptic powder needle for injection).The medicine of above-mentioned various formulation all can be prepared according to the ordinary method of pharmaceutical field.

Prey Bahrain medicament (such as, capsule etc.) of now list marketing, it can be used for the assisting therapy for the treatment of generalized anxiety disorder, diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia syndrome, epilepsy.The invention provides a kind of new Prey Bahrain, it has satisfactory stability performance, and Prey Bahrain that therefore the present invention is new can be used for the assisting therapy for the treatment of generalized anxiety disorder, diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia syndrome, epilepsy equally.

Embodiment

Can be conducted further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite not deviating from the spirit and scope of the present invention, can carry out various change and modification to the present invention.The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and working method is well known in the art, the present invention still describes in detail as far as possible at this.

In test below, use the present invention [HPLC method A], concrete condition determination wherein used is:

Chromatographic column: ZORBAX Eclipse XDB-C18 chromatographic column is (purchased from Agilent company, 200mm*4.6mm*5 μm), column temperature 25 ° of C, flow velocity 1ml/min, formula I retention time is about 3.4min, the resolution at Prey Bahrain and undesirable lactam impurity peak is greater than 10, the auxiliary material peak that solvent peak and the pharmaceutical preparation adding pharmaceutical excipient show all eluted before 2.1min, in the relative retention time of formula I for 1, the relative retention time of RRT1.45 impurity is between 1.35 ~ 1.55, the relative retention time of RRT1.73 impurity is between 1.63 ~ 1.83, the relative retention time of RRT1.94 impurity is between 1.84 ~ 2.04, the relative retention time of RRT2.15 impurity is 2.05 ~ 2.25.Also find in test, use column length is other brand C18 post of 15 ~ 30cm, or a certain temperature column temperature is set between 20 ~ 40 ° of C, or person is by a certain value of flow rate set between 0.8 ~ 1.5ml/min, the relative retention time of RRT1.45 impurity, RRT1.73 impurity, RRT1.94 impurity, RRT2.15 impurity four impurity is all in their above-mentioned respective range.

raw material preparation example 1: prepare Prey Bahrain raw material

Prey Bahrain raw material is prepared according to the method for embodiment 1 ([0092] section is to [0165] section) in CN101848905A (Chinese Patent Application No. 200880107269.2).

The formula II compound of product also can use aforesaid method and obtain through silica column purification in contrast.Use the ratio of " content ratio (I/II) " expression I content and formula II compounds content in the present invention, the peak area ratio of color atlas compounds of formula I and RRT1.45 impurity is represented, the peak area ratio also similar expression of formula I and other impurity with " peak area ratio (I/RRT1.73) ".

Measure through [HPLC method A], in this bulk drug, formula I content 98.6%, formula II compounds content 0.76%, content ratio (I/II)=130; In bulk drug HPLC collection of illustrative plates, peak area ratio (I/RRT1.45)=103, peak area ratio (I/RRT1.73)=96, peak area ratio (I/RRT1.94)=93, peak area ratio (I/RRT2.15)=126.

raw material preparation example 2: prepare Prey Bahrain raw material

Prey Bahrain raw material is prepared according to the method for embodiment 1 to embodiment 7 ([0096] section is to [0133] section) in CN101821228A (Chinese Patent Application No. 200880110859.0, science and technology institute of Korea S).

Measure through [HPLC method A], in this bulk drug, formula I content 97.7%, formula II compounds content 1.26%, content ratio (I/II)=78; In bulk drug HPLC collection of illustrative plates, peak area ratio (I/RRT1.45)=96, peak area ratio (I/RRT1.73)=78, peak area ratio (I/RRT1.94)=81, peak area ratio (I/RRT2.15)=103.

raw material preparation example 3: prepare Prey Bahrain raw material

Prey Bahrain raw material is prepared according to the method for embodiment 1 to embodiment 9 in CN101585778A (Chinese Patent Application No. 200810037609.0, Shanghai minister nation).

Measure through [HPLC method A], in this bulk drug, formula I content 98.4%, formula II compounds content 0.74%, content ratio (I/II)=133; In bulk drug HPLC collection of illustrative plates, peak area ratio (I/RRT1.45)=138, peak area ratio (I/RRT1.73)=107, peak area ratio (I/RRT1.94)=74, peak area ratio (I/RRT2.15)=76.

test compound preparation example 1: formula I and the RRT1.94 impurity of preparing substantially pure

Using raw material preparation example 3 gained Prey Bahrain as raw material, the chromatographic condition of [HPLC method A], use preparative ZORBAX Eclipse XDB-C18 chromatographic column (purchased from, Agilent company, 300mm*10mm*7 μm), the chromatographic peak elutriant of interception type I and the elutriant of retention time chromatographic peak corresponding to RRT1.94 impurity () respectively, gained elutriant is desolventized respectively, recrystallization is carried out respectively again by the method for Examples below 1, obtain formula I and the RRT1.94 impurity of substantially pure respectively, the two measures chromatographic purity with [HPLC method A] and is all greater than 99.9%, and in gained formula I, formula II compound and RRT1.45 impurity do not detected, RRT1.73 impurity, RRT1.94 impurity, RRT2.15 impurity.If needed, RRT1.45 impurity, RRT1.73 impurity, RRT2.15 impurity also can obtain by similar fashion.

