CN111671721B - Clomipramine hydrochloride injection composition and preparation method thereof - Google Patents

Clomipramine hydrochloride injection composition and preparation method thereof Download PDF

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CN111671721B
CN111671721B CN202010632533.7A CN202010632533A CN111671721B CN 111671721 B CN111671721 B CN 111671721B CN 202010632533 A CN202010632533 A CN 202010632533A CN 111671721 B CN111671721 B CN 111671721B
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clomipramine hydrochloride
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clomipramine
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CN111671721A (en
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侯奇伟
柳静
白钟
贺云彪
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Hunan Dongting Pharmaceutical Co Ltd
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Abstract

The invention relates to a clomipramine hydrochloride injection composition and a preparation method thereof. The injection of the invention comprises: 15-35 g of clomipramine hydrochloride and 2000ml of water for injection, wherein the injection can also comprise the following auxiliary materials: 8-15 g of glycerol, sodium sulfite, sodium metabisulfite, sodium chloride and vitamin C. The invention also relates to a method for preparing clomipramine hydrochloride, comprising the following steps: reacting bromochloropropane with dimethylamine to obtain an intermediate compound I; reacting the morus compound with potassium hydroxide to obtain an intermediate II; reacting the intermediate II with the intermediate I compound to obtain a clomipramine hydrochloride crude product; adding the obtained clomipramine hydrochloride crude product and a solvent into a reaction kettle, heating to dissolve, then adding medicinal carbon for reflux decolorization, filtering to remove carbon, cooling for crystallization, filtering to obtain crystals, and drying to obtain a clomipramine hydrochloride finished product. The clomipramine hydrochloride injection and the method for preparing the clomipramine hydrochloride have the effects shown in the specification.

Description

Clomipramine hydrochloride injection composition and preparation method thereof
Technical Field
The invention belongs to the technical field of medicines, and relates to an injection composition of an antipsychotic drug clomipramine, in particular to a medicinal salt thereof; the invention also relates to a preparation method of the antipsychotic drug clomipramine, in particular to a medicinal salt thereof, and more particularly relates to a method for preparing the tricyclic antidepressant drug clomipramine hydrochloride. The method for preparing clomipramine hydrochloride, the method for preparing the clomipramine hydrochloride injection and the prepared clomipramine hydrochloride injection have the following excellent technical effects.
Background
Clomipramine, CAS: 303-49-1, formula: C19H23ClN2, molecular weight: 314.85, the chemical information of the hydrochloride salt, clomipramine hydrochloride, which is commonly used clinically is as follows:
Figure BDA0002569607860000011
the chemical name is N, N-dimethyl-10, 11-dihydro-3-chloro-5H-dibenzo [ b, f ] aza-5-propylamine hydrochloride. Also known as 3-chloro-5- (3-dimethylaminopropyl) -10, 11-dihydro-5H-dibenzo (6,5) azepine hydrochloride. The clomipramine hydrochloride is white to yellowish crystalline powder, has no odor and gradually turns yellow when being mixed with light. Clomipramine hydrochloride is very soluble in chloroform or glacial acetic acid, soluble in water and ethanol, slightly soluble in acetone and practically insoluble in diethyl ether. The melting point of the clomipramine hydrochloride is 190-196 ℃. Is clinically used for treating depression and obsessive-compulsive disorder.
The clomipramine hydrochloride is a tricyclic antidepressant developed by Nowa company of Switzerland, has the main effects of blocking reuptake of norepinephrine and 5-hydroxytryptamine in the central nervous system, effectively improving depression and anxiety symptoms, and playing a role in sedation and choline resistance, and the clomipramine hydrochloride is approved by FDA to be on the market in 12 months in 1989, has the trade name of ANAFRANIL, and is an oral capsule; the pharmaceutical clomipramine approved by the Ministry of health in Beijing Nowa in 1993 9 months is on the market in China, and the Chinese commodity is Annafeni.
The currently approved clomipramine varieties in China on the market comprise raw material medicines, tablets and injection. The 2015 edition of Chinese pharmacopoeia also receives raw material drugs, tablets (sugar-coated tablets or film-coated tablets, 10 mg/tablet or 25 mg/tablet) and small-volume aqueous sterile injection (2 ml: 25 mg).
In fact, clomipramine was reported as early as 60 years ago, for example, the p.n.craig et al publication discloses its preparation in 1961 (p.n.craig et al, j.org.chem.26,135 (1961)). Other preparation methods are for example CH 371799 and US 3467650 from w.schindler, h.dietrich (1963 and 1969, respectively, all owned by Geigy chemicals). The crystal and molecular structures of clomipramine hydrochloride are described in m.l. post, a.s. horn, Acta crystallogr.33b,2590 (1977). Clomipramine HPLC assays in serum are described in h.weigmann et al, j.chromagor.b 710,227 (1998). Animal trials for canine obsessive compulsive disorder are described in: c.j.hewson et al, j.am.vet.med.assoc.213,1760 (1998). Animal trials of canine separation anxiety disorder are described in: s.petit et al, rev.med.vet.150,133 (1999). A review of pharmacological and clinical experience in obsessive-compulsive disorders and depression is set forth in: m.d. peters et al, clin.pharm.9,165-178 (1990).
Clomipramine, a classical tricyclic antidepressant (TCA), is a potent 5-HT reuptake blocker, the metabolite of which is a potent norepinephrine reuptake inhibitor. Common therapeutic indications for clomipramine include: obsessive compulsive disorder, depressive disorder, major and refractory depressive disorders, cataplexy syndrome, anxiety, insomnia, neuropathic/chronic pain.
Although clomipramine hydrochloride has been used clinically for 30 years, technical documents thereof are still quite limited, and for example, a new method for preparing clomipramine hydrochloride and a method for preparing clomipramine hydrochloride injection with excellent properties are still expected.
Disclosure of Invention
The invention aims to provide a novel method for preparing clomipramine hydrochloride injection, and the clomipramine hydrochloride injection prepared by the method is expected to have excellent technical effects. Furthermore, the object of the present invention is to provide a novel process for the preparation of clomipramine hydrochloride, which is expected to have excellent technical effects. It has been surprisingly found that clomipramine hydrochloride and clomipramine hydrochloride injection solutions prepared by the process of the present invention exhibit one or more technical effects as described in the present specification, and the present invention has been completed based on such findings.
To this end, the invention provides, in a first aspect, a process for the preparation of clomipramine hydrochloride, comprising the steps of:
(1) preparation of intermediate I:
Figure BDA0002569607860000021
reacting 1, 3-bromochloropropane with dimethylamine in the presence of a base (e.g., sodium hydroxide) to provide an intermediate I compound;
(in the present invention, intermediate I may also be referred to as a side chain or as a side chain compound, which is a side chain of clomipramine hydrochloride)
(2) Preparation of intermediate II
Figure BDA0002569607860000022
Adding morus substance and potassium hydroxide into toluene, and heating for reaction to obtain an intermediate II;
(in the present invention, intermediate II may also be referred to as a hydrolyzate or a Morse hydrolyzate)
(3) Preparation of clomipramine
Figure BDA0002569607860000031
Adding potassium carbonate and potassium hydroxide into the intermediate II obtained in the step (2), heating the reactant, then adding a mixed solution of the intermediate I product obtained in the step (1) and toluene, continuing to heat until the reaction is finished, then cooling the reaction solution, and adding water for extraction to obtain an organic layer containing clomipramine;
(4) preparation of clomipramine hydrochloride crude product
Figure BDA0002569607860000032
Concentrating the product obtained in the step (3) under reduced pressure to obtain an oily substance, adding acetone, dropwise adding hydrochloric acid until the pH of the reactant is 2-3, then crystallizing, centrifuging to obtain crystals, and drying to obtain a crude clomipramine hydrochloride product;
(5) preparation of a refined clomipramine hydrochloride product
Figure BDA0002569607860000033
And (4) adding the clomipramine hydrochloride crude product obtained in the step (4) and a solvent into a reaction kettle, heating for dissolving, then adding medicinal carbon for reflux and decoloration, filtering for decarbonization, cooling for crystallization, filtering for crystallization, and drying to obtain a clomipramine hydrochloride finished product.
The process according to the first aspect of the present invention, wherein in the step (1), the base is sodium hydroxide.
The process according to the first aspect of the present invention, wherein in step (1), dimethylamine is added in the form of an aqueous solution thereof, for example a 40% aqueous solution.
The process according to the first aspect of the present invention, wherein in the step (1), 0.8 to 1.5 parts by weight of a 40% aqueous dimethylamine solution based on 1 part by weight of 1, 3-bromochloropropane is added.
The method according to the first aspect of the present invention comprises the steps of (1), adding 1 part by weight of 1, 3-bromochloropropane into a reaction flask, dropwise adding 0.8-1.5 parts by weight of 40% dimethylamine aqueous solution while stirring, stirring for 30-40 minutes while maintaining the temperature after the addition is completed, dropwise adding 1-1.5 parts by weight of 40% sodium hydroxide solution at 15-30 ℃, and reacting for 3-5 hours while maintaining the temperature after the addition is completed.
