CN113004265A - Pidotimod histidine salt crystal form and preparation method thereof - Google Patents

Pidotimod histidine salt crystal form and preparation method thereof Download PDF

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CN113004265A
CN113004265A CN201911318940.4A CN201911318940A CN113004265A CN 113004265 A CN113004265 A CN 113004265A CN 201911318940 A CN201911318940 A CN 201911318940A CN 113004265 A CN113004265 A CN 113004265A
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pidotimod
histidine
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张贵民
翟立海
卢元圣
张朝花
夏祥来
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Lunan Pharmaceutical Group Corp
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Abstract

The invention belongs to the technical field of chemical drugs, and discloses a pidotimod histidine salt; and the crystal form is detected and analyzed by X-ray powder diffraction. The preparation method comprises the steps of reacting pidotimod and histidine in a proper solvent at an equimolar feeding ratio, cooling, crystallizing and drying to constant weight; the pidotimod histidine salt obtained by the method improves the stability of pidotimod, and further improves the solubility of pidotimod; the salt can be widely applied to the fields of pidotimod tablets, capsules, injections and the like. The salt preparation method is simple and suitable for industrial production.

Description

Pidotimod histidine salt crystal form and preparation method thereof
Technical Field
The invention belongs to the technical field of chemical drugs, and relates to a pidotimod salt crystal form and a preparation method thereof.
Background
Pidotimod (Pidotimod), chemical name: (R) -3- [ (S) - (5-oxo-2-pyrrolidinyl) carbonyl ] -thiazolidine-4-carboxylic acid, having the following molecular structural formula (formula I):
Figure BDA0002326622970000011
the molecular formula is as follows: c9H12N2O4S, molecular weight 244.26. Pidotimod is a synthetic dipeptide drug, has in vivo and in vitro biological and immunological activities, is a safe and effective immune function promoter, and effectively promotes nonspecific immune reaction. On the one hand, it can improve natural killer cell function, enhance phagocytic activity of monocytes, or enhance activity of monocytes, alter chemotaxis of neutrophils. On the other hand, pidotimod can promote lymphocyte proliferation, restore the ratio of CD4+/CD8, or increase the release of interleukin-2 (IL-2) and interferon. These phenomena have been applied in clinical studies, demonstrating the effectiveness of pidotimod in reducing the recurrence rate of respiratory and urinary tract infections in children. The same results were also obtained in recurrent acute respiratory infections (arts) in adults. Pidotimod is mainly aimed at preventing and curing allergic rhinitis, asthma and ARTIs of children. In addition, it has more obvious effect on patients with hypoimmunity caused by aging, virus infection, Down syndrome, cancer or other chronic diseases.
The poor water solubility of pidotimod seriously affects the therapeutic effects such as bioavailability, so that a larger amount of pidotimod is required in the prepared medicament, and the safety of the medicament is also affected. CN1680427A), including pidotimod arginine salt, pidotimod lysine salt, pidotimod meglumine salt; particularly discloses the pidotimod 1:1 molecular number ratio salt. They have somewhat improved water solubility but are less thermally stable.
CN101411684A discloses that pidotimod sodium is generated by the reaction of equal mole of pidotimod and sodium hydroxide in water or ethanol or a mixed solution of the water and the ethanol, and the solubility of pidotimod is improved by sodium salt formation when the pidotimod sodium is prepared into injection or freeze-dried into powder injection. CN101766603A is prepared through the reaction of pidotimod and sodium hydroxide, potassium hydroxide, arginine, etc in water, ethanol or their mixture to produce pidotimod sodium salt, potassium salt or arginine salt, and the subsequent compounding into injection. The resulting sodium salt was shown to deliquesce or partially deliquesce at 57% RH, 41 ℃.
CN101768156A discloses that equal moles of pidotimod and arginine react under certain conditions to generate pidotimod arginine salt, so as to increase the stability of pidotimod and improve the water solubility of pidotimod.
CN101768157A discloses that the use of equal molar pidotimod and amantadine under certain conditions produces equal molar amantadine pidotimod carboxylate, which has good water solubility and lipid solubility, reaches a moderate state, and is more beneficial to drug absorption.