embodiment 1: prepare Prey Bahrain of the present invention

The Prey Bahrain raw material 1g above raw material preparation example 1 obtained adds in the mixing solutions of 100ml Virahol and 40ml acetonitrile, be heated to about 50 ° of C and make dissolving, 1.0ml lactic acid is added in mixing solutions, stir, slowly be cooled to about 5 ° of C (leaving standstill about 8 hours at this temperature) to separate out precipitation, leach precipitation, by washed with isopropyl alcohol, 40 ° of C vacuum-dryings; Repeat above operation more once, obtain the Prey Bahrain that can be used as formulating medicinal preparations, yield 86.4%.

Measure through [HPLC method A], in the present embodiment gained Prey Bahrain, formula I content 99.6%, formula II compounds content 0.03%, content ratio (I/II)=3320; In the present embodiment gained Prey Bahrain HPLC collection of illustrative plates, peak area ratio (I/RRT1.45)=725, peak area ratio (I/RRT1.73)=453, peak area ratio (I/RRT1.94)=650, peak area ratio (I/RRT2.15)=2854.

embodiment 2: prepare Prey Bahrain of the present invention

The Prey Bahrain raw material 1g above raw material preparation example 1 obtained adds in the mixing solutions of 100ml Virahol and 35ml acetonitrile, be heated to about 50 ° of C and make dissolving, in mixing solutions, add 1.35ml lactic acid, stir, be slowly cooled to about 5 ° of C (leaving standstill about 8 hours at this temperature) to separate out precipitation, leach precipitation, by washed with isopropyl alcohol, 40 ° of C vacuum-dryings, then repeat above operation once, obtain the Prey Bahrain that can be used as formulating medicinal preparations, yield 78.6%.

Measure through [HPLC method A], in the present embodiment gained Prey Bahrain, formula I content 99.7%, formula II compounds content 0.04%, content ratio (I/II)=2493; In the present embodiment gained Prey Bahrain HPLC collection of illustrative plates, peak area ratio (I/RRT1.45)=520, peak area ratio (I/RRT1.73)=375, peak area ratio (I/RRT1.94)=360, peak area ratio (I/RRT2.15)=1535.

embodiment 3: prepare Prey Bahrain of the present invention

The Prey Bahrain raw material 1g above raw material preparation example 1 obtained adds in the mixing solutions of 100ml Virahol and 45ml acetonitrile, be heated to about 50 ° of C and make dissolving, 0.725ml lactic acid is added in mixing solutions, stir, be slowly cooled to about 5 ° of C (leaving standstill about 8 hours at this temperature) and, to separate out precipitation, leach precipitation, by washed with isopropyl alcohol, 40 ° of C vacuum-dryings, to obtain final product, yield 91.3%.

Measure through [HPLC method A], in the present embodiment gained Prey Bahrain, formula I content 99.3%, formula II compounds content 0.198%, content ratio (I/II)=502; In the present embodiment gained Prey Bahrain HPLC collection of illustrative plates, peak area ratio (I/RRT1.45)=225, peak area ratio (I/RRT1.73)=213, peak area ratio (I/RRT1.94)=210, peak area ratio (I/RRT2.15)=207.

embodiment 4: prepare Prey Bahrain of the present invention

The Prey Bahrain 1g above embodiment 3 obtained, the method according to embodiment 1 carries out processing (recrystallization repeats 2 times), yield 77.3%.

Measure through [HPLC method A], in the present embodiment gained Prey Bahrain, formula I content 99.8%, formula II compounds content 0.01%, content ratio (I/II)=9980; In the present embodiment gained Prey Bahrain HPLC collection of illustrative plates, peak area ratio (I/RRT1.45)=8325, peak area ratio (I/RRT1.73)=9720, peak area ratio (I/RRT1.94)=9830, peak area ratio (I/RRT2.15)=8950.

embodiment 5: prepare Prey Bahrain of the present invention

The Prey Bahrain 1g above embodiment 3 obtained, the method according to embodiment 1 carries out processing (but recrystallization process repeats 3 times), yield 43.5%.

Measure through [HPLC method A], in the present embodiment gained Prey Bahrain, formula I content 99.8%, formula II compounds content 0.005%, content ratio (I/II)=19960; In the present embodiment gained Prey Bahrain HPLC collection of illustrative plates, peak area ratio (I/RRT1.45)=14430, peak area ratio (I/RRT1.73)=19310, peak area ratio (I/RRT1.94)=13860, peak area ratio (I/RRT2.15)=18550.

