CN115093337A - Trimebutine maleate crystal form and preparation method thereof - Google Patents
Trimebutine maleate crystal form and preparation method thereof Download PDFInfo
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- CN115093337A CN115093337A CN202210569880.9A CN202210569880A CN115093337A CN 115093337 A CN115093337 A CN 115093337A CN 202210569880 A CN202210569880 A CN 202210569880A CN 115093337 A CN115093337 A CN 115093337A
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- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C219/20—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C219/22—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
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- C07C57/145—Maleic acid
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Abstract
The invention relates to the field of compounds, in particular to a trimebutine maleate crystal form and a preparation method thereof. A crystal form of trimebutine maleate has diffraction peaks at diffraction angles of 2 theta (8.779 degrees +/-0.02 degrees), 11.44 degrees +/-0.02 degrees, 11.676 degrees +/-0.02 degrees, 13.2 degrees +/-0.02 degrees, 15.397 degrees +/-0.02 degrees, 16.363 degrees +/-0.02 degrees, 17.596 degrees +/-0.02 degrees, 20.121 degrees +/-0.02 degrees, 21.561 degrees +/-0.02 degrees, 22.322 degrees +/-0.02 degrees, 23.401 degrees +/-0.02 degrees, 24.68 degrees +/-0.02 degrees, 25.418 degrees +/-0.02 degrees and 27.882 degrees +/-0.02 degrees in an X-ray powder diffraction pattern using a radiation source of Cu-Ka. The trimebutine maleate has better crystal form stability, and the obtained trimebutine maleate has less impurity content.
Description
Technical Field
The invention relates to the field of compounds, in particular to a trimebutine maleate crystal form and a preparation method thereof.
Background
Common name of Chinese: trimebutine maleate
Common name of English: trimebutine emalate
Chemical name: (±) -3, 4, 5-trimethoxybenzoic acid (2-dimethylamino-2-phenyl) butyl maleate
The English name: 2- (dimethyllamino) -2-phenylbutyl 3,4, 5-trimethyloxybenzoate maleate
Structural formula (xvi):
the molecular formula is as follows: c 22 H 29 NO5﹒C 4 H 4 O 4
Molecular weight: 503.55
CAS number: 34140-59-5
Trimebutine maleate is mainly used for treating inappetence, nausea, vomit, belching, abdominal distension, bellyache, diarrhea, constipation and other symptoms caused by gastrointestinal tract movement dysfunction; irritable bowel syndrome.
Irritable bowel syndrome is a chronic and disordered intestinal disease of intestinal functions, has the characteristics of continuous attack and intermittent attack, is mainly accompanied by clinical symptoms such as abdominal pain, defecation habits, abdominal distension and stool character change, and typical symptoms of patients are abdominal distension and abdominal pain. The mechanism is influenced by various factors, such as adverse psychological mood, adverse dietary habits, familial inheritance, gastrointestinal motility disorder, intestinal infection and the like, wherein the adverse psychological mood can regulate the plant psychology, so that intestinal peristalsis is hindered, intestinal secretion dysfunction is caused, and intestinal dysfunction is caused; poor dietary habits tend to aggravate the disease condition and lead to repeated attack of the disease conditionDiarrhea occurs; familial inheritance refers to the onset of disease in the infant stage of some patients; gastrointestinal motility disorder mainly refers to the condition that transitional compound movement is abnormal when small intestines are digested, so that the movement period is shortened, and a large amount of discrete cluster contraction waves are generated in jejunum; intestinal tract infection is mainly caused by bacterial, parasite and virus infection, which causes intestinal dysfunction of gastroenteritis patients and irritable bowel syndrome after infection. If the patient is not treated in time, the work, study and life of the patient are seriously affected. In recent years, the incidence of the diseases is continuously improved, and the prevalence rate of the diseases of the common people is 15 to 20 percent. The treatment mainly comprises drug treatment. Trimebutine maleate serving as a regulator of full-digestive tract movement can excite or inhibit the digestive tract movement, quickly promote the gastrointestinal tract function to be recovered to a normal state, and can also be used for cell membrane K + Inhibition of the channel, enlargement of smooth muscle excitability, and ca on the cell membrane 2+ Block, pair ca 2 Inhibition is carried out, and the cell excitability is effectively controlled; in addition, the compound can play a bidirectional regulating role on smooth muscle nerve receptors, if the gastrointestinal tract hypomotility is too low, the compound can play a role on adrenergic receptors to control the release of adrenalin, so that the gastrointestinal tract has the movement rhythmicity; if the gastrointestinal tract hypermotility is caused, the action on cholinergic receptors is generated, the release amount of acetylcholine is inhibited, and the gastrointestinal tract hypermotility is relieved.