CN102100903A discloses pidotimod potassium salt prepared from pidotimod and equal moles of potassium hydroxide in a suitable solvent, and the pidotimod potassium salt is mixed with a proper amount of binder, disintegrant, lubricant, etc. and then encapsulated. The pidotimod exists in a potassium salt form, so that the water solubility and the stability of the pidotimod are improved under the environment of normal pH of a human body. CN102100664A and CN102101881A, the pidotimod potassium salt is prepared into injections, and the injections are aseptically subpackaged into powder injections or freeze-dried powder injections. Studies have shown deliquescence at 40% RH, RT or at 30% RH, RT.
CN103059099A discloses a novel pidotimod crystal form and a preparation method thereof, wherein the stability of the crystal form is very obvious through stability inspection at 40 ℃.
CN105753938A discloses a pidotimod crystal form which has high crystal purity and low impurity content and is stable to light and heat, and the pidotimod crystal form is obtained by subjecting an isopropyl alcohol-water mixed solution of pidotimod raw materials to sectional cooling crystallization, filtering and drying. And examined by stability under intense light irradiation (4500Lx + -500 Lx) and 40 ℃. Although the stability of the crystal form is improved, the solubility is difficult to be greatly improved.
CN107337708A discloses a pidotimod crystal form, which is prepared by carrying out crystal transformation in a mixed solution of acetone and/or tetrahydrofuran and water by a three-step method, wherein the crystal transformation is carried out by stirring at room temperature, cooling and then stirring, and heating to room temperature and then stirring. But the conditions and the process are complex and are not beneficial to industrial production.
WO2016112977a1, UY36515A discloses a series of di-pidotimod benzyl ethylenediamine salts and solid forms thereof, such as form M, form H hydrate, amorphous form, isopropyl alcohol solvate form J, isopropyl alcohol solvate form O, ethanol solvate form S, ethanol solvate form W, form X, form T. The amorphous form is converted into hydrated H form at 60% RH or 75%, the hydrated H form is converted into H form after being placed at 20-25 ℃ for 15-25H, the J form is converted into O form after being placed in an open vial for 22.5H, the W form is converted into X form after being placed in a vial in a sealed manner for 15 days, and the W form is converted into X form and 20% H form after being placed at 40-44% RH for 3 days. Thermogravimetric analysis shows that the isopropyl alcohol solvate O, the ethanol solvate S and the ethanol solvate W have weight loss at 24-25 ℃, and the solvent is unstably volatilized. Form X by TGA technique, a weight loss of 3.1% is observed between about 23.2 ℃ and 122.7 ℃. In conclusion, the M form in a series of the di-pidotimod benediamine salt and the solid forms thereof is a relatively stable form.
Therefore, the search for more suitable salts and crystal forms of pidotimod to increase the solubility and stability of pidotimod is an urgent problem to be solved by the skilled person.
Disclosure of Invention
The invention relates to a salt and a crystal form preparation method thereof. In view of the improvement of the defects in the prior art, the invention provides pidotimod histidine salt and a crystal form thereof, and performs characterization research on the structure of the pidotimod histidine salt. Provides a way for improving the water solubility and bioavailability of the pidotimod and reducing the toxic and side effects, and the obtained salt is a tiny flaky crystal, has good fluidity and is not easy to agglomerate, thereby greatly improving the stability. The alkaline compound histidine adopted by the invention has good water solubility and is alkaline, and can easily form H proton offset salt with pidotimod. Histidine (molecular structure shown as formula II), molecular formula C6H9N3O2Histidine is considered to be a semi-essential amino acid for humans. In addition, the traditional Chinese medicine composition can be used as a medicine for treating heart diseases, anemia, rheumatic arthritis and other diseases, and is not harmful to human health after being taken in a small amount. The molecular formula of the pidotimod histidine salt is as follows: [ C ]9H12N2O4S]·a[C6H9N3O2]The a is the number of molecules of histidine salified with pidotimod, namely the molar ratio of multiple active center histidines to pidotimod in the pidotimod histidine salt, the value range of the a is 0.1-20, the value of the a can be decimal or integer, during preparation, the feeding reaction amount of the pidotimod and the histidine can be controlled, the value of the a can be controlled to be different, and pidotimod histidine salts with different salification ratios can be prepared, wherein the pidotimod histidine salt is prepared according to the proportion of 1: 1.