The display of above result, although products therefrom impurity reduces greatly, yield can reduce greatly, and this goes out to continue to improve product quality but yield situation about greatly reducing inadvisable from industrial production in the prerequisite obtaining the bulk drug with better quality; Yield described in embodiment 4 is desirable more than 75%, namely in gained Prey Bahrain of the present invention bulk drug, formula I content is 500 ~ 10000 times of formula II compounds content, and the peak area ratio of the RRT1.94 impurity that formula I and [HPLC method A] determine or other four impurity is 200 ~ 10000 is desirable.

embodiment 6: prepare Prey Bahrain of the present invention

The Prey Bahrain raw material above raw material preparation example 2 obtained, the method according to embodiment 1 processes, and obtains the Prey Bahrain that can be used as formulating medicinal preparations, yield 79.6%.

Measure through [HPLC method A], in the present embodiment gained Prey Bahrain, formula I content 99.6%, formula II compounds content 0.013%, content ratio (I/II)=7662; In the present embodiment gained Prey Bahrain HPLC collection of illustrative plates, peak area ratio (I/RRT1.45)=4225, RRT1.73 impurity does not detect, peak area ratio (I/RRT1.94)=475, peak area ratio (I/RRT2.15)=4854.

embodiment 7: prepare Prey Bahrain of the present invention

The Prey Bahrain raw material above raw material preparation example 3 obtained, the method according to embodiment 1 processes, and obtains the Prey Bahrain that can be used as formulating medicinal preparations, yield 81.3%.

Measure through [HPLC method A], in the present embodiment gained Prey Bahrain, formula I content 99.5%, formula II compounds content 0.083%, content ratio (I/II)=1199; In the present embodiment gained Prey Bahrain HPLC collection of illustrative plates, peak area ratio (I/RRT1.45)=645, peak area ratio (I/RRT1.73)=312, peak area ratio (I/RRT1.94)=275, peak area ratio (I/RRT2.15)=1635.

The present inventor also finds in other test, if in above embodiment 1-7, do not add lactic acid, then effectively can not improve peak area ratio (I/RRT1.94), particularly be difficult to this peak area ratio (I/RRT1.94) to bring up to more than 150, namely effectively can not remove RRT1.94 impurity wherein.Such as in embodiment 1, if do not add lactic acid, in products therefrom, peak area ratio (I/RRT1.94) is 133, and in example 2, if do not add lactic acid, in products therefrom, peak area ratio (I/RRT1.94) is 117.

embodiment 8: the preparation of the artificial combination thing containing Prey Bahrain and RRT1.94

The formula I using " test compound preparation example 1 " above to prepare and RRT1.94 impurity, carry out the two according to a certain percentage combining that (formula I and RRT1.94 impurity weight ratio reach value listed in Table with the peak area ratio meeting the two in the wide region of 100:0.0001 ~ 0.5, the peak area ratio about 360 of such as, when the two weight ratio is 100:0.01 combination display; Because the two weight differential is large, the two is made to be dissolved in methyl alcohol during proportioning mixing, then methyl alcohol is removed so that the two mixes), obtain many parts of compositions, these proportionings combination resulting composition measures the peak area ratio (I/RRT1.94) showing following table respectively, i.e. numerical value shown in following table I/RRT1.94 hurdle under [HPLC method A] condition.

Composition No	#80	#81	#82	#83	#84	#85	#86	#87	#88	#89	#891
												I/RRT1.94	35710	7143	3570	715	310	210	143	70	36	24	18
II increment/%	0	0	0	0.0006	0.0011	0.0018	0.072	0.168	0.413	1.244	2.429

50C-4M tests: each for above #80 to #891 powder composition is placed in sealed glass jars, places April (placing April under can representing these 50 ° of C with " 50C-4M " in the present invention to dispose) under 50 ° of C.Then content (the % of this sample compound of formula H is measured, represent with C4), also measure the content (% of this sample without its compound of formula H during 50C-4M in addition, represent with C0), calculate the content increased value of formula II compound after 50C-4M in this sample, i.e. II increment (%), calculates with following formula: II increment=C4-C0.Result sees the above table, visible, 200 up-to-date style II compound increasing amounts are greater than atomic at peak area ratio (I/RRT1.94), and when peak area ratio (I/RRT1.94) is less than 200, display type II compound increases obviously, particularly when peak area ratio (I/RRT1.94) reaches 24, itself reaches more than 1% without Prey Bahrain compound of formula H content of the substantially pure of formula II compound, completely can not fulfilling medicinal requirements.Typically as in Prey Bahrain of Medicinal crude drug, the content of formula II compound should lower than 0.2%, and the content of Prey Bahrain bulk drug compound of formula H of fine quality should, lower than 0.1%, particularly preferably be lower than 0.05%; And if be unacceptable higher than 0.5%.Above-mentioned 50C-4M test method can be used for the context of the invention.