At present, trimebutine maleate has low stability, and the content of related substances is increased after long-term storage, so that the related substances are unqualified when the trimebutine maleate is prepared into injection or other dosage forms.
Disclosure of Invention
The invention aims to provide a crystal form of trimebutine maleate with good stability;
the invention also aims to provide a preparation method of the trimebutine maleate crystal form.
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
a crystal form of trimebutine maleate has diffraction peaks at diffraction angles of 2 theta (8.779 degrees +/-0.02 degrees), 11.44 degrees +/-0.02 degrees, 11.676 degrees +/-0.02 degrees, 13.2 degrees +/-0.02 degrees, 15.397 degrees +/-0.02 degrees, 16.363 degrees +/-0.02 degrees, 17.596 degrees +/-0.02 degrees, 20.121 degrees +/-0.02 degrees, 21.561 degrees +/-0.02 degrees, 22.322 degrees +/-0.02 degrees, 23.401 degrees +/-0.02 degrees, 24.68 degrees +/-0.02 degrees, 25.418 degrees +/-0.02 degrees and 27.882 degrees +/-0.02 degrees in an X-ray powder diffraction pattern using a radiation source of Cu-Ka.
The invention also discloses a preparation method of the trimebutine maleate crystal form, which comprises the following steps:
(1) adding trimebutine, 1-3 times of maleic acid and 10-20 times of water into a reaction bottle, and heating to 80-100 ℃; stirring for 2-4 hours under heat preservation;
(2) cooling to 0-10 ℃, separating out solids, and stirring for 2 hours under heat preservation; filtering, and washing a filter cake with 1-3 times of water; drying at 60-65 ℃ to obtain a crude product;
(3) adding a crude product and 1-3 times of absolute ethyl alcohol into a single-mouth bottle, and heating until reflux; stirring for 0.5 hour under heat preservation;
(4) cooling to 10-30 ℃, and stirring for 2 hours under heat preservation; filtering, and washing a filter cake with 1-3 times of the amount of the anhydrous ethanol; drying for 14 hours at the temperature of 60-70 ℃ to obtain the trimebutine maleate crystal form.
The trimebutine maleate has better crystal form stability, and the obtained trimebutine maleate has less impurity content.
Drawings
FIG. 1: the crystal form XRD pattern of trimebutine maleate obtained in example 1;
FIG. 2: crystalline form XRD pattern of trimebutine maleate obtained in example 2.
Detailed Description
The present invention will be further illustrated by the following specific examples.
Example 1: preparation of trimebutine maleate crystal form
Adding trimebutine, 3eq maleic acid and 20V water into a reaction bottle, and heating to 80 ℃; stirring for 4h under heat preservation; cooling to 8 ℃, separating out solids, and stirring for 2 hours under heat preservation; filtering, and washing a filter cake with 3V water; drying at 65 ℃; adding the crude product and 3V absolute ethyl alcohol into a single-mouth bottle, and heating to reflux; stirring for 0.5h under heat preservation; cooling to 20 ℃, and stirring for 2h under heat preservation; filtering, and washing the filter cake with 0.8V of iced absolute ethyl alcohol; drying for 14h at 70 ℃ to obtain the trimebutine maleate crystal form, wherein the HPLC content is 99.3%, and the melting point is 106.3-108.6 ℃. The XRD pattern of the crystal form is shown in figure 1.
Example 2: preparation of trimebutine maleate crystal form
Adding trimebutine, 3eq maleic acid and 20V water into a reaction bottle, and heating to 80 ℃; stirring for 4h under heat preservation; cooling to 10 ℃, separating out solids, and stirring for 2h under heat preservation; filtering, and washing a filter cake with 3V water; drying at 65 ℃; adding the crude product and 3V isopropanol into a single-mouth bottle, and heating to reflux; stirring for 0.5h under heat preservation; cooling to 20 ℃, and stirring for 2 hours under heat preservation; filtering, washing filter cake with 0.8V isopropanol; drying for 14h at 70 ℃ to obtain the trimebutine maleate crystal form with HPLC content of 99.2% and melting point of 129.8-130.5 ℃. The XRD pattern of the crystal form is shown in figure 2.