Figure BDA0002326622970000031
The compound salt compound of the pidotimod has pharmacological action completely consistent with that of the pidotimod, and because the compound salt compound has better water solubility, a safe basic compound is used as a compound salt ligand, a new water-soluble compound form is provided for the application of the pidotimod in medicaments, the pidotimod can be used for preparing medicaments and is more convenient to use, and the compound salt compound can be prepared into any pharmaceutically acceptable medicament dosage forms, such as powder injection and injection solution for injection, by adopting proper pharmaceutical excipients and a preparation method; tablets for oral administration, oral liquids, granules and the like.
The pidotimod histidine salt crystal form uses Cu-Kalpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 9.3 +/-0.2 degrees, 15.1 +/-0.2 degrees, 17.1 +/-0.2 degrees, 18.8 +/-0.2 degrees, 20.9 +/-0.2 degrees, 23.8 +/-0.2 degrees, 29.6 +/-0.2 degrees and 30.6 +/-0.2 degrees.
Preferably, the pidotimod histidine salt crystal form has characteristic peaks at 9.3 +/-0.2 °, 15.1 +/-0.2 °, 17.1 +/-0.2 °, 18.8 +/-0.2 °, 20.9 +/-0.2 °, 21.9 +/-0.2 °, 22.3 +/-0.2 °, 23.8 +/-0.2 °, 29.6 +/-0.2 °, 30.6 +/-0.2 °, 34.0 +/-0.2 ° and 41.7 +/-0.2 ° in an X-ray diffraction spectrum expressed by 2 theta by using Cu-Ka radiation.
Preferably, the pidotimod histidine salt crystal form has characteristic peaks at 9.3 +/-0.2 °, 15.1 +/-0.2 °, 17.1 +/-0.2 °, 18.8 +/-0.2 °, 20.9 +/-0.2 °, 21.9 +/-0.2 °, 22.3 +/-0.2 °, 23.8 +/-0.2 °, 29.6 +/-0.2 °, 30.4 +/-0.2 °, 30.6 +/-0.2 °, 31.9 +/-0.2 °, 33.4 +/-0.2 °, 34.0 +/-0.2 °, 37.5 +/-0.2 °, 39.7 +/-0.2 ° and 41.7 +/-0.2 ° in an X-ray diffraction spectrum expressed by 2 theta under Cu-Kalpha radiation.
The pidotimod histidine salt crystal form adopts Cu-Kalpha radiation, and the characteristic peaks of the pidotimod histidine salt crystal form accord with an X-ray powder diffraction pattern shown in figure 1.
The pidotimod histidine salt crystal form has TGA and DSC analysis charts shown in figure 2.
A second aspect of the present invention provides a pidotimod histidine salt and a crystalline form preparation method thereof, which specifically comprises the following steps: dissolving pidotimod in an organic solvent A, dissolving histidine in an equal mole in purified water, dropwise adding a histidine aqueous solution into the pidotimod solution at room temperature, cooling, crystallizing, filtering, and drying in vacuum to constant weight to obtain pidotimod histidine salt and a crystal form thereof; wherein, the pidotimod is selected from the following groups: amorphous or crystalline products.
The organic solvent A is one or a mixed solvent of at least two of acetone, methanol, ethanol, isopropanol and acetonitrile.
Further, the organic solvent A is one or two of acetone, methanol and ethanol.
In the system, the mass-volume ratio of the pidotimod to the organic solvent A is 1: 20-100, wherein the mass is in g and the volume is in ml; preferably 1: 80.
the mass volume ratio of histidine to water in the system is 1: 10-15, wherein the mass is in g and the volume is in ml.
In the step, the temperature is reduced to 0-20 ℃; preferably 0 to 10 ℃.
The crystallization time is 3-12 hours.
The drying temperature is 30-100 ℃.