It should be noted that, when calculating comprises the pharmaceutical preparation of pharmaceutical excipient, owing to being wherein added with pharmaceutical excipient, therefore the content of formula I in pharmaceutical preparation can represent with the percentage ratio of the absolute magnitude of preparation compounds of formula I divided by the theoretical labelled amount gained of this part of preparation compounds of formula I; And for formula II compound wherein, its content represents with the absolute magnitude of the said preparation compound of formula H percentage ratio divided by the absolute magnitude of formula I, if when other material as impurity represents with content in pharmaceutical preparation, also have and implication like formula II compounds.

embodiment 81: the pharmaceutical preparation containing Prey Bahrain and RRT1.94

Using each for above #80 to #891 powder composition as bulk drug, get its 75mg respectively, evenly also 80 mesh sieves are crossed by ground and mixed respectively with lactose 10mg, W-Gum 13mg, talcum powder 2mg, load in empty hard capsule, obtain 11 kinds of capsules containing formula I, every capsules, containing Prey Bahrain 75mg, often criticizes system 5000.Use 50C-4M these capsules of test determination formula II compound amount increased value after 50C-4M process.Result shows, the result of " II increment " bulk drug corresponding to it of each capsule is substantially identical, the II increment of such as #80 to #82 each powder composition gained capsule is 0, the II increment of #83 to #85 each powder composition gained capsule is all in 0.0005 ~ 0.002% scope, the II increment of #86 to #891 each powder composition gained capsule differs to the II increment of corresponding bulk drug in upper table and is less than 0.05% unit, such as, be 1.265% with the II increment of #89 raw material gained capsule.

embodiment 9: the preparation of the artificial combination thing containing Prey Bahrain and RRT1.94

The formula I prepare appropriate " test compound preparation example 1 " above or RRT1.94 impurity add (to be jointly dissolved in methyl alcohol then except methyl alcohol adds to make the mode of mixing of materials) in foregoing embodiments 1 gained Prey Bahrain of the present invention to, under [HPLC method A] condition, the peak area ratio (I/RRT1.94) showing following table is respectively measured to make the artificial combination thing that gained contains Prey Bahrain and RRT1.94 and other impurity, such as can reduce peak area ratio (I/RRT1.94) when embodiment 1 gained Prey Bahrain adds RRT1.94 impurity.

Composition No	#90	#91	#92	#93	#94	#95	#96	#97	#98	#99	#991
												I/RRT1.94	32300	9550	3520	690	325	205	165	81	35	25	20
II increment/%	0	0	0	0.0005	0.0011	0.0015	0.077	0.165	0.431	1.289	2.503

According to the II increment (%) of more than 50C-4M determination of test method each artificial composition after 50C-4M disposes.Result and embodiment are substantially similar.Visible, in as Prey Bahrain of bulk drug when control peak area ratio (I/RRT1.94) be greater than 150 be particularly greater than 200 time, the control for the amount of its Chinese style II undesirable lactam impurity compound is very favorable.

embodiment 91: the pharmaceutical preparation containing Prey Bahrain and RRT1.94

Using each for above #90 to #991 powder composition as bulk drug, get its 75mg respectively, evenly also 80 mesh sieves are crossed by ground and mixed respectively with lactose 10mg, W-Gum 13mg, talcum powder 2mg, load in empty hard capsule, obtain 11 kinds of capsules containing formula I, every capsules, containing Prey Bahrain 75mg, often criticizes system 5000.Use 50C-4M these capsules of test determination formula II compound amount increased value after 50C-4M process.Result shows, the result of " II increment " bulk drug corresponding to it of each capsule is substantially identical, the II increment of such as #90 to #92 each powder composition gained capsule is 0, the II increment of #93 to #95 each powder composition gained capsule is all in 0.0005 ~ 0.0018% scope, the II increment of #86 to #891 each powder composition gained capsule differs to the II increment of corresponding bulk drug in upper table and is less than 0.05% unit, such as, be 1.273% with the II increment of #89 raw material gained capsule.

Above embodiment 81 and embodiment 91 result visible, in pharmaceutical preparation prepared by the raw material with the RRT1.94 impurity of certain content, the degraded product formula II undesirable lactam impurity of activeconstituents has the Changing Pattern substantially identical with bulk drug equally.Therefore for the composition of first aspect present invention and the pharmaceutical preparation of second aspect, RRT1.94 impurity wherein containing lower aq, and in the HPLC collection of illustrative plates that its warp [HPLC method A] measures, it is preferred that peak area ratio (I/RRT1.94) is greater than 150, and particularly peak area ratio (I/RRT1.94) is greater than 200 is very preferred.

pharmaceutical preparation example 1: the capsule medicine composition preparing Prey Bahrain

Example 1 gained Prey Bahrain 75mg and lactose 10mg, W-Gum 13mg, talcum powder 2mg evenly also cross 80 mesh sieves by ground and mixed, load in empty hard capsule, obtain Prey Bahrain capsule, every capsules, containing Prey Bahrain 75mg, often criticizes system 5000.Capsule 1 is called in the present invention with the capsule that embodiment 1 gained Prey Bahrain obtains thus for raw material.