The method according to the first aspect of the present invention comprises the steps of (1), after the reaction is completed, standing, removing an alkaline water layer on the lower layer, acidifying the upper layer solution to a pH of 2-3 with concentrated hydrochloric acid, then stirring for 10-20 minutes, standing, removing the lower layer solution, further alkalifying the upper layer solution to a pH of 11-13 with sodium hydroxide solution (with a concentration of 1-2 mol/L), standing after the addition is completed, removing the alkaline water layer on the lower layer, obtaining an intermediate I on the upper layer, then adding a proper amount of drying agent (such as anhydrous magnesium sulfate or anhydrous sodium carbonate), drying, and standing for later use.
The method according to the first aspect of the present invention, wherein the step (1) is carried out as follows:
adding 1 part by weight of 1, 3-bromochloropropane into a reaction bottle, dropwise adding 0.8-1.5 parts by weight of 40% dimethylamine aqueous solution while stirring, stirring for 30-40 minutes while keeping the temperature after adding, dropwise adding 1-1.5 parts by weight of 40% sodium hydroxide solution at 15-30 ℃, keeping the temperature and stirring for reacting for 3-5 hours after adding,
and (3) standing after the reaction is finished, removing an alkaline water layer on the lower layer, acidifying the upper layer liquid to pH 2-3 with concentrated hydrochloric acid, stirring for 10-20 minutes, standing to remove the lower layer liquid, alkalifying the upper layer liquid to pH 11-13 with sodium hydroxide solution (with the concentration of 1-2 mol/L), standing after the addition is finished, removing the alkaline water layer on the lower layer, obtaining an intermediate I on the upper layer, adding a proper amount of drying agent (such as anhydrous magnesium sulfate or anhydrous sodium carbonate), drying, and standing for later use.
The method according to the first aspect of the present invention, wherein in the step (2), 5 to 10 parts by weight of toluene is added based on 1 part by weight of morus substance. Wherein morus is commercially available or prepared by literature procedures (e.g., CN 104876870A).
The method according to the first aspect of the present invention, wherein in the step (2), 1 to 1.7 parts by weight of potassium hydroxide is added based on 1 part by weight of morus substance.
The process according to the first aspect of the present invention, wherein in the step (2), the reaction temperature is controlled at 80 ℃ to 90 ℃.
The method according to the first aspect of the present invention, wherein the step (2) is carried out as follows:
adding 5-10 parts by weight of toluene into a reaction bottle, then adding 1 part by weight of morus material (which can be obtained by a commercial way or prepared by a literature (such as CN 104876870A)) and 1-1.7 parts by weight of potassium hydroxide (powder), starting heating, heating to 85 ℃, reacting for 5-7 hours, controlling the temperature of the reaction to be 80-90 ℃, and cooling the reaction liquid to room temperature after the reaction is finished to obtain an intermediate II for later use.
The method according to the first aspect of the present invention, wherein in the step (3), 1 part by weight of the intermediate II is reacted with 1 to 3 parts by weight of potassium hydroxide 1.2 to 2.5 parts by weight.
The method according to the first aspect of the present invention, wherein in the step (3), the intermediate II is reacted with the base at a temperature of 110 ℃ to 115 ℃ for 1 to 3 hours.
The process according to the first aspect of the present invention, wherein in the step (3), 1 part by weight of the intermediate II is reacted with 2.0 to 2.4 parts by weight of the intermediate I after the reaction with the base.
The method according to the first aspect of the present invention, wherein in the step (3), the intermediate I is added in the form of a mixture of 2.0 to 2.4 parts by weight of the intermediate I and 0.9 to 2 parts by weight of toluene.
The method according to the first aspect of the present invention, wherein in the step (3), the intermediate I is reacted at 110 ℃ to 115 ℃ for 1 to 3 hours.
According to the method of the first aspect of the invention, in the step (3), after the intermediate II and the intermediate I are reacted, the reaction liquid is cooled to 10-50 ℃, 4-6 parts by weight of purified water is added, the mixture is stirred for 10-30 minutes, the mixture is kept stand, an alkaline water layer is separated, and an organic layer containing clomipramine is placed for standby.
The method according to the first aspect of the present invention, wherein the step (3) is performed as follows:
adding 1-3 parts by weight of potassium carbonate (or a mixture of potassium carbonate and sodium carbonate) and 1.2-2.5 parts by weight of potassium hydroxide into the product of the step (2) containing 1 part by weight of the intermediate II, heating to 110-115 ℃, reacting for 1-3 hours while counting, slowly adding a mixed solution of the product of the step (1) (containing 2.0-2.4 parts by weight of the intermediate I) and 0.9-2 parts by weight of toluene, heating to 110-115 ℃ to react for 1-3 hours to the end point of the reaction, cooling the reaction liquid to 10-50 ℃, adding 4-6 parts by weight of purified water, stirring for 10-30 minutes, standing, separating an alkaline water layer, and standing an organic layer containing clomipramine for later use.
The method according to the first aspect of the present invention, wherein in the step (4), 5 to 20 parts by weight of acetone as a solvent is added to 1 part by weight of clomipramine to form a salt.
According to the method of the first aspect of the invention, in the step (4), the product of the step (3) containing 1 part by weight of clomipramine is subjected to reduced pressure concentration until no solution drips out to obtain an oily substance, 5-20 parts by weight of acetone is added to stir and dissolve the oily substance, then, the reagent hydrochloric acid is dripped at room temperature until the pH of the reactant is 2-3, then, the reactant is crystallized at-15 ℃ for 4-12 hours, crystals obtained by centrifugation are washed by a proper amount of acetone, and the crystals are dried to constant weight, so that a clomipramine hydrochloride crude product is obtained.
The process according to the first aspect of the present invention, wherein in the step (5), the solvent is selected from: acetone, ethanol, diethyl ether, acetone/diethyl ether mixture, and ethanol/diethyl ether mixture. The amount of the solvent is an amount that brings the solute close to saturation under the condition of dissolution by heating, which is a conventional operation for recrystallizing a purified substance.
The process according to the first aspect of the present invention, wherein in the step (5), the medicinal charcoal is added in an amount of 20% by volume of the liquid material.
According to the method of the first aspect of the present invention, in the step (5), medicinal charcoal is added, and the reflux decoloring treatment is performed for 30 to 120 minutes.
The method according to the first aspect of the present invention, wherein in the step (5), the filtered liquid is cooled to-10 to 30 ℃ for crystallization for 3 to 30 hours.
The method according to the first aspect of the present invention, wherein the step (5) is carried out as follows:
adding the crude product and a solvent (selected from acetone, ethanol, diethyl ether, acetone/diethyl ether mixed solution and ethanol/diethyl ether mixed solution) into a reaction kettle, heating to dissolve the crude product, adding medicinal carbon (added according to the amount of 20% of the volume of the liquid material), performing reflux decoloring treatment for 30-120 minutes, filtering to another reaction kettle, cooling to-10-30 ℃, crystallizing for 3-30 hours, filtering to obtain crystals, and drying to obtain a clomipramine hydrochloride finished product.
The method according to the first aspect of the invention, comprising the steps of:
(1) preparation of intermediate I:
adding 1 part by weight of 1, 3-bromochloropropane into a reaction bottle, dropwise adding 0.8-1.5 parts by weight of 40% dimethylamine aqueous solution while stirring, stirring for 30-40 minutes while keeping the temperature after adding, dropwise adding 1-1.5 parts by weight of 40% sodium hydroxide solution at 15-30 ℃, keeping the temperature and stirring for reacting for 3-5 hours after adding,
standing after the reaction is finished, removing an alkaline water layer on the lower layer, acidifying the upper layer liquid to pH 2-3 with concentrated hydrochloric acid, then stirring for 10-20 minutes, standing to remove the lower layer liquid, alkalifying the upper layer liquid to pH 11-13 with sodium hydroxide solution (with the concentration of 1-2 mol/L), standing after the addition is finished, removing the alkaline water layer on the lower layer, obtaining an intermediate I on the upper layer, adding a proper amount of drying agent (such as anhydrous magnesium sulfate or anhydrous sodium carbonate), drying, and standing for later use;
(2) preparation of intermediate II
Adding 5-10 parts by weight of toluene into a reaction bottle, then adding 1 part by weight of morus material (which can be obtained by a commercial way or prepared by a literature (such as CN 104876870A)) and 1-1.7 parts by weight of potassium hydroxide (powder), starting heating, heating to 85 ℃, reacting for 5-7 hours, controlling the temperature of the reaction to be 80-90 ℃, and cooling the reaction liquid to room temperature after the reaction is finished to obtain an intermediate II for later use;
(3) preparation of clomipramine
Adding 1-3 parts by weight of potassium carbonate (or a mixture of potassium carbonate and sodium carbonate) and 1.2-2.5 parts by weight of potassium hydroxide into the product of the step (2) containing 1 part by weight of the intermediate II, heating to 110-115 ℃ after the addition is finished, timing to react for 1-3 hours, then slowly adding a mixed solution of the product of the step (1) (containing 2.0-2.4 parts by weight of the intermediate I) and 0.9-2 parts by weight of toluene, heating to 110-115 ℃ to react for 1-3 hours to the end point of the reaction, cooling the reaction liquid to 10-50 ℃, adding 4-6 parts by weight of purified water, stirring for 10-30 minutes, standing, separating an alkaline water layer, and standing an organic layer containing clomipramine for later use;
(4) preparation of clomipramine hydrochloride crude product
Concentrating the product of the step (3) containing 1 part by weight of clomipramine under reduced pressure until no solution drips out to obtain an oily substance, adding 5-20 parts by weight of acetone, stirring to dissolve the oily substance, dripping reagent hydrochloric acid at room temperature until the pH of the reactant is 2-3, then crystallizing at-15 ℃ for 4-12 hours, washing crystals obtained by centrifugation with a proper amount of acetone, and drying to constant weight to obtain a clomipramine hydrochloride crude product;
(5) preparation of a refined clomipramine hydrochloride product
Adding the crude product and a solvent (selected from acetone, ethanol, diethyl ether, acetone/diethyl ether mixed solution and ethanol/diethyl ether mixed solution) into a reaction kettle, heating to dissolve the crude product, adding medicinal carbon (added according to the amount of 20% of the volume of the liquid material), performing reflux decoloring treatment for 30-120 minutes, filtering to another reaction kettle, cooling to-10-30 ℃, crystallizing for 3-30 hours, filtering to obtain crystals, and drying to obtain a clomipramine hydrochloride finished product.