A third aspect of the present application provides a pharmaceutical composition comprising (a) the pidotimod histidine salt crystalline form according to the present invention and (b) a pharmaceutically acceptable carrier.
Preferably, the pharmaceutical composition of the present invention is prepared as follows: the pidotimod histidine salt crystalline form of the invention is combined with pharmaceutically acceptable solid or liquid carriers, and optionally with pharmaceutically acceptable adjuvants and excipients, using standard and conventional techniques, to prepare useful dosage forms.
Preferably, the other components include other active ingredients, excipients, fillers, etc. that may be used in combination.
Preferably, the pharmaceutical composition is a spray, a tablet, a capsule, a powder injection, a liquid injection and the like.
Confirmation of the Crystal Structure
The X-ray powder diffraction test instrument and the test conditions of the invention are as follows: x-ray powder diffractometer PANalytical E; Cu-K alpha; a sample stage: a flat plate; the incident light path is BBHD; diffraction light path: PLXCEL; voltage 45kv and current 40 mA; a diverging slot 1/4; an anti-scatter slit 1; 0.04rad of cable pull slit; step length: 0.5 s; scanning range: 3 to 50 degrees.
According to the crystallography data, the characteristic peak in the corresponding X-ray powder diffraction pattern (Cu-Ka) is detailed in figure 1 and table 1.
Table 1 PXRD peaks for pidotimod histidine salts
Figure BDA0002326622970000051
All samples prepared in the examples have the same crystallographic parameters and X-ray powder diffraction patterns.
Pidotimod histidine salt profile data: ESI-MS (M/z):243.2[ M [, M ]1-H]-,156.1[M2+H]+。
The TGA/DSC thermal analysis tester and the test conditions in the invention are as follows: TGA/DSC thermogram METTLER TOLEDO TGA/DSC3 +; dynamic temperature section: 30-300 ℃; heating speedRate: 10 ℃/min; segment gas N2(ii) a Gas flow rate: 50 mL/min; crucible: an aluminum crucible of 40. mu.l.
The Differential Scanning Calorimetry (DSC) result of the crystalline form of pidotimod histidine salt prepared by the method of the invention is shown in figure 2, wherein the Differential Scanning Calorimetry (DSC) only has one endothermic peak 278.96 ℃, which is different from the melting point 196 ℃ of pidotimod and the melting point 282 ℃ of histidine. And thermogravimetric analysis (TGA) of the pidotimod histidine salt only has one weight loss step, which indicates that the structure of the pidotimod histidine salt is stable.
The method for preparing the pidotimod histidine salt provided by the invention is simple and convenient to operate, the prepared crystal purity is high, and the pidotimod histidine salt crystal form provided by the invention has better stability and better water solubility in all salts reported at present.
Drawings
FIG. 1: the X-ray powder diffraction pattern of the pidotimod histidine salt crystal form obtained by the invention.
FIG. 2: TGA and DSC analysis chart of the pidotimod histidine salt crystal form obtained by the invention.
Detailed Description
The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
In the examples below, unless otherwise indicated, the test procedures described are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the used experimental equipment and reagents can be obtained by a commercially available mode and meet the requirements of medicinal quality standards.
Example 1
0.50g of pidotimod is taken and added with 40ml of absolute ethyl alcohol to form suspension by ultrasound, 0.31g of histidine is taken and added with 4ml of purified water to be dissolved, histidine solution is slowly dripped into the pidotimod suspension at room temperature, the solution is added and shaken up, the temperature is reduced to 5 ℃, the solution is continuously stirred and crystallized for 5h, crystalline powder is obtained by filtration, the solution is washed with absolute ethyl alcohol for 2-3 times, 5ml of solution is added each time, and the solution is dried for 10h at 40 ℃ under vacuum until the weight is constant, thus obtaining the pidotimod histidine salt, the crystalline powder, the yield is 95.2%, and the purity is 99.97% (detected by active ingredient pidotimod).