Equally, respectively using embodiment 2,3,4,5,6,7 gained Prey Bahrain as raw material, the method with capsule 1 prepares capsule, obtains capsule 2, capsule 3, capsule 4, capsule 5, capsule 6, capsule 7 respectively.

Equally, respectively using raw material preparation example 1, raw material preparation example 2, raw material preparation example 3 gained Prey Bahrain as raw material, the method with capsule 1 prepares capsule, obtains capsule 01, capsule 02, capsule 03 respectively.

pharmaceutical preparation example 2: the troche medical composition preparing Prey Bahrain

Prepare 10000 scales, every sheet consists of: embodiment 2 gained Prey Bahrain 75mg, N.F,USP MANNITOL 100mg, W-Gum 90mg, colloid silica 2mg, polyvidone (K25) 5mg, Magnesium Stearate 3mg.

Preparation method: (a) each material was crushed to 60 ~ 80 orders in advance.Prey Bahrain, N.F,USP MANNITOL, W-Gum (2/3 amount) are loaded in fluidised bed granulator; B polyvidone is dissolved in the water to form solution by (), and by the particle of this spray solution in this fluidised bed granulator, these mixtures are made particle to form particulate mixtures; C this particulate mixtures is dried to the end point moisture content of about 1.0% to about 2.5% by (); D this particulate mixtures of step (c) mixes with colloid silica, surplus W-Gum and Magnesium Stearate by (), and blending is to form final blend; E () uses tabletting machine that this final blend is pressed into tablet.

pharmaceutical preparation example 3: the slow releasing tablet pharmaceutical composition preparing Prey Bahrain

Prepare 10000 scales, every sheet consists of: embodiment 3 gained Prey Bahrain 150mg, hypromellose 2208 (Methocel K15M) 150mg, W-Gum 100mg, Carbopol 941 ( , 71G) 10mg, colloid silica 5mg, Magnesium Stearate 3mg.

Preparation method: each component was ground into 60-80 object fine powder by (1) in advance.In a mixer, activeconstituents and small part (about 15%) hypromellose is made to be pre-mixed; (2) then in a mixer, the mixture in step (1) is mixed with remaining hypromellose, W-Gum, carbomer, then adds colloid silica and Magnesium Stearate, material is fully mixed; (3) by by final mixture compressing tablet in suitable tabletting machine, the matrix tablet of slow release type is prepared.

pharmaceutical preparation example 4: the oral medicine liquid composition preparing Prey Bahrain

Preparation 10000ml scale, every 5ml oral liquid consists of: embodiment 3 gained Prey Bahrain 75mg, propylene glycol 0.5ml, mud moor gold ethyl ester 10mg, stevioside 5mg, water add to 5ml in right amount.

Preparation method: each component is mixed by suitable quantity of water, dissolves, add water to full dose, be dispensed in vial, obtain the pharmaceutical preparation of drink form.

stability test example 1: study on the stability is carried out to various sample

Investigate sample: raw material preparation example 1,2,3 gained Prey Bahrain raw material, Prey Bahrain prepared by embodiment 1,2,3,4,5,6,7, capsule 1 to capsule 7 prepared by pharmaceutical preparation example 1 and capsule 01 to capsule 03, tablet prepared by pharmaceutical preparation example 2, slow releasing tablet prepared by pharmaceutical preparation example 3, pharmaceutical preparation example 4 oral liquid, and commercially available capsule (Prey Bahrain capsule, 75mg/ grain, the accurate word J20100102 of traditional Chinese medicines, lot identification mark 9408423023, in January, 2012 production time) totally 24 samples as sample, carry out study on the stability.

Above-mentioned each bulk drug or capsule or tablet are packed with aluminium foil bag respectively, oral liquid is packaged in vial, be placed in 45 ° of C thermostat containers to place May (can be described as " 45C-5M test "), measure each sample content of activeconstituents and content of formula II compound when 0 month (namely before setting-out) and May.

For each sample, with May active component content divided by the percentage value of 0 month active component content gained, as the activeconstituents relative content (%) after high-temperature treatment May, namely calculating formula is as follows:

Activeconstituents relative content (%)=(content ÷ in May 0 month content) × 100%

For each sample, measure the content (% of this sample compound of formula H, represent with C5), also measure the content (% of this sample without its compound of formula H during 45C-5M in addition, represent with C0), calculate the content increased value of formula II compound after 45C-5M in this sample, i.e. II increment (%), calculate with following formula: II increment=C5-C0.