The method according to the first aspect of the present invention, wherein in the step (2), 0.1 part by weight of triethylamine and 0.2 part by weight of simethicone are further added together with morus substance. As described hereinafter in the present invention, it has been surprisingly found that the amount of impurity B in the final product can be significantly reduced after the simultaneous addition of triethylamine and simethicone during the preparation of intermediate II from morus alba.
Further, the second aspect of the present invention provides a clomipramine hydrochloride injection, wherein each 2000ml of the injection comprises: 15-35 g (for example, 20g) of clomipramine hydrochloride, and 2000ml of water for injection.
The clomipramine hydrochloride injection according to the second aspect of the present invention further contains glycerin. In one embodiment, the liquid medicine contains 8-15 g of glycerol, such as 10g, per 2000ml of liquid medicine.
The clomipramine hydrochloride injection according to the second aspect of the present invention further contains sodium sulfite, sodium metabisulfite, and sodium chloride. In one embodiment, every 2000ml of the liquid medicine contains 1g of sodium sulfite, 2g of sodium metabisulfite and 13g of sodium chloride.
The clomipramine hydrochloride injection according to the second aspect of the present invention further contains sodium sulfite, sodium metabisulfite, sodium chloride, and vitamin C. In one embodiment, every 2000ml of the liquid medicine contains 1g of sodium sulfite, 2g of sodium metabisulfite, 13g of sodium chloride and 2g of vitamin C.
The clomipramine hydrochloride injection according to the second aspect of the present invention further comprises propylene glycol and malic acid. In one embodiment, each 2000ml of the liquid medicine comprises 8-12 g of propylene glycol and 4-6 g of malic acid; for example, each 2000ml of the liquid medicine contains 10g of propylene glycol and 5g of malic acid.
In the above-described steps of the preparation method of the present invention, although the specific steps described therein are distinguished in some detail or in language description from the steps described in the preparation examples of the detailed embodiments below, those skilled in the art can fully summarize the above-described method steps in light of the detailed disclosure throughout the present disclosure.
Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict. The invention is further described below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
Clomipramine is a safe, reliable and quick-acting antidepressant, and has an antidepressant effect by inhibiting reuptake of a presynaptic membrane on na and 5-ht, and also has an anxiolytic and sedative effect. The oral administration has good absorption, and the steady blood concentration can be reached within 1-2 weeks. The norclomipramine metabolite is metabolized by CYP4502D6 and 1A2 in the liver, and the concentration of the metabolite norclomipramine is 2 times higher than that of the original drug. Norclomipramine is an active metabolite, a noradrenaline reuptake blocker, and is metabolized by CYP 4501 a 2. The plasma protein binding rate was 97.6%, and t1/2 was 21 hours. About 70% is excreted in urine and 30% is excreted in feces.
Clomipramine is indicated for the treatment of endogenous, reactive, neurological, occult depression and various depressive states; schizophrenia with depression; obsessive compulsive disorder, phobias; various pains, etc. The use of clomipramine is as follows: treatment of depression, obsessive compulsive disorder: orally administered, initially 25mg once, 3 times a day (or as a sustained release tablet, 75mg, 1 time per night), gradually increasing to the optimum therapeutic amount within 1 week. The maximum dose is 250mg in 1 day, and the dose is maintained at 50-100 mg (75 mg of sustained release tablet per day) per day after the symptoms of the infant or young patient are improved and 200mg per day. ② intramuscular injection: the dosage is changed to oral maintenance dosage after the symptoms are improved after the dosage is increased to 25-50 mg at the beginning and is increased to 100-150 mg every day. ③ intravenous injection: beginning with 25-75 mg, dissolving in 250-500 ml isotonic saline or 5% glucose injection, and infusing 1 time per day within 1.5-3 hours, preferably infusing in the morning every day. Generally takes effect in the 1 st week, continuously drips for 3-5 days after taking effect, and then changes to oral administration maintenance dose. And fourthly, the old patient starts to increase 10mg per day to 30-50 mg per day (about 10 days), and then the maintenance dose is changed. Fifth, the children: oral administration: the daily dose is 10mg, 10 days later, the dose is increased to 20mg for children of 5-7 years old, 20-25 mg for children of 8-14 years old, and 50mg for children over 14 years old or according to the required dose, and the administration is divided into several times. The mechanism of action of clomipramine is: increase 5-HT and norepinephrine neurotransmitters; blocking the 5-HT reuptake pump (5-HT transporter), may therefore increase 5-HT neurotransmission; blocking the norepinephrine reuptake pump (norepinephrine transporter), and may therefore increase norepinephrine neurotransmission; may desensitize 5-HT and beta norepinephrine receptors; since dopamine is inactivated by the reuptake of norepinephrine by the frontal cortex, where the dopamine transporter is severely deficient, clomipramine can increase dopamine neurotransmitter at this site. Onset of clomipramine: the effect is quick when the insomnia or the anxiety is treated; the onset of action is usually delayed for 2-4 weeks when the depressive disorder is treated; the effect is delayed for 6-12 weeks when the obsessive-compulsive disorder is treated; if treatment of depressive disorder remains ineffective for 6-8 weeks, increased doses may be required or may be ineffective; if treatment for obsessive-compulsive disorder has not been effective for 12 weeks, the drug may not be effective; can be used for several years to prevent recurrence of symptoms.
The invention provides a beneficial method for producing clomipramine hydrochloride, and the prepared clomipramine hydrochloride has one or more technical effects.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible.
The following examples are carried out in accordance with the following reaction schemes.