Example 2
0.50g of pidotimod is taken and added with 50ml of absolute ethyl alcohol to form suspension by ultrasound, 0.31g of histidine is taken and added with 4.7ml of purified water to be dissolved, histidine solution is slowly dripped into the pidotimod suspension at room temperature, the solution is stirred uniformly after being added, the temperature is reduced to 5 ℃, the solution is continuously stirred and crystallized for 5 hours, crystalline powder is obtained by filtration, the crystalline powder is washed with absolute ethyl alcohol for 2 to 3 times, 5ml of the solution is obtained each time, and the crystalline powder is dried for 10 hours at 40 ℃ under vacuum until the constant weight is reached, thus obtaining the pidotimod histidine, the yield is 92.1 percent, and the purity is 99.90 percent (the detection of the active ingredient pidoti.
Example 3
0.50g of pidotimod is added with 10ml of absolute ethyl alcohol to form suspension by ultrasound, 0.31g of histidine is added with 3.2ml of purified water to be dissolved, histidine solution is slowly dripped into the pidotimod suspension at room temperature, the solution is stirred uniformly after being added, the temperature is reduced to 5 ℃, the solution is continuously stirred and crystallized for 5h, crystalline powder is obtained by filtration, the solution is washed with absolute ethyl alcohol for 2 to 3 times, 5ml of the solution is added each time, and the solution is dried for 10h at 40 ℃ under vacuum until the constant weight is reached, thus obtaining the pidotimod histidine salt, the crystalline powder has the yield of 91.3% and the purity of 99.96% (the detection of the active ingredient pidotimod).
Example 4
0.50g of pidotimod is taken and added with 40ml of acetone to form suspension by ultrasound, 0.31g of histidine is taken and added with 4ml of purified water to be dissolved, histidine solution is slowly dripped into the pidotimod suspension at room temperature, the mixture is evenly shaken after being added, the temperature is reduced to 0 ℃, the mixture is continuously stirred and crystallized for 6h, crystal powder is obtained by filtration, acetone is used for washing for 2-3 times, 5ml of the solution is used each time, and the crystal powder, the yield of which is 93.3 percent and the purity of which is 99.89 percent (active ingredient pidotimod detection), is obtained by drying for 10h at 40 ℃ under vacuum.
Example 5
Dissolving 0.50g of pidotimod in 40ml of acetonitrile, dissolving 0.31g of histidine in 4ml of purified water, slowly and dropwise adding a histidine solution into the pidotimod solution at room temperature, uniformly shaking after adding, cooling to 10 ℃, continuously stirring for crystallization for 6h, filtering to obtain crystalline powder, washing with acetone or acetonitrile for 2-3 times, 5ml each time, drying at 60 ℃ for 10h under vacuum until constant weight to obtain the pidotimod histidine salt, wherein the crystalline powder has the yield of 91.5% and the purity of 99.87% (active ingredient pidotimod detection).
Example 6
0.50g of pidotimod is added with 40ml of absolute ethanol to form suspension by ultrasonic treatment, 0.31g of histidine is added with 4ml of purified water to be dissolved, histidine solution is slowly dripped into the pidotimod suspension at room temperature, the solution is stirred uniformly after being added, the temperature is reduced to 20 ℃, the solution is continuously stirred and crystallized for 6h, crystalline powder is obtained after filtration, the crystalline powder is washed with ethanol for 2-3 times, 5ml of the solution is added each time, and the solution is dried for 10h at 40 ℃ under vacuum until the constant weight is achieved, thus obtaining the pidotimod histidine salt, the crystalline powder has the yield of 90.5% and the purity of 99.92% (the detection of the active ingredient pidotimod).
Example 7
0.50g of pidotimod is added with 40ml of anhydrous methanol to form suspension by ultrasound, 0.31g of histidine is added with 3ml of purified water to be dissolved, histidine solution is slowly dripped into the pidotimod suspension at room temperature, the solution is stirred uniformly after being added, the temperature is reduced to 5 ℃, the solution is continuously stirred and crystallized for 6h, crystalline powder is obtained after filtration, methanol or ethanol is used for washing for 2-3 times, 5ml of the solution is used for each time, and the solution is dried for 10h at 40 ℃ under vacuum until the constant weight is reached, thus obtaining the pidotimod histidine salt, the crystalline powder has the yield of 92.5% and the purity of 99.90% (the detection of the active ingredient pidotimod).