Test example 1: x-ray powder diffraction pattern analysis of trimebutine maleate crystal form
The instrument model is as follows: D/Max-2550pc
The manufacturer: japan science
The working conditions of the instrument are as follows: power 40kV x 250mA, CuKa radiation
The scanning range is 3-40 degrees (2 theta), the step width is 0.02 degree, and the scanning speed is 5 degrees/min.
The X-ray powder diffraction pattern of the trimebutine maleate crystal form prepared in example 1 is shown in figure 1, wherein the parameters of the diffraction angle 2 theta value \ crystal face crystal distance of the characteristic peak and the relative intensity of the characteristic peak are shown in the following table:
the X-ray powder diffraction pattern of the trimebutine maleate crystal form prepared in example 2 is shown as figure 2, wherein the parameters of the diffraction angle 2 theta value \ crystal face crystal distance of the characteristic peak and the relative intensity of the characteristic peak are shown as the following table:
test example 2: accelerated testing and long-term sample retention stability investigation
And (3) accelerated test: two batches of samples (HCB1607-IV-08-47 and HCB 1607-IV-08-48) obtained in example 1 and one batch of samples (HCB 1607-IV-08-46) obtained in example 2 are taken, 3 batches of samples are packaged according to raw materials (including a low-density polyethylene bag for internal package and an aluminum plastic bag for external package), the samples are placed in a constant temperature and humidity incubator with the relative humidity of 75% at 40 ℃ for 9 months, and samples are respectively taken at 3 rd, 6 th and 9 th months of the test to detect related substances (HPLC method detection), and the results are compared with the results of 0 month, and are shown in the following table.
The results show that the total impurity of the crystal form of example 2 in the accelerated test shows a relatively increased course, and is less stable than the crystal form of example 1.
And (3) long-term sample retention stability investigation: and (3) long-term sample retention stability investigation: two batches of samples (two batches of HCB1607-IV-08-47 and HCB 1607-IV-08-48) obtained in example 1 and one batch of samples (one batch of HCB 1607-IV-08-46) obtained in example 2 are taken, 3 batches of samples are packaged according to raw materials (including a medicinal low-density polyethylene bag and an aluminum plastic bag), the samples are placed in a constant temperature and humidity incubator with the temperature of 25 ℃ and the relative humidity of 60%, the incubator is placed for 9 months, and samples are respectively sampled and detected on the 3 rd, 6 th and 9 th months of the test (HPLC method detection), and the results are compared with the results of 0 month, and the results are shown in the table below.
The results show that the total impurity of the crystalline form of example 2 in the long-term sample retention data shows a relatively increased course, which is not as stable as the crystalline form of example 1, consistent with the conclusion of the accelerated test.
Claims (2)
1. An form of electrically active form of trimebutine, characterized in that the form of electrically active form of trimebutine has, in an X-ray powder diffraction pattern using a Cu-Ka radiation source, diffraction angles at 2 θ -8.779 ± 0.02 °, 11.44 ± 0.02 °, 11.676 ± 0.02 °, 13.2 ± 0.02 °, 15.397 ± 0.02 °, 16.363 ± 0.02 °, 17.596 ± 0.02 °, 20.121 ± 0.02 °, 21.561 ± 0.02 °, 22.322 ± 0.02 °, 23.401 ± 0.02 °, 24.68 ± 0.02 °, 25.418 ± 0.02, 27.882 ± 0.02 peak at an angle of 2 θ -Ka.
2. The process for the preparation of the crystalline form of trimebutine maleate, according to claim 1, characterized by the fact of comprising the following steps:
(1) adding trimebutine, 1-3 times of maleic acid and 10-20 times of water into a reaction bottle, and heating to 80-100 ℃; stirring for 2-4 hours under heat preservation;
(2) cooling to 0-10 ℃, separating out solids, and stirring for 2 hours while keeping the temperature; filtering, and washing a filter cake with 1-3 times of water; drying at 60-65 ℃ to obtain a crude product;
(3) adding the crude product and 1-3 times of absolute ethyl alcohol into a single-mouth bottle, and heating to reflux; stirring for 0.5 hour under heat preservation;
(4) cooling to 10-30 ℃, and stirring for 2 hours under heat preservation; filtering, and washing a filter cake with 1-3 times of the amount of the anhydrous ethanol; drying for 14 hours at the temperature of 60-70 ℃ to obtain the trimebutine maleate crystal form.
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