(1) Preparation of intermediate I:
Figure BDA0002569607860000081
(2) preparation of intermediate II:
Figure BDA0002569607860000082
(3) preparation of clomipramine:
Figure BDA0002569607860000091
(4) preparation of a crude clomipramine hydrochloride product:
Figure BDA0002569607860000092
(5) preparation of a clomipramine hydrochloride refined product:
Figure BDA0002569607860000093
example 1: preparation of clomipramine hydrochloride
(1) Preparation of intermediate I:
adding 1 weight part of 1, 3-bromochloropropane into a reaction bottle, dropwise adding 1.2 weight parts of 40% dimethylamine aqueous solution under stirring, keeping the temperature and stirring for 35 minutes after the addition is finished, dropwise adding 1.2 weight parts of 40% sodium hydroxide solution at 25 ℃, keeping the temperature and stirring for reaction for 4 hours after the addition is finished,
standing after the reaction is finished, removing an alkaline water layer on the lower layer, acidifying the upper layer liquid to pH 2.5 by using concentrated hydrochloric acid, then stirring for 15 minutes, standing to remove the lower layer liquid, alkalifying the upper layer liquid to pH 12 by using sodium hydroxide solution (with the concentration of 1-2 mol/L), standing after the addition is finished, removing the alkaline water layer on the lower layer, obtaining an intermediate I on the upper layer, adding a proper amount of drying agent (anhydrous magnesium sulfate), drying, and standing for later use;
through detection, the content of the intermediate I is more than 95 percent
(2) Preparation of intermediate II:
adding 7.5 parts by weight of toluene into a reaction bottle, then adding 1 part by weight of morus and 1.3 parts by weight of potassium hydroxide (powder), starting heating, heating to 85 ℃, timing to react for 6 hours, controlling the reaction temperature to be 80-90 ℃, and cooling the reaction liquid to room temperature after the reaction is finished to obtain an intermediate II for later use;
and (3) controlling the reaction end point: dissolving 0.2g Morus alba with 10ml acetone to obtain reference substance; taking 1ml of reaction stock solution, and adding 10ml of acetone for dilution to obtain a sample; respectively sampling sample and reference substance with capillary, spreading with developing agent (cyclohexane: acetone: 10:4) on silica gel G254 plate, and determining that there is no Morse residue, i.e. reaction reaches end point
(3) Preparation of clomipramine
Adding 2 parts by weight of potassium carbonate and 1.8 parts by weight of potassium hydroxide into the product of the step (2) containing 1 part by weight of the intermediate II, heating to 110-115 ℃ after the addition is finished, timing to react for 2 hours, slowly adding a mixed solution of the product of the step (1) (containing 2.2 parts by weight of the intermediate I) and 1.5 parts by weight of toluene, heating to 110-115 ℃ to react for 1-3 hours to the end point of the reaction, cooling the reaction solution to 30 ℃, adding 5 parts by weight of purified water, stirring for 20 minutes, standing, separating an alkaline water layer, and placing an organic layer containing clomipramine for later use;
and (3) controlling the reaction end point: and (5) taking 0.2g of the intermediate IIs, and adding 10ml of acetone to dissolve the intermediate IIs to obtain a reference substance. Taking 1ml of reaction stock solution, adding 10ml of acetone for dilution, and filtering to obtain a sample. The samples and the control were spotted on a silica gel G254 plate, developed with a developing reagent (cyclohexane: acetone ═ 8:3), and no intermediate II was confirmed to remain, i.e., the reaction reached the end point
(4) Preparation of clomipramine hydrochloride crude product
Concentrating the product of the step (3) containing 1 part by weight of clomipramine under reduced pressure until no solution drips out to obtain an oily substance, adding 12 parts by weight of acetone, stirring to dissolve the oily substance, dripping reagent hydrochloric acid at room temperature until the pH of the reactant is 2-3, then crystallizing for 8 hours at 2 ℃, washing crystals obtained by centrifugation with a proper amount of acetone, and drying to constant weight to obtain a clomipramine hydrochloride crude product;
(5) preparation of a refined clomipramine hydrochloride product
Adding the crude product and a solvent (acetone) into a reaction kettle, heating to dissolve the crude product and the solvent (acetone) clearly, then adding medicinal carbon (added according to the amount of 20% of the volume of the liquid material), refluxing and decoloring for 75 minutes, filtering to another reaction kettle, then cooling to 10 ℃, crystallizing for 15 hours, filtering to obtain crystals, and drying to obtain a finished product of the clomipramine hydrochloride.
The amount of the above-mentioned crude product added to the solvent is such that it is soluble by adding the crude product to the solvent heated to a temperature below the boiling point, i.e., an amount close to saturated dissolution at this heating temperature, which is a routine procedure for those skilled in the art.
The control requirements and methods (e.g., control of the end point of the reaction) during the operation of the following examples are similar to those of example 1.
Example 2: preparation of clomipramine hydrochloride
(1) Preparation of intermediate I:
adding 1 weight part of 1, 3-bromochloropropane into a reaction bottle, dropwise adding 0.8 weight part of 40% dimethylamine aqueous solution under stirring, keeping the temperature and stirring for 40 minutes after the addition is finished, dropwise adding 1 weight part of 40% sodium hydroxide solution at 15 ℃, keeping the temperature and stirring for reaction for 5 hours after the addition is finished,
standing after the reaction is finished, removing an alkaline water layer on the lower layer, acidifying the upper layer liquid by concentrated hydrochloric acid until the pH value is 2, then stirring for 10 minutes, standing to remove the lower layer liquid, then alkalifying the upper layer liquid by a sodium hydroxide solution (with the concentration of 1-2 mol/L) until the pH value is 11, standing after the addition is finished, removing the alkaline water layer on the lower layer, obtaining an intermediate I on the upper layer, then adding a proper amount of drying agent (anhydrous sodium carbonate), drying, and standing for later use;
(2) preparation of intermediate II:
adding 5 parts by weight of toluene into a reaction bottle, then adding 1 part by weight of morus and 1.7 parts by weight of potassium hydroxide (powder), starting heating, heating to 85 ℃, reacting for 7 hours while keeping the temperature at 80-90 ℃, and cooling the reaction liquid to room temperature after the reaction is finished to obtain an intermediate II for later use;
(3) preparation of clomipramine
Adding 3 parts by weight of potassium carbonate and 1.2 parts by weight of potassium hydroxide into the product of the step (2) containing 1 part by weight of the intermediate II, heating to 110-115 ℃ after the addition is finished, timing to react for 1 hour, slowly adding a mixed solution of the product of the step (1) (containing 2.4 parts by weight of the intermediate I) and 0.9 part by weight of toluene, heating to 110-115 ℃ to react for 1-3 hours to the end point of the reaction, cooling the reaction solution to 10 ℃, adding 6 parts by weight of purified water, stirring for 10 minutes, standing, separating an alkaline water layer, and placing an organic layer containing clomipramine for later use;
(4) preparation of clomipramine hydrochloride crude product
Concentrating the product of the step (3) containing 1 weight part of clomipramine under reduced pressure until no solution drips out to obtain an oily substance, adding 5 weight parts of acetone, stirring to dissolve the oily substance, dripping reagent hydrochloric acid at room temperature until the pH of the reactant is 2-3, then crystallizing for 12 hours at-15 ℃, washing crystals obtained by centrifugation with a proper amount of acetone, and drying to constant weight to obtain a clomipramine hydrochloride crude product;
(5) preparation of a refined clomipramine hydrochloride product
Adding the crude product and a solvent (ethanol) into a reaction kettle, heating for dissolving, then adding medicinal carbon (added according to the amount of 20% of the volume of the liquid material), refluxing and decoloring for 120 minutes, filtering to another reaction kettle, then cooling to-10 ℃ for crystallization for 3 hours, filtering to obtain crystals, and drying to obtain the finished product of the clomipramine hydrochloride.
Example 3: preparation of clomipramine hydrochloride
(1) Preparation of intermediate I:
adding 1 weight part of 1, 3-bromochloropropane into a reaction bottle, dropwise adding 1.5 weight parts of 40% dimethylamine aqueous solution under stirring, keeping the temperature and stirring for 30 minutes after the addition is finished, dropwise adding 1.5 weight parts of 40% sodium hydroxide solution at 30 ℃, keeping the temperature and stirring for reaction for 3 hours after the addition is finished,
standing after the reaction is finished, removing an alkaline water layer on the lower layer, acidifying the upper layer liquid by concentrated hydrochloric acid until the pH value is 3, then stirring for 20 minutes, standing to remove the lower layer liquid, then alkalifying the upper layer liquid by a sodium hydroxide solution (with the concentration of 1-2 mol/L) until the pH value is 13, standing after the addition is finished, removing the alkaline water layer on the lower layer, obtaining an intermediate I on the upper layer, then adding a proper amount of drying agent (anhydrous magnesium sulfate), drying, and standing for later use;
(2) preparation of intermediate II:
adding 10 parts by weight of toluene into a reaction bottle, then adding 1 part by weight of morus substance and 1 part by weight of potassium hydroxide (powder), starting heating, heating to 85 ℃, reacting for 5 hours, controlling the reaction temperature to be 80-90 ℃, and cooling the reaction liquid to room temperature after the reaction is finished to obtain an intermediate II for later use;
(3) preparation of clomipramine
Adding 1 part by weight of potassium carbonate and 2.5 parts by weight of potassium hydroxide into the product of the step (2) containing 1 part by weight of the intermediate II, heating to 110-115 ℃ after the addition is finished, timing to react for 3 hours, slowly adding a mixed solution of the product of the step (1) (containing 2.0 parts by weight of the intermediate I) and 2 parts by weight of toluene, heating to 110-115 ℃ to react for 1-3 hours to the end point of the reaction, cooling the reaction solution to 50 ℃, adding 4 parts by weight of purified water, stirring for 30 minutes, standing, separating an alkaline water layer, and standing an organic layer containing clomipramine for later use;
(4) preparation of clomipramine hydrochloride crude product
Concentrating the product of the step (3) containing 1 part by weight of clomipramine under reduced pressure until no solution drips out to obtain an oily substance, adding 20 parts by weight of acetone, stirring to dissolve the oily substance, dripping reagent hydrochloric acid at room temperature until the pH of the reactant is 2-3, then crystallizing for 4 hours at 15 ℃, washing crystals obtained by centrifugation with a proper amount of acetone, and drying to constant weight to obtain a clomipramine hydrochloride crude product;
(5) preparation of a refined clomipramine hydrochloride product
Adding the crude product and a solvent (diethyl ether) into a reaction kettle, heating for dissolving, then adding medicinal carbon (added according to the amount of 20% of the volume of the liquid material), refluxing and decoloring for 30 minutes, filtering to another reaction kettle, then cooling to 30 ℃ for crystallization for 30 hours, filtering to obtain crystals, and drying to obtain the finished product of the clomipramine hydrochloride.