Example 8
0.50g of pidotimod is added with 40ml of anhydrous isopropanol to form suspension by ultrasound, 0.31g of histidine is added with 4ml of purified water to be dissolved, histidine solution is slowly dripped into the pidotimod suspension at room temperature, the solution is stirred uniformly after being added, the temperature is reduced to 20 ℃, the solution is continuously stirred and crystallized for 6h, crystalline powder is obtained by filtration, acetone or ethanol is used for washing for 2-3 times, 5ml of the solution is used for each time, and the solution is dried for 10h at 40 ℃ under vacuum until the constant weight is reached, thus obtaining the pidotimod histidine salt, the crystalline powder has the yield of 92.8% and the purity of 99.88% (the detection of the active ingredient pidotimod).
Example 9
0.50g of pidotimod is taken and added with 50ml of absolute ethyl alcohol to form suspension by ultrasound, 0.31g of histidine is taken and added with 3ml of purified water to be dissolved, histidine solution is slowly dripped into the pidotimod suspension at room temperature, the solution is added and shaken up, the temperature is reduced to 5 ℃, the solution is continuously stirred and crystallized for 5h, crystalline powder is obtained by filtration, the solution is washed with absolute ethyl alcohol for 2-3 times, 5ml of solution is added each time, and the solution is dried for 10h at 40 ℃ under vacuum until the weight is constant, thus obtaining the pidotimod histidine salt, the crystalline powder, the yield is 91.6%, and the purity is 99.91% (detected by active ingredient pidotimod).
Example 10
0.50g of pidotimod is added with 10ml of absolute ethyl alcohol to form suspension by ultrasound, 0.31g of histidine is added with 4.7ml of purified water to be dissolved, histidine solution is slowly dripped into the pidotimod suspension at room temperature, the solution is stirred uniformly after being added, the temperature is reduced to 5 ℃, the solution is continuously stirred and crystallized for 5h, crystalline powder is obtained by filtration, the solution is washed with absolute ethyl alcohol for 2 to 3 times, 5ml of the solution is added each time, and the solution is dried for 10h at 40 ℃ under vacuum until the constant weight is reached, thus obtaining the pidotimod histidine salt, the crystalline powder has the yield of 90.1% and the purity of 99.97% (detection of active ingredient pidotimod).
Comparative example 1 preparation of pidotimod arginine salt (1:1)
0.50g (0.002mol) of pidotimod is added with 3ml of absolute ethyl alcohol to prepare a suspension, 0.35g (0.002mol) of L-arginine is added with 2ml of water to be dissolved, the L-arginine solution is slowly dripped into the suspension of pidotimod at room temperature, after the L-arginine solution is completely added, the suspension is continuously shaken to be dissolved completely to be in a clear state, 12ml of absolute ethyl alcohol is added into the solution to obtain milky turbid liquid, the turbid liquid is frozen in a refrigerator overnight to precipitate, supernatant liquid is removed, the precipitate is dried in vacuum to constant weight to obtain crystalline powder, the crystalline powder is rinsed for 2-3 times with absolute ethyl alcohol, and the crystalline powder is obtained after filtering and decompressing and steaming to remove the absolute ethyl alcohol, and the pidotimod arginine salt is in a white crystalline powder, and the yield is 92.1%.
COMPARATIVE EXAMPLE 2 Pidotimod arginine salt (1:1)
0.01mol of pidotimod, 0.01mol of arginine and 20ml of water are added into a 100ml glass cup, the mixture is stirred for 10min at room temperature, the raw materials are quickly dissolved, and the obtained solution is colorless and transparent. The resulting solution was concentrated under reduced pressure or ethanol was evaporated off, gradually turning to a white solid. The product is pidotimod arginine salt.
COMPARATIVE EXAMPLE 3 Pidotimod lysine salt (1:1)
Dissolving 3.0g (0.02mol) of L-lysine in 30ml of water, adding 5.0g (0.02mol) of pidotimod, fully stirring to completely dissolve the mixed solution to be clear, finely filtering, and freeze-drying the filtrate by adopting a freeze-drying process to obtain white solid powder, namely the pidotimod lysine salt.