After above 45C-5M test is disposed, the activeconstituents relative content of commercially available capsule is 97.7%, and after 45C-5M, the content increased value of formula II compound is 0.076%; Other each sample the results are shown in following table:

Sample	I content	II increment	Sample	I content	II increment
						Raw material preparation example 1	94.4%	0.163%	Capsule 01	87.5%	0.274%
Raw material preparation example 2	92.7%	0.194%	Capsule 02	85.8%	0.304%
						Raw material preparation example 3	93.1%	0.206%	Capsule 03	86.4%	0.338%
Embodiment 1	98.7%	<0.001%	Capsule 1	96.4%	<0.001%
						Embodiment 2	98.8%	<0.001%	Capsule 2	97.3%	<0.001%
Embodiment 3	99.2%	0.0014%	Capsule 3	96.2%	0.0018%
						Embodiment 4	98.4%	0	Capsule 4	96.7%	0
Embodiment 5	98.6%	0	Capsule 5	98.1%	0
						Embodiment 6	98.7%	<0.001%	Capsule 6	96.5%	<0.001%
Embodiment 7	98.9%	0.0011%	Capsule 7	96.8%	0.0014%
						Pharmaceutical preparation example 2	96.5%	0.0012%
Pharmaceutical preparation example 3	96.8%	0.0021%
						Pharmaceutical preparation example 4	96.3%	0.0024%

In table, " I content " hurdle represents the relative content of activeconstituents formula I.

Result from table, Prey Bahrain of the present invention all have under bulk drug or formulated state than the better chemical stability of the result prepared in prior art, particularly show one of them and quite expect that the undesirable lactam impurity avoided is in controlled level.

Claims

1. the bulk drug of lyrica, it comprises with compounds of Formula I:

i, and as impurity with Formula Il compound:

iI; This bulk drug compounds of formula I content is 100 ~ 20000 times of formula II compounds content; Also comprise the RRT1.94 impurity determined by [HPLC method A] in this bulk drug, in the HPLC collection of illustrative plates of described [HPLC method A] gained, the peak area ratio of formula I and RRT1.94 impurity is 200 ~ 10000; Described RRT1.94 impurity refers to that using described [HPLC method A] to measure relative retention time compared with formula I is the impurity of 1.84 ~ 2.04; Described formula II compound is also called undesirable lactam impurity;

The method of described [HPLC method A] comprises the following steps:

Step 2, chromatographic condition and system suitability: be weighting agent with octadecylsilane chemically bonded silica, the mixed solution of water-methanol-acetonitrile-phosphate buffered saline buffer volume ratio 550:350:100:1 is moving phase, determined wavelength is 210nm, number of theoretical plate calculates by lyrica peak and is not less than 1800, and the resolution at lyrica and undesirable lactam impurity peak should be greater than 8; The compound method of wherein said phosphate buffered saline buffer is: get potassium primary phosphate 3.5g and Sodium phosphate dibasic dodecahydrate 14.62g, be dissolved in water and be diluted to 1000ml, by phosphoric acid or potassium hydroxide solution adjust ph to 7.0, to obtain final product;

Prepared by step 3, need testing solution: get the sample to be tested being equivalent to lyrica 50mg, accurately weighed, puts in 50ml measuring bottle, adds moving phase and dissolves, and stirring or acutely jolting 15 minutes, shake up, be diluted to scale by moving phase, shake up, as need testing solution;

Prepared by step 4, reference substance solution: get lyrica reference substance 50mg, accurately weighed, puts in 50ml measuring bottle, adds moving phase and dissolves, and stirring or acutely jolting 15 minutes, shake up, be diluted to scale by moving phase, shake up, in contrast product solution;

The preparation of step 5,1 ‰ contrast solutions: precision measures above-mentioned need testing solution 5ml, puts in 250ml measuring bottle, is diluted to scale by moving phase, shake up; Precision measures this diluent 5ml, puts in 100ml measuring bottle, is diluted to scale by moving phase, shake up, as 1 ‰ contrast solutions;

The preparation of step 6, undesirable lactam impurity solution: modus ponens II undesirable lactam impurity reference substance 10mg, accurately weighed, put in 250ml measuring bottle, add moving phase and dissolve, be diluted to scale by moving phase, shake up; Accurate this solution of amount 5ml, puts in 200ml measuring bottle, is diluted to scale by moving phase, shake up, as undesirable lactam impurity reference substance solution again;

Step 7, assay method:

Step 71, precision measure 1 ‰ contrast solution 50 μ l injection liquid chromatographies, regulate detection sensitivity, make the peak height of principal constituent chromatographic peak be 10% of full range;

Step 72, precision measure 1 ‰ contrast solution 50 μ l injection liquid chromatographies, and record color atlas is to 8 times of principal constituent chromatographic peak retention time, and this color atlas is designated as color atlas A, reads retention time and the peak area at the principal constituent peak in this color atlas A;