Example 4: preparation of clomipramine hydrochloride
(1) Preparation of intermediate I:
adding 1 weight part of 1, 3-bromochloropropane into a reaction bottle, dropwise adding 1.4 weight parts of 40% dimethylamine aqueous solution under stirring, keeping the temperature and stirring for 38 minutes after the addition is finished, dropwise adding 1.1 weight parts of 40% sodium hydroxide solution at 18 ℃, keeping the temperature and stirring for reacting for 4.5 hours after the addition is finished,
standing after the reaction is finished, removing an alkaline water layer on the lower layer, acidifying the upper layer liquid to pH 2.8 by using concentrated hydrochloric acid, then stirring for 12 minutes, standing to remove the lower layer liquid, alkalifying the upper layer liquid to pH 12.5 by using sodium hydroxide solution (with the concentration of 1-2 mol/L), standing after the addition is finished, removing the alkaline water layer on the lower layer, taking the upper layer as an intermediate I, adding a proper amount of drying agent (anhydrous sodium carbonate), drying, and standing for later use;
(2) preparation of intermediate II:
adding 6 parts by weight of toluene into a reaction bottle, then adding 1 part by weight of morus substance and 1.5 parts by weight of potassium hydroxide (powder), starting heating, heating to 85 ℃, reacting for 5.5 hours, controlling the reaction temperature to be 80-90 ℃, and cooling the reaction liquid to room temperature after the reaction is finished to obtain an intermediate II for later use;
(3) preparation of clomipramine
Adding 1.5 parts by weight of potassium carbonate and 1.5 parts by weight of potassium hydroxide into the product of the step (2) containing 1 part by weight of the intermediate II, heating to 110-115 ℃ after the addition is finished, timing to react for 1.5 hours, then slowly adding a mixed solution of the product of the step (1) (containing 2.3 parts by weight of the intermediate I) and 1.1 parts by weight of toluene, heating to 110-115 ℃ to react for 1-3 hours to the end of the reaction, cooling the reaction solution to 40 ℃, adding 5.5 parts by weight of purified water, stirring for 15 minutes, standing, separating an alkaline water layer, and standing an organic layer containing clomipramine for later use;
(4) preparation of clomipramine hydrochloride crude product
Concentrating the product of the step (3) containing 1 part by weight of clomipramine under reduced pressure until no solution drips out to obtain an oily substance, adding 8 parts by weight of acetone, stirring to dissolve the oily substance, dripping reagent hydrochloric acid at room temperature until the pH of the reactant is 2-3, then crystallizing for 10 hours at 0 ℃, washing crystals obtained by centrifugation with a proper amount of acetone, and drying to constant weight to obtain a clomipramine hydrochloride crude product;
(5) preparation of a refined clomipramine hydrochloride product
Adding the crude product and a solvent (acetone/diethyl ether mixed solution, 1/1) into a reaction kettle, heating for dissolving, then adding medicinal carbon (added according to the amount of 20% of the volume of the liquid material), performing reflux decoloring treatment for 30-120 minutes, filtering to another reaction kettle, cooling to 20 ℃, crystallizing for 27 hours, filtering, crystallizing, and drying to obtain a clomipramine hydrochloride finished product.
Example 5: preparation of clomipramine hydrochloride
(1) Preparation of intermediate I:
adding 1 weight part of 1, 3-bromochloropropane into a reaction bottle, dropwise adding 0.9 weight part of 40% dimethylamine aqueous solution under stirring, keeping the temperature and stirring for 32 minutes after the addition is finished, dropwise adding 1.4 weight parts of 40% sodium hydroxide solution at 28 ℃, keeping the temperature and stirring for reacting for 3.5 hours after the addition is finished,
standing after the reaction is finished, removing an alkaline water layer on the lower layer, acidifying the upper layer liquid to pH 2.2 by using concentrated hydrochloric acid, then stirring for 18 minutes, standing to remove the lower layer liquid, alkalifying the upper layer liquid to pH 11.5 by using sodium hydroxide solution (with the concentration of 1-2 mol/L), standing after the addition is finished, removing the alkaline water layer on the lower layer, taking the upper layer as an intermediate I, adding a proper amount of drying agent (anhydrous magnesium sulfate), drying, and standing for later use;
(2) preparation of intermediate II:
adding 9 parts by weight of toluene into a reaction bottle, then adding 1 part by weight of morus substance and 1.2 parts by weight of potassium hydroxide (powder), starting heating, heating to 85 ℃, reacting for 6.5 hours, controlling the reaction temperature to be 80-90 ℃, and cooling the reaction liquid to room temperature after the reaction is finished to obtain an intermediate II for later use;
(3) preparation of clomipramine
Adding 2.5 parts by weight of potassium carbonate and 2.2 parts by weight of potassium hydroxide into the product of the step (2) containing 1 part by weight of the intermediate II, heating to 110-115 ℃ after the addition is finished, timing to react for 2.5 hours, then slowly adding a mixed solution of the product of the step (1) (containing 2.1 parts by weight of the intermediate I) and 1.8 parts by weight of toluene, heating to 110-115 ℃ to react for 1-3 hours to the end of the reaction, cooling the reaction solution to 20 ℃, adding 4.5 parts by weight of purified water, stirring for 25 minutes, standing, separating an alkaline water layer, and standing an organic layer containing clomipramine for later use;
(4) preparation of clomipramine hydrochloride crude product
Concentrating the product of the step (3) containing 1 part by weight of clomipramine under reduced pressure until no solution drips out to obtain an oily substance, adding 17 parts by weight of acetone, stirring to dissolve the oily substance, dripping reagent hydrochloric acid at room temperature until the pH of the reactant is 2-3, then crystallizing for 6 hours at 5 ℃, washing crystals obtained by centrifugation with a proper amount of acetone, and drying to constant weight to obtain a clomipramine hydrochloride crude product;
(5) preparation of a refined clomipramine hydrochloride product
Adding the crude product and a solvent (ethanol/diethyl ether mixed solution, 1/2) into a reaction kettle, heating for dissolving, then adding medicinal carbon (added in an amount of 20% of the volume of the liquid material), performing reflux decoloring treatment for 40-100 minutes, filtering to another reaction kettle, then cooling to 0 ℃, crystallizing for 5 hours, filtering, crystallizing, and drying to obtain a clomipramine hydrochloride finished product.
Test example 1: method for measuring substance concerned
The measurement was carried out by using the method standard described in "0512 high performance liquid chromatography" of the four parts of the Chinese pharmacopoeia 2015 edition.
The solution was used immediately after preparation and care was taken to avoid light.
Test solutions: dissolving 20.0mg of a substance to be detected by using a mixed solution of 25 volumes of mobile phase B and 75 volumes of mobile phase A, and diluting the substance to be detected to 10.0mL by using the mobile phase mixed solution;
reference solution (a): dissolving 22.6mg imipramine hydrochloride reference substance, 4.0mg impurity C reference substance, 4.0mg impurity D reference substance and 2.0mg impurity F reference substance by using a mixed solution of 25 volumes of mobile phase B and 75 volumes of mobile phase A, diluting the mixed solution to 100.0mL by using the mobile phase mixed solution, and then taking 1.0mL of the mixed solution to be diluted to 10.0mL by using the mobile phase mixed solution;
reference solution (b): taking 1.0mL of test solution, and diluting the test solution to 100.0mL by using a mixed solution of 25 volumes of mobile phase B and 75 volumes of mobile phase A;
reference solution (c): 10.0mg of clomipramine hydrochloride control and 3.0mg of impurity C control were dissolved in a mixture of 25 volumes of mobile phase B and 75 volumes of mobile phase A, and diluted to 20.0mL with the above mobile phase mixture, and 1.0mL of this solution was then diluted to 10.0mL with the above mobile phase mixture.
A chromatographic column: the column length is 0.25m, the inner diameter is 4.6mm, the stationary phase is cyano propyl silica-based silica gel (5 μm), and the column temperature is 30 ℃.
Mobile phase:
mobile phase A: 1.2g of sodium dihydrogen phosphate was dissolved in water, 1.1mL of nonanamine was added, the pH was adjusted to 3.0 with phosphoric acid, and the solution was diluted to 1000mL with water,
mobile phase B: and (3) acetonitrile.
Gradient elution procedure is as follows:
time (min) Mobile phase A (% V/V) Mobile phase B (% V/V)
0-10 75 25
10-20 75→65 25→35
20-32 65 35
32-34 65→75 35→25
34-44 75 25
Flow rate: 1.5 mL/min.
A detector: and an ultraviolet spectrophotometry detector for detecting the wavelength of 254 nm.
Sample introduction amount: 20 μ L.
The retention time of clomipramine is about 8min, and the relative retention time of the clomipramine is taken as a reference: about 0.5% for impurity a, about 0.7% for impurity B, about 0.9% for impurity C, about 1.7% for impurity D, about 2.5% for impurity E, about 3.4% for impurity F, and about 4.3% for impurity G.
The reference solution (c) was used for the systematic suitability test: the degree of separation between clomipramine and impurity C is greater than 3.0.