Comparative example 4 Pidotimod meglumine salt (1:1)
Adding 5.0g (0.02mol) of pidotimod and 4.0g (0.02mol) of meglumine into 100ml of water, stirring at room temperature until the raw materials are completely dissolved, and spray-drying to obtain white powder, namely the pidotimod meglumine salt.
Comparative example 5 crystalline form M of di-pidotimod benzathine salt
Pidotimod (4.0169g) was dissolved in dimethylformamide/methanol (V) at about 55 deg.CDimethyl formamide/V Methanol30/70) in 50 ml. 0.5 molar equivalent of benzylethylenediamine (1.93 ml) was added. The solution was slowly cooled to room temperature and a white solid precipitated. The slurry was stirred at room temperature for about 4 hours, and then the solid was air dried with suction.
Weighing 795.1mg of the obtained solid, dissolving in 8ml of ethyl acetate, carrying out oil bath heat preservation and stirring at the temperature of about 45 ℃ for 3 days, carrying out suction filtration on the solid, and carrying out vacuum drying at the temperature of about 40 ℃ for 1 day to obtain the M-type crystal seed of the di-pidotimod benzylethylenediamine salt.
0.5 molar equivalent of benzylethylenediamine was dissolved in a solution of N, N-dimethylformamide, added to a solution of pidotimod in dimethylformamide at 80 ℃ and stirred for 30 minutes. Adding the M-type seed crystal, continuing stirring for 1 hour, then cooling to 70 ℃, continuously adding enough ethyl acetate in about 6 hours to separate out crystals, continuing stirring for 1 hour, cooling to 0 ℃, and keeping the temperature and stirring for 12 hours. And (3) carrying out suction filtration, washing a filter cake by ethyl acetate, and carrying out vacuum drying at 40 ℃ for 3 days to obtain the bis-pidotimod benzyl ethylenediamine salt M-type crystal form with the yield of 80%.
According to the guiding principles of crystal form research and crystal form quality control of 9015 medicine in the fourth general rule of Chinese pharmacopoeia 2015 edition. The following investigation and study was carried out on the crystal form of the present invention and the crystal forms similar to the present invention related to the prior art:
1. stability test
Influence factor test: the crystal form obtained in example 1 and the crystal forms of various salts obtained or accumulated in each comparative example were placed in a petri dish and spread in a thin layer with a thickness of 10mm or less, and the following experiments were performed:
1) and (3) performing high-temperature test, namely opening the sample to be tested into a proper clean container, standing at the temperature of 60 ℃ for 10 days, sampling on the 5 th day and the 10 th day, and detecting the purity of the pidotimod according to the stability focus examination item.
2) High humidity test, placing the sample in a constant humidity closed container at an opening, standing at 25 deg.C under the condition of relative humidity of 40% and 5% for 10 days, sampling at 5 days and 10 days, and observing the deliquescence condition according to stability.
3) In the intense light irradiation test, the opening of a sample is placed in a lighting box or other suitable lighting devices provided with fluorescent lamps, the sample is placed for 10 days under the condition that the illumination intensity is 4500lx and 500lx, samples are taken on the 5 th day and the 10 th day, the purity of the pidotimod is detected according to the stability focus examination item, and the change of the appearance of the sample is particularly noticed. The stability results are shown in Table 2.
Table 2 stability test results
Figure BDA0002326622970000101
Compared with the prior art, the crystal form provided by the invention has good stability. Can better avoid crystal transformation and impurity generation in the process of medicine storage and development, thereby avoiding the change of bioavailability and efficacy. The crystal forms obtained in examples 2 to 10 have the same stabilizing effect as the crystal form obtained in example 1.
2. Solubility determination
Taking the crystal form product obtained in example 1 as an example, the solubility of the crystal form or amorphous sample related in the prior art is measured and compared.
The crystal form of the invention and a sample prepared by the prior art are dissolved by simulated intestinal fluid (FeSSIF), Simulated Gastric Fluid (SGF) and water respectively at room temperature, and the solubility of the crystal form and the sample is measured. The results of the experiment are shown in table 3.