Step 75, precision measures need testing solution 50 μ l injection liquid chromatography, record color atlas is to 8 times of principal constituent chromatographic peak retention time, this color atlas is designated as color atlas D, in this color atlas D, ignore in solvent peak and optional pharmaceutical excipient peak, with the relative retention time of principal constituent chromatographic peak for 1, reading relative retention time in this color atlas D is respectively the impurity of 1.35 ~ 1.55, relative retention time is the impurity of 1.63 ~ 1.83, relative retention time is the impurity of 1.84 ~ 2.04, relative retention time is retention time and the peak area of the impurity of 2.05 ~ 2.25, and the peak area of the impurity peaks corresponding to undesirable lactam impurity retention time in color atlas B in this color atlas D, wherein, in described color atlas D relative retention time be 1.35 ~ 1.55 impurity be called RRT1.45 impurity, relative retention time be 1.63 ~ 1.83 impurity be called RRT1.73 impurity, relative retention time be 1.84 ~ 2.04 impurity be called RRT1.94 impurity, relative retention time be 2.05 ~ 2.25 impurity be called RRT2.15 impurity, impurity peaks corresponding to undesirable lactam impurity retention time in color atlas B in described color atlas D is called undesirable lactam impurity peak,

Step 8, calculating:

In the sample tested,

The content of formula I: the sample weighting amount using dosing in principal constituent peak-to-peak area in color atlas C and color atlas D and step 3 and step 4, by external standard method with the content of calculated by peak area sample to be tested compounds of formula I,

The content of formula II compound: the sample weighting amount using dosing in the peak area at the undesirable lactam impurity peak in color atlas B and color atlas D and step 3 and step 6, by external standard method with the content of calculated by peak area sample to be tested compound of formula H,

The each long-pending ratio of formula I and the peak between formula II compound, RRT1.45 impurity, RRT1.73 impurity, RRT1.94 impurity, RRT2.15 impurity or other impurity, is calculated as follows respectively:

，

。

2. bulk drug according to claim 1, its compounds of formula I content is 150 ~ 15000 times of formula II compounds content.

3. bulk drug according to claim 1, its compounds of formula I content is 200 ~ 10000 times of formula II compounds content.

4. bulk drug according to claim 1, its compounds of formula I content is 250 ~ 10000 times of formula II compounds content.

5. bulk drug according to claim 1, its compounds of formula I content is 500 ~ 10000 times of formula II compounds content.

6. bulk drug according to claim 1, wherein also optionally comprise can be determined by [HPLC method A] be selected from one or more following other impurity: RRT1.45 impurity, RRT1.73 impurity, RRT2.15 impurity.

7. bulk drug according to claim 6, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this bulk drug gained HPLC collection of illustrative plates: the peak area ratio of described formula I and RRT1.45 impurity is 100 ~ 20000.

8. bulk drug according to claim 6, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this bulk drug gained HPLC collection of illustrative plates: the peak area ratio of described formula I and RRT1.45 impurity is 100 ~ 15000.

9. bulk drug according to claim 6, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this bulk drug gained HPLC collection of illustrative plates: the peak area ratio of described formula I and RRT1.45 impurity is 100 ~ 10000.

10. bulk drug according to claim 6, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this bulk drug gained HPLC collection of illustrative plates: the peak area ratio of described formula I and RRT1.45 impurity is 150 ~ 10000.

11. bulk drugs according to claim 6, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this bulk drug gained HPLC collection of illustrative plates: the peak area ratio of described formula I and RRT1.45 impurity is 200 ~ 10000.

12. bulk drugs according to claim 6, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this bulk drug gained HPLC collection of illustrative plates: the peak area ratio of described formula I and RRT1.73 impurity is 100 ~ 20000.

13. bulk drugs according to claim 6, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this bulk drug gained HPLC collection of illustrative plates: the peak area ratio of described formula I and RRT1.73 impurity is 100 ~ 15000.

14. bulk drugs according to claim 6, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this bulk drug gained HPLC collection of illustrative plates: the peak area ratio of described formula I and RRT1.73 impurity is 100 ~ 10000.

15. bulk drugs according to claim 6, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this bulk drug gained HPLC collection of illustrative plates: the peak area ratio of described formula I and RRT1.73 impurity is 150 ~ 10000.

16. bulk drugs according to claim 6, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this bulk drug gained HPLC collection of illustrative plates: the peak area ratio of described formula I and RRT1.73 impurity is 200 ~ 10000.

17. bulk drugs according to claim 6, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this bulk drug gained HPLC collection of illustrative plates: the peak area ratio of described formula I and RRT2.15 impurity is 100 ~ 20000.

18. bulk drugs according to claim 6, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this bulk drug gained HPLC collection of illustrative plates: the peak area ratio of described formula I and RRT2.15 impurity is 100 ~ 15000.

19. bulk drugs according to claim 6, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this bulk drug gained HPLC collection of illustrative plates: the peak area ratio of described formula I and RRT2.15 impurity is 100 ~ 10000.

20. bulk drugs according to claim 6, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this bulk drug gained HPLC collection of illustrative plates: the peak area ratio of described formula I and RRT2.15 impurity is 150 ~ 10000.

21. bulk drugs according to claim 6, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this bulk drug gained HPLC collection of illustrative plates: the peak area ratio of described formula I and RRT2.15 impurity is 200 ~ 10000.