For pharmaceutical drug substances, the limits of impurities in clomipramine hydrochloride are generally required as follows: impurity B was found to be less than 1.0% using reference solution (a), impurities C and D were both less than 0.2%, and impurity F was found to be less than 0.1%, any other impurities were found to be less than 0.1%, the total amount of other impurities was less than 0.2%, the total impurities was less than 1.0%, and the disregard limit was 0.01% using reference solution (B).
The structure and chemical name of impurity a is:
Figure BDA0002569607860000151
the structure and chemical name of impurity B are:
Figure BDA0002569607860000152
the structure and chemical name of impurity C is:
Figure BDA0002569607860000153
the structure and chemical name of impurity D, E, F, G are:
Figure BDA0002569607860000154
the percentage content of the impurity B relative to clomipramine in the products of the respective steps (3), (4) and (5) of examples 1 to 5 (the quotient of the content of the impurity B in the test substance divided by the content of clomipramine is multiplied by 100%, which is simply referred to as the relative content of the impurity B) was determined by the HPLC method as described above, and the results were:
the relative content of the impurity B in the product of the step (3) in each of the examples 1 to 5 is within the range of 0.44 to 0.51%, for example, the relative content of the impurity B in the product of the step (3) in example 1 is 0.463%;
the relative content of the impurity B in the product of the step (4) in each of the examples 1 to 5 is within the range of 0.46 to 0.52%, for example, the relative content of the impurity B in the product of the step (4) in example 1 is 0.468%;
the relative content of the impurity B in the product of the step (5) in each of the examples 1 to 5 is within the range of 0.45 to 0.53%, for example, the relative content of the impurity B in the product of the step (5) in example 1 is 0.457%;
it can be seen that the obtained clomipramine free base, after salification and purification, has an unchanged relative content of impurity B, i.e. impurity B does not decrease with the work-up of the free base.
Further, the limits of the respective impurities in the products of the respective steps (5) of examples 1 to 5 were determined by the HPLC method as described above, and as a result:
impurities C and D are respectively less than 0.06 percent, impurities F are respectively less than 0.03 percent, any other impurities are respectively less than 0.02 percent, the total amount of other impurities is respectively less than 0.08 percent, and the total impurities are respectively less than 0.7 percent, measured by using a reference solution (b); for example
Example 5 limits for each impurity in the product of step (5), results: 0.464% of impurity B, 0.051% of impurity C, 0.063% of impurity D and 0.034% of impurity F, wherein any other impurity is less than 0.03% by measurement of reference solution (B), the total amount of other impurities is 0.076%, and the total amount of impurities is 0.688%;
it can be seen that the final product obtained by the above method completely meets the limit of the field generally specified for the impurity in the clomipramine hydrochloride bulk drug, although the impurity B content is higher. Of course, it would be advantageous if the impurity B content could be further reduced.
Example 6: preparation of clomipramine hydrochloride
Reference is made to the procedures of examples 1-5, respectively, except that in step (2) 0.1 parts by weight triethylamine and 0.25 parts by weight simethicone are added with morus (morus, bromochloropropane, dimethylamine, etc. starting materials are all the same lot as in examples 1-5) and 5 lots of preparative experiments are performed, referred to as example 61, example 62, … …, example 65, respectively.
The percentage content of impurity B relative to clomipramine in the products of steps (3), (4) and (5) of examples 61-65 was determined by HPLC method of test example 1, and the results were:
the relative content of the impurity B in the product of the step (3) of each of the examples 61-65 is within the range of 0.08-0.10%, for example, the relative content of the impurity B in the product of the step (3) of the example 61 is 0.091%;
the relative content of the impurity B in the product of the step (4) in each of the examples 61-65 is within the range of 0.07-0.11%, for example, the relative content of the impurity B in the product of the step (4) in the example 61 is 0.079%;
the relative content of the impurity B in the products of the step (5) of each of the examples 61-65 is within the range of 0.08-0.12%, for example, the relative content of the impurity B in the product of the step (5) of the example 61 is 0.096%;
it can be seen that the clomipramine free base obtained in example 6 and the hydrochloride salt obtained subsequently thereto have a significantly reduced content of impurity B.
Further, the limits of the respective impurities in the products of the respective steps (5) of examples 61 to 65 were determined by the HPLC method of test example 1, and the results were as follows:
impurities C and D are respectively less than 0.05 percent, impurities F are respectively less than 0.03 percent, any other impurities are respectively less than 0.02 percent, the total amount of other impurities is respectively less than 0.06 percent, and the total impurities is less than 0.35 percent, which are measured by a reference solution (b); for example
Example 65 limits for each impurity in the product of step (5), results: 0.089% of impurity B, 0.041% of impurity C, 0.035% of impurity D and 0.026% of impurity F, less than 0.02% of any other impurity, 0.051% of the total of other impurities and 0.242% of the total impurities, measured with reference solution (B);
it can be seen that the final product prepared by the method in example 6 completely meets the limit of the field on the impurities in the clomipramine hydrochloride bulk drug, and the content of the impurity B is significantly lower than that in the products in examples 1 to 5.
Example 7: preparation of clomipramine hydrochloride
Reference is made to the procedures of examples 1 to 5, respectively, except that in step (2) 0.1 parts by weight triethylamine is added with morgans (starting materials such as morgans, bromochloropropane, dimethylamine, etc. are in the same batch as in examples 1 to 5) and 5 batches of preparative experiments are carried out, referred to as example 71, example 72, … …, example 75, respectively.
The percentage content of impurity B relative to clomipramine in the products of steps (3), (4) and (5) of examples 71 to 75 was determined by the HPLC method of test example 1, and the results were:
the relative content of the impurity B in the product of the step (3) of each of the examples 71 to 75 is within the range of 0.47 to 0.50%, for example, the relative content of the impurity B in the product of the step (3) of the example 71 is 0.487%;
the relative content of the impurity B in the product of the step (4) in each of examples 71-75 is within the range of 0.46-0.53%, for example, the relative content of the impurity B in the product of the step (4) in example 71 is 0.511%;
the relative content of the impurity B in the product of the step (5) in each of examples 71-75 is within the range of 0.47-0.51%, for example, the relative content of the impurity B in the product of the step (5) in example 71 is 0.493%;
it can be seen that the content of the impurity B in the clomipramine free base prepared in example 7 and the hydrochloride obtained subsequently thereof is not obviously different from that in examples 1 to 5.
Further, the limits of the respective impurities in the products of the respective steps (5) of examples 71 to 75 were determined by the HPLC method of test example 1, and the results were as follows:
the impurities C and D are respectively less than 0.05 percent, the impurity F is less than 0.04 percent, any other impurity is less than 0.02 percent, the total amount of other impurities is less than 0.07 percent and the total impurity is less than 0.7 percent by using the reference solution (b), and the results are not obviously different from the results of the examples 1 to 5;
it can be seen that the final product prepared by the method in example 7 completely meets the limit of the field on the impurities in the clomipramine hydrochloride bulk drug, and the content of each impurity has no obvious difference from that of the products in examples 1 to 5.
Example 8: preparation of clomipramine hydrochloride
Reference is made to the procedures of examples 1-5, respectively, except that in step (2) 0.25 parts by weight of dimethicone is also added with mordant (starting materials such as mordant, bromochloropropane, dimethylamine, etc. are all in the same batch as examples 1-5), and 5 batches of preparative trials are performed, referred to as example 81, example 82, … …, example 85, respectively.
The percentage content of impurity B relative to clomipramine in the products of steps (3), (4) and (5) of examples 81 to 85, respectively, was determined by HPLC method of test example 1, and the results were:
examples 81-85, for example, the product of step (3) of example 81 had a relative content of 0.510% for impurity B, all of which were in the range of 0.48-0.53%;
the relative content of the impurity B in the product of the step (4) in each of examples 81-85 is within the range of 0.48-0.52%, for example, the relative content of the impurity B in the product of the step (4) in example 81 is 0.502%;
the relative content of the impurity B in the product of the step (5) in each of examples 81-85 is within the range of 0.47-0.51%, for example, the relative content of the impurity B in the product of the step (5) in example 81 is 0.493%;
it can be seen that the content of the impurity B in the clomipramine free base prepared in the example 8 and the hydrochloride obtained subsequently is not obviously different from that in the examples 1 to 5.
Further, the limits of the respective impurities in the products of the respective steps (5) of examples 81 to 85 were determined by the HPLC method of test example 1, and the results were as follows:
the impurities C and D are respectively less than 0.06 percent, the impurity F is less than 0.03 percent, any other impurity is less than 0.02 percent, the total amount of other impurities is less than 0.07 percent and the total impurity is less than 0.7 percent by using the reference solution (b), and the results are not obviously different from the results of the examples 1-5;
it can be seen that the final product prepared by the method in example 8 completely meets the limit of the field on the impurities in the clomipramine hydrochloride bulk drug, and the content of each impurity has no obvious difference from the content of each impurity in the products in examples 1 to 5.