TABLE 3 determination of solubility
Figure BDA0002326622970000111
It can be seen that the solubility of the crystalline form of the present invention is higher than that of the crystalline form of the prior art. Pidotimod and histidine salification promote the dissolution of the pidotimod, and the analysis shows that the reason may be that the imidazolyl group of the histidine can dissociate protons, the concentration of the dissociated protons is close to that of water, and the salification of the histidine and the pidotimod still has the capacity of serving as a proton donor and a proton acceptor, so that the pidotimod is promoted to have high solubility in simulated intestinal fluid and simulated gastric acid. The crystal forms obtained in examples 2 to 10 have the same effects as those of the crystal form obtained in example 1.

Claims (10)

1. A pidotimod histidine salt crystal form is characterized in that Cu-Kalpha radiation is used, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 9.3 +/-0.2 degrees, 15.1 +/-0.2 degrees, 17.1 +/-0.2 degrees, 18.8 +/-0.2 degrees, 20.9 +/-0.2 degrees, 23.8 +/-0.2 degrees, 29.6 +/-0.2 degrees and 30.6 +/-0.2 degrees.
2. The crystalline form of claim 1, having an X-ray diffraction pattern, expressed in terms of 2 Θ, using Cu-ka radiation, characterized by characteristic peaks at 9.3 ± 0.2 °, 15.1 ± 0.2 °, 17.1 ± 0.2 °, 18.8 ± 0.2 °, 20.9 ± 0.2 °, 21.9 ± 0.2 °, 22.3 ± 0.2 °, 23.8 ± 0.2 °, 29.6 ± 0.2 °, 30.6 ± 0.2 °, 34.0 ± 0.2 °, 41.7 ± 0.2 °.
3. The crystalline form of claim 1, having an X-ray diffraction pattern, expressed in terms of 2 Θ, using Cu-ka radiation, characterized by characteristic peaks at 9.3 ± 0.2 °, 15.1 ± 0.2 °, 17.1 ± 0.2 °, 18.8 ± 0.2 °, 20.9 ± 0.2 °, 21.9 ± 0.2 °, 22.3 ± 0.2 °, 23.8 ± 0.2 °, 29.6 ± 0.2 °, 30.4 ± 0.2 °, 30.6 ± 0.2 °, 31.9 ± 0.2 °, 33.4 ± 0.2 °, 34.0 ± 0.2 °, 37.5 ± 0.2 °, 39.7 ± 0.2 °, 41.7 ± 0.2 °.
4. The crystalline form of claim 1, characterized by the use of Cu-ka radiation and having characteristic peaks according to the X-ray powder diffraction pattern shown in figure 1; the crystalline form has the TGA and DSC analysis diagrams shown in figure 2.
5. A method for preparing the crystal form of any one of claims 1 to 4, which is characterized by comprising the following steps:
dissolving pidotimod in an organic solvent A, dissolving histidine in an equal mole in purified water, dropwise adding a histidine aqueous solution into the pidotimod solution at room temperature, cooling, crystallizing, filtering, and drying in vacuum to constant weight to obtain the pidotimod histidine salt and the crystal form thereof.
6. The method for preparing the crystal form according to claim 5, wherein in the step (a), the organic solvent A is one or a mixed solvent of at least two of acetone, methanol, ethanol, isopropanol and acetonitrile.
7. The preparation method of the crystalline form according to claim 5, wherein in the step (a), the mass-to-volume ratio of pidotimod and the organic solvent A in the system is 1: 20 to 100, wherein the mass is in g and the volume is in ml.
8. The method for preparing the crystalline form according to claim 5, wherein in the step (a), the mass-to-volume ratio of histidine to water in the system is 1: 10-15, wherein the mass is in g and the volume is in ml.
9. The preparation method of the crystal form according to claim 5, wherein in the step, the temperature for cooling and crystallization is 0-20 ℃; the drying temperature is 30-100 ℃.
10. A pharmaceutical composition, said composition comprising: (a) the crystalline form of any one of claims 1-4, and (b) a pharmaceutically acceptable carrier.
CN201911318940.4A 2019-12-19 2019-12-19 Pidotimod histidine salt crystal form and preparation method thereof Pending CN113004265A (en)

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