22. 1 kinds of pharmaceutical preparations, wherein comprise bulk drug described in any one of claim 1-21, and the acceptable auxiliary material of pharmacy.

23. pharmaceutical preparations according to claim 22, it is in liquid preparation or the form of solid preparation.

24. pharmaceutical preparations according to claim 23, wherein said liquid preparation is the form of oral liquid or injection liquid, and described solid preparation is the form of tablet or capsule.

25. pharmaceutical preparations according to claim 22, it is in quick-release or the tablet of slowly-releasing or the form of capsule.

26. pharmaceutical preparations according to claim 25, wherein comprise the formula I of 5 ~ 500mg in each tablet or capsule.

27. according to the pharmaceutical preparation of any one of claim 22-26, wherein contained I, and as the formula II compound of impurity and the RRT1.94 impurity determined by [HPLC method A], its compounds of formula I content is 100 ~ 20000 times of formula II compounds content, in the HPLC collection of illustrative plates of described [HPLC method A] gained, the peak area ratio of formula I and RRT1.94 impurity is 200 ~ 10000; Described RRT1.94 impurity refers to that using described [HPLC method A] to measure relative retention time compared with formula I is the impurity of 1.84 ~ 2.04; The method of described [HPLC method A] as claimed in claim 1.

28. pharmaceutical preparations according to claim 27, its compounds of formula I content is 150 ~ 15000 times of formula II compounds content.

29. pharmaceutical preparations according to claim 27, its compounds of formula I content is 200 ~ 10000 times of formula II compounds content.

30. pharmaceutical preparations according to claim 27, its compounds of formula I content is 250 ~ 10000 times of formula II compounds content.

31. pharmaceutical preparations according to claim 27, its compounds of formula I content is 500 ~ 10000 times of formula II compounds content.

32. pharmaceutical preparations according to claim 27, wherein also optionally comprise determined by [HPLC method A] be selected from one or more following other impurity: RRT1.45 impurity, RRT1.73 impurity, RRT2.15 impurity.

33. according to the pharmaceutical preparation of claim 32, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this pharmaceutical preparation gained HPLC collection of illustrative plates, described formula I peak area is 100 ~ 20000 times of formula II compound peaks area.

34. according to the pharmaceutical preparation of claim 32, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this pharmaceutical preparation gained HPLC collection of illustrative plates, described formula I peak area is 100 ~ 15000 times of formula II compound peaks area.

35. according to the pharmaceutical preparation of claim 32, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this pharmaceutical preparation gained HPLC collection of illustrative plates, the peak area ratio of described formula I and RRT1.45 impurity is 100 ~ 20000.

36. according to the pharmaceutical preparation of claim 32, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this pharmaceutical preparation gained HPLC collection of illustrative plates, the peak area ratio of described formula I and RRT1.45 impurity is 100 ~ 15000.

37. according to the pharmaceutical preparation of claim 32, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this pharmaceutical preparation gained HPLC collection of illustrative plates, the peak area ratio of described formula I and RRT1.45 impurity is 100 ~ 10000.

38. according to the pharmaceutical preparation of claim 32, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this pharmaceutical preparation gained HPLC collection of illustrative plates, the peak area ratio of described formula I and RRT1.73 impurity is 100 ~ 20000.

39. according to the pharmaceutical preparation of claim 32, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this pharmaceutical preparation gained HPLC collection of illustrative plates, the peak area ratio of described formula I and RRT1.73 impurity is 100 ~ 15000.

40. according to the pharmaceutical preparation of claim 32, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this pharmaceutical preparation gained HPLC collection of illustrative plates, the peak area ratio of described formula I and RRT1.73 impurity is 100 ~ 10000.

41. according to the pharmaceutical preparation of claim 32, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this pharmaceutical preparation gained HPLC collection of illustrative plates, the peak area ratio of described formula I and RRT2.15 impurity is 100 ~ 20000.

42. according to the pharmaceutical preparation of claim 32, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this pharmaceutical preparation gained HPLC collection of illustrative plates, the peak area ratio of described formula I and RRT2.15 impurity is 100 ~ 15000.

43. according to the pharmaceutical preparation of claim 32, under the high performance liquid chromatography chromatographic condition wherein making the resolution between formula I and formula II compound be greater than 8 in described [HPLC method A], in this pharmaceutical preparation gained HPLC collection of illustrative plates, the peak area ratio of described formula I and RRT2.15 impurity is 100 ~ 10000.

44. methods preparing any one of claim 1-21 bulk drug, it comprises the steps: lyrica to add in the mixing solutions of Virahol and acetonitrile, heating makes dissolving, in mixing solutions, add the lactic acid of 0.5-2%v/v, stir, be slowly cooled to 5 DEG C to separate out precipitation, leach precipitation, by washed with isopropyl alcohol, 40 DEG C of vacuum-dryings, to obtain final product.