In addition, according to the detection method under the item of the chlorimipramine hydrochloride on page 1090 of the second part of the Chinese pharmacopoeia 2015 edition, all the refined chlorimipramine hydrochloride finished products obtained in the examples 1 to 8 are measured, and the result shows that all the products accord with the regulations of the pharmacopoeia, for example, the melting point is in the range of 192-195 ℃ and the melting distance of each batch of samples is less than 1.6 ℃. The reason why the content of the impurity B cannot be measured by the method for measuring a substance related to the term "clomipramine hydrochloride" on page 1090 of the second part of the chinese pharmacopoeia 2015 is that the degree of separation from other nearby chromatographic peaks is not satisfactory.
Based on the results of the above examples 1 to 8, the present inventors have unexpectedly found that the content of dechlorination impurity in clomipramine or hydrochloride thereof can be significantly reduced when triethylamine and simethicone are further added along with morus substance in step (2), whereas the content of dechlorination impurity in clomipramine or hydrochloride thereof is significantly higher when only triethylamine or simethicone or neither is added.
In the following examples of the preparation of clomipramine hydrochloride injection, the clomipramine hydrochloride used is the same batch of the starting drug (example 61) and complies with the regulations of the chinese pharmacopoeia of the 2015 edition; the pH regulator is 2M hydrochloric acid solution and/or 2M sodium hydroxide solution. In view of the excellent water solubility of clomipramine hydrochloride, the following preparation process of the injection is a conventional process, and the effect is basically unchanged, wherein the preparation process can be properly adjusted by a person skilled in the art according to the actual production situation, for example, the preparation process is changed to 121-15 min for autoclave sterilization. The following prescription is expressed by proportion, and the actual feeding amount is not less than 20 liters of liquid medicine per batch.
Example 11: preparation of clomipramine hydrochloride injection
Prescription: 25g of clomipramine hydrochloride and water for injection are added to 2000 ml.
The preparation method comprises the following steps:
dissolving clomipramine hydrochloride by using injection water with the formula amount of 50-60%, adjusting the pH value of the liquid medicine to 4.0-4.3 by using an acid-base regulator, and circularly filtering the liquid medicine by using a titanium filtering system;
adding water for injection to full dose, adjusting the pH value of the liquid medicine to 4.0-4.3 by using an acid-base regulator if necessary, and circularly filtering the liquid medicine by using a 0.45 mu m and 0.22 mu m filter;
encapsulating the medicinal liquid (2 ml/bottle), and sterilizing under hot pressure (105-30 min).
Example 12: preparation of clomipramine hydrochloride injection
Prescription: 25g of clomipramine hydrochloride, 10g of glycerol and 2000ml of water.
The preparation method comprises the following steps:
dissolving clomipramine hydrochloride and the rest materials except the injection water by using the injection water with the formula amount of 50-60%, adjusting the pH value of the liquid medicine to 4.0-4.3 by using an acid-base regulator, and circularly filtering the liquid medicine by using a titanium filtering system;
adding water for injection to full dose, adjusting the pH value of the liquid medicine to 4.0-4.3 by using an acid-base regulator if necessary, and circularly filtering the liquid medicine by using a 0.45 mu m and 0.22 mu m filter;
encapsulating the medicinal liquid (2 ml/bottle), and sterilizing under hot pressure (105-30 min).
Example 13: preparation of clomipramine hydrochloride injection
Prescription: 25g of clomipramine hydrochloride, 1g of sodium sulfite, 2g of sodium metabisulfite, 13g of sodium chloride and 2000ml of water.
The preparation method comprises the following steps:
dissolving clomipramine hydrochloride and the rest materials except the injection water by using the injection water with the formula amount of 50-60%, adjusting the pH value of the liquid medicine to 4.0-4.3 by using an acid-base regulator, and circularly filtering the liquid medicine by using a titanium filtering system;
adding water for injection to full dose, adjusting the pH value of the liquid medicine to 4.0-4.3 by using an acid-base regulator if necessary, and circularly filtering the liquid medicine by using a 0.45 mu m and 0.22 mu m filter;
encapsulating the medicinal liquid (2 ml/bottle), and sterilizing under hot pressure (105-30 min).
Example 14: preparation of clomipramine hydrochloride injection
Prescription: 15g of clomipramine hydrochloride and 2000ml of water for injection are added.
The preparation method comprises the following steps:
dissolving clomipramine hydrochloride by using injection water with the formula amount of 50-60%, adjusting the pH value of the liquid medicine to 4.0-4.3 by using an acid-base regulator, and circularly filtering the liquid medicine by using a titanium filtering system;
adding water for injection to full dose, adjusting the pH value of the liquid medicine to 4.0-4.3 by using an acid-base regulator if necessary, and circularly filtering the liquid medicine by using a 0.45 mu m and 0.22 mu m filter;
encapsulating the medicinal liquid (2 ml/bottle), and sterilizing under hot pressure (105-30 min).
Example 15: preparation of clomipramine hydrochloride injection
Prescription: 35g of clomipramine hydrochloride and 2000ml of water for injection are added.
The preparation method comprises the following steps:
dissolving clomipramine hydrochloride by using injection water with the formula amount of 50-60%, adjusting the pH value of the liquid medicine to 4.0-4.3 by using an acid-base regulator, and circularly filtering the liquid medicine by using a titanium filtering system;
adding water for injection to full dose, adjusting the pH value of the liquid medicine to 4.0-4.3 by using an acid-base regulator if necessary, and circularly filtering the liquid medicine by using a 0.45 mu m and 0.22 mu m filter;
encapsulating the medicinal liquid (2 ml/bottle), and sterilizing under hot pressure (105-30 min).
Example 16: preparation of clomipramine hydrochloride injection
Prescription: 15g of clomipramine hydrochloride, 15g of glycerol and 2000ml of water.
The preparation method comprises the following steps:
dissolving clomipramine hydrochloride and the rest materials except the injection water by using the injection water with the formula amount of 50-60%, adjusting the pH value of the liquid medicine to 4.0-4.3 by using an acid-base regulator, and circularly filtering the liquid medicine by using a titanium filtering system;
adding water for injection to full dose, adjusting the pH value of the liquid medicine to 4.0-4.3 by using an acid-base regulator if necessary, and circularly filtering the liquid medicine by using a 0.45 mu m and 0.22 mu m filter;
encapsulating the medicinal liquid (2 ml/bottle), and sterilizing under hot pressure (105-30 min).
Example 17: preparation of clomipramine hydrochloride injection
Prescription: 35g of clomipramine hydrochloride, 8g of glycerol and 2000ml of water.
The preparation method comprises the following steps:
dissolving clomipramine hydrochloride and the rest materials except the injection water by using the injection water with the formula amount of 50-60%, adjusting the pH value of the liquid medicine to 4.0-4.3 by using an acid-base regulator, and circularly filtering the liquid medicine by using a titanium filtering system;
adding water for injection to full dose, adjusting the pH value of the liquid medicine to 4.0-4.3 by using an acid-base regulator if necessary, and circularly filtering the liquid medicine by using a 0.45 mu m and 0.22 mu m filter;
encapsulating the medicinal liquid (2 ml/bottle), and sterilizing under hot pressure (105-30 min).
Example 18: preparation of clomipramine hydrochloride injection
Prescription: 20g of clomipramine hydrochloride, 1g of sodium sulfite, 2g of sodium metabisulfite, 13g of sodium chloride and 2000ml of water.
The preparation method comprises the following steps:
dissolving clomipramine hydrochloride and the rest materials except the injection water by using the injection water with the formula amount of 50-60%, adjusting the pH value of the liquid medicine to 4.0-4.3 by using an acid-base regulator, and circularly filtering the liquid medicine by using a titanium filtering system;
adding water for injection to full dose, adjusting the pH value of the liquid medicine to 4.0-4.3 by using an acid-base regulator if necessary, and circularly filtering the liquid medicine by using a 0.45 mu m and 0.22 mu m filter;
encapsulating the medicinal liquid (2 ml/bottle), and sterilizing under hot pressure (105-30 min).
Example 19: preparation of clomipramine hydrochloride injection
Prescription: 30g of clomipramine hydrochloride, 1g of sodium sulfite, 2g of sodium metabisulfite, 2g of vitamin C, 13g of sodium chloride and water to reach 2000 ml.
The preparation method comprises the following steps:
dissolving clomipramine hydrochloride and the rest materials except the injection water by using the injection water with the formula amount of 50-60%, adjusting the pH value of the liquid medicine to 4.0-4.3 by using an acid-base regulator, and circularly filtering the liquid medicine by using a titanium filtering system;
adding water for injection to full dose, adjusting the pH value of the liquid medicine to 4.0-4.3 by using an acid-base regulator if necessary, and circularly filtering the liquid medicine by using a 0.45 mu m and 0.22 mu m filter;
encapsulating the medicinal liquid (2 ml/bottle), and sterilizing under hot pressure (105-30 min).
Example 21: preparation of clomipramine hydrochloride injection
The prescription and the preparation method are as follows: reference is made to the formulations and preparation processes of examples 11 to 19, respectively, except that 10g of propylene glycol and 5g of malic acid are added (per 2000ml of the drug solution prepared) with the active drug at the time of preparation to give 9 batches of injection solutions (referred to as example 211 (prepared with reference to example 11, and the following example numbers have similar meanings), example 212, and example …, respectively, example 219).
In the present invention, unless otherwise specified, all references to propylene glycol refer to 1, 2-propanediol and all references to malic acid refer to DL-malic acid.
Example 22: preparation of clomipramine hydrochloride injection
The prescription and the preparation method are as follows: referring to the formulations and methods of examples 11-13, respectively, except that 8g propylene glycol and 6g malic acid were added (per 2000ml of the drug solution) with the active drug during the preparation, 3 batches of injections (or referred to as examples 221, 222, respectively,
Example 223).
Example 23: preparation of clomipramine hydrochloride injection
The prescription and the preparation method are as follows: referring to the formulations and methods of examples 11-13, respectively, except that 12g propylene glycol and 4g malic acid were added (2000 ml of each solution prepared) with the active drug during preparation to obtain 3 batches of injection (or referred to as examples 231, 232, respectively),
Example 233).
Example 24: preparation of clomipramine hydrochloride injection
The prescription and the preparation method are as follows: reference is made to the formulations and preparation methods of examples 11 to 19, respectively, except that 10g of propylene glycol is added (per 2000ml of solution prepared) with the active drug during preparation to prepare 9 batches of injection solutions (referred to as examples 241, 242, …, 249, respectively).
Example 25: preparation of clomipramine hydrochloride injection
The prescription and the preparation method are as follows: with reference to the formulations and preparation methods of examples 11 to 19, 9 batches of injection solutions (referred to as example 251, example 252, …, example 259, respectively) were prepared by adding 5g malic acid (2000 ml of drug solution per preparation) along with the active drug.
Example 26: preparation of clomipramine hydrochloride injection
The prescription and the preparation method are as follows: referring to the formulations and methods of examples 1 and 3, respectively, 2 batches of injections (referred to as examples 261 and 262, respectively) were prepared by adding 10g of glycerin and 5g of malic acid (per 2000ml of drug solution prepared) together with the active drug at the time of preparation.
Test example 2: stability test of injection
All of the injection solutions obtained in examples 11 to 19 and 21 to 26 were left at 40 ℃ for 6 months in the dark, and the stability changes of the injection solutions at 0 month and 6 months were examined.
The substances of all the injections obtained in examples 11 to 19 and examples 21 to 26 were measured at 0 month and 6 months by the HPLC method of test example 1 above, and the respective changes of impurity A, impurity B, impurity C, impurity D, impurity E, impurity F and impurity G at 0 month and 6 months were compared, and the percentage increase was calculated for each impurity by the following formula:
the percentage increase of a certain impurity is [ (6 month content-0 month content) ÷ 0 month content ] × 100%
As a result:
in the clomipramine hydrochloride raw material medicine prepared by the method in the embodiment 61, the content of the impurity B is 0.096%, the content of the impurity C is 0.038%, the content of the impurity D is 0.040%, the content of the impurity F is 0.021%, and the content of other impurities is less than 0.01%;
when all the injection is injected for 0 month, the content of the impurity B is within the range of 0.084-0.113%, the content of the impurity C is within the range of 0.036-0.42%, the content of the impurity D is within the range of 0.038-0.041%, the content of the impurity F is within the range of 0.019-0.023%, and other impurities are less than 0.01%, so that the results are not obviously different from the raw material medicines;
after each injection is treated for 40-6 months, the impurities A-E and the impurity G are not obviously increased, the percentage increase of the impurities A-E and the impurity G of all the injections is in the range of-4% -18%, for example, the percentage increase of the impurity A of the injection in example 11 is 9.3%;
after a 40-6 month treatment, the increase of impurity F in different injections showed different trends: the impurity F increase percentage of all the injection solutions prepared in examples 11 to 19 and 24 to 26 is within the range of 213 to 276 percent, for example, the impurity F increase percentage of the injection solution prepared in example 11 is 243.7 percent; the percentage increase of impurity F in all injection solutions prepared in examples 21-23 was within the range of 33% -48%, for example, the percentage increase of impurity F in the injection solution of example 211 was 39.2%.
Although the absolute content of the impurity F in the injection solutions of examples 11 to 19 and examples 24 to 26 is still relatively small (less than 0.1% even if the absolute content is determined to be in accordance with the Chinese pharmacopoeia) after being treated for 40 to 6 months, the trend of the absolute content is greatly increased and is urgently expected to be avoided by the skilled person.
It has been unexpectedly found that the increase of the impurity F can be significantly inhibited by adding propylene glycol and malic acid to the injection solution of the present invention, but the effect of inhibiting the increase of the impurity F cannot be obtained without either or both of them or by using propylene glycol in place of glycerin.
Further, all the injections obtained in examples 11 to 19 and 21 to 26 were measured according to "clomipramine hydrochloride injection" on page 1092 of the second part of the Chinese pharmacopoeia 2015 edition, and as a result, the respective test items of all the injections at 0 month and 6 months were in accordance with the standard.
The above-mentioned embodiments are merely preferred embodiments for fully illustrating the present invention, and the scope of the present invention is not limited thereto. The equivalent substitution or change made by the technical personnel in the technical field on the basis of the invention is all within the protection scope of the invention. The protection scope of the invention is subject to the claims.

Claims (8)

1. The clomipramine hydrochloride injection comprises every 2000ml of liquid medicine: 15-35 g of clomipramine hydrochloride, 8-12 g of propylene glycol, 4-6 g of malic acid and 2000ml of water for injection.
2. The clomipramine hydrochloride injection solution according to claim 1, which contains 20g of clomipramine hydrochloride per 2000ml of the medical solution.
3. The clomipramine hydrochloride injection according to claim 1, further comprising 8 to 15g of glycerin per 2000ml of the liquid medicine.
4. The clomipramine hydrochloride injection according to claim 1, which further comprises 10g of glycerin per 2000ml of the liquid medicine.
5. The clomipramine hydrochloride injection according to claim 1, which further comprises 1g of sodium sulfite, 2g of sodium metabisulfite, and 13g of sodium chloride per 2000ml of the liquid medicine.
6. The clomipramine hydrochloride injection according to claim 1, which further comprises 1g of sodium sulfite, 2g of sodium metabisulfite, 13g of sodium chloride, 2g of vitamin C per 2000ml of the liquid medicine.
7. The clomipramine hydrochloride injection according to claim 1, which contains 10g of propylene glycol and 5g of malic acid per 2000ml of the liquid medicine.
8. The clomipramine hydrochloride injection according to claim 1, which is a formulation according to any one of the following formulations 1 to 15:
prescription 1: 25g of clomipramine hydrochloride, 10g of propylene glycol, 5g of malic acid and 2000ml of water for injection;
prescription 2: 25g of clomipramine hydrochloride, 10g of glycerol, 10g of propylene glycol, 5g of malic acid and 2000ml of water for injection;
prescription 3: 25g of clomipramine hydrochloride, 1g of sodium sulfite, 2g of sodium metabisulfite, 13g of sodium chloride, 10g of propylene glycol, 5g of malic acid and 2000ml of water for injection;
prescription 4: 15g of clomipramine hydrochloride, 10g of propylene glycol, 5g of malic acid and 2000ml of water for injection;
prescription 5: 35g of clomipramine hydrochloride, 10g of propylene glycol, 5g of malic acid and 2000ml of water for injection;
prescription 6: 15g of clomipramine hydrochloride, 15g of glycerol, 10g of propylene glycol, 5g of malic acid and 2000ml of water for injection;
prescription 7: 35g of clomipramine hydrochloride, 8g of glycerol, 10g of propylene glycol, 5g of malic acid and 2000ml of water for injection;
prescription 8: 20g of clomipramine hydrochloride, 1g of sodium sulfite, 2g of sodium metabisulfite, 13g of sodium chloride, 10g of propylene glycol, 5g of malic acid and 2000ml of water for injection;
prescription 9: 30g of clomipramine hydrochloride, 1g of sodium sulfite, 2g of sodium metabisulfite, 2g of vitamin C, 13g of sodium chloride, 10g of propylene glycol, 5g of malic acid and 2000ml of water for injection;
prescription 10: 25g of clomipramine hydrochloride, 8g of propylene glycol, 6g of malic acid and 2000ml of water for injection;
prescription 11: 25g of clomipramine hydrochloride, 10g of glycerol, 8g of propylene glycol, 6g of malic acid and 2000ml of water for injection;
prescription 12: 25g of clomipramine hydrochloride, 1g of sodium sulfite, 2g of sodium metabisulfite, 13g of sodium chloride, 8g of propylene glycol, 6g of malic acid and 2000ml of water for injection;
prescription 13: 25g of clomipramine hydrochloride, 12g of propylene glycol, 4g of malic acid and 2000ml of water for injection;
prescription 14: 25g of clomipramine hydrochloride, 10g of glycerol, 12g of propylene glycol, 4g of malic acid and 2000ml of water for injection;
prescription 15: 25g of clomipramine hydrochloride, 1g of sodium sulfite, 2g of sodium metabisulfite, 13g of sodium chloride, 12g of propylene glycol, 4g of malic acid and 2000ml of water for injection.
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