CN110003195B - Lurasidone crystal, preparation method thereof and application thereof in injection drug delivery system - Google Patents
Lurasidone crystal, preparation method thereof and application thereof in injection drug delivery system Download PDFInfo
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Abstract
The invention relates to the technical field of medicines, and discloses a lurasidone crystal, a preparation method thereof and application thereof in an injection drug delivery system. The method comprises the following steps: dissolving lurasidone and pamoic acid in tetrahydrofuran to obtain a first mixed solution; adding ethyl acetate into the first mixed solution, stirring, heating for reaction, and cooling to room temperature to obtain a second mixed solution; and (3) spin-drying the second mixed solution, adding ethyl acetate, crystallizing with dichloromethane, separating out crystals, and filtering. The equilibrium solubility of the pamoic acid lurasidone crystal is 0.12-73 mu g/ml at pH2.0-7.8, the absolute change value of the solubility is small, the general trend is stable, the influence of pH value is avoided, and the pH dependency is avoided.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a lurasidone pamoate crystal, a lurasidone pamoate nanocrystal and preparation methods and applications thereof.
Background
Lurasidone hydrochloride (Lurasidone hydrochloride) is a novel anti-schizophrenia drug discovered by Dainippon Sumitomo pharmacy, and FDA approves oral tablets to be sold on the market in 10 months 2010. Lurasidone hydrochloride has higher affinity with dopamine D2 receptor and 5-HT2A receptor, and also has higher affinity with 5-HT7, 5-HT1A and α c adrenergic receptor subtypes.
The lurasidone hydrochloride is chemically named aS (3aR,4S,7R,7aS) -2- [ (1R,2R) -2- (4- (1, 2-phenylpropionyl isothiazole-3-yl) piperazine-1-ylmethyl) cyclohexylmethyl ] hexahydro-4, 7-methylisoindole-1, 3-dione hydrochloride, is white to off-white crystal powder, is slightly soluble in methanol, slightly soluble in ethanol and very slightly soluble in water and acetone, belongs to a BCSII medicament in the biological pharmaceutical classification, and has the characteristics of low solubility and high permeability.
Lurasidone hydrochloride solubility is greatly affected by pH, exhibits a certain pH dependence in the pH range of 2.0-6.8, and exhibits a maximum solubility at pH 3.8, about 0.78 mg/ml. When the pH value is more than 3.8, the solubility is smaller and smaller along with the increase of the pH value, and the solubility is only 0.007mg/ml at the pH value of 6.8. The pH of gastric acid in a human body is about 2.0, the pH of intestinal juice is about 6.8, the bioavailability of lurasidone hydrochloride is seriously reduced due to the lower solubility of lurasidone hydrochloride in the pH environment of the gastrointestinal tract, and the absolute bioavailability in the human body is 9-19%. Therefore, lurasidone hydrochloride is also the current schizophrenia treatment drug with the largest administration dosage (the maximum specification is 120mg), and the lurasidone hydrochloride is taken together with food to improve the absorption in clinical use.
At present, the technical scheme for improving the solubility of lurasidone focuses on preparing novel lurasidone hydrochloride crystals or amorphous. For example, the Chinese patent application 201310066819.3 discloses a lurasidone hydrochloride crystal form, a preparation method and application thereof, but the patent only discloses characteristic parameters of the prepared lurasidone hydrochloride crystal, no crystal transformation phenomenon in the processes of storage, grinding and the like, and does not disclose data of solubility improvement. The Chinese patent application 201310071135.2 discloses three new crystal forms of lurasidone hydrochloride A, B, C and a preparation method thereof, the solubility of the prepared lurasidone hydrochloride crystal under the acidic conditions of water and pH2.0 is respectively 3.4mg/ml and 8.0mg/ml, the solubility difference is about 4.6mg/ml, the difference is large, and the characteristic that the release rate of ideal injection raw materials does not have dependence on pH does not exist. Secondly, the solubility of the lurasidone hydrochloride crystals in the pH range of the gastrointestinal tract is not disclosed, so that the effects of the release, absorption process and diet on the lurasidone hydrochloride crystals and the real improvement of bioavailability cannot be completely reflected.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a lurasidone pamoate crystal, a lurasidone pamoate nanocrystal, and preparation methods and applications thereof. Preparing lurasidone into a lurasidone pamoate crystal, wherein the solubility of the lurasidone crystal is basically unchanged within a pH range of 2.0-7.8, and the solubility of the lurasidone crystal is about 0.07mg/ml at the maximum within the pH range; the injection prepared from the prepared pamoic acid lurasidone crystal can improve absolute bioavailability and has a long-acting slow-release effect.
The invention provides a lurasidone pamoate crystal which is radiated by Cu-K α, and an X-ray powder diffraction spectrum expressed by 2 theta has diffraction peaks at 9.327 degrees, 10.961 degrees, 15.296 degrees, 18.354 degrees, 18.801 degrees, 19.152 degrees, 21.185 degrees, 21.968 degrees, 23.096 degrees, 24.893 degrees, 25.989 degrees, 29.564 degrees and 33.771 degrees.
Preferably, the solubility of the pamoic acid lurasidone crystal is 0.12-73 mu g/ml between pH 2-7.8.
Preferably, the solubility of the pamoic acid lurasidone crystal is 46-73 mu g/ml between pH 7-7.4.
The invention also provides a pimaric acid lurasidone nanocrystal which is radiated by Cu-K α, and an X-ray powder diffraction spectrum expressed by 2 theta has diffraction peaks at 9.696 degrees, 15.610 degrees, 17.274 degrees, 19.184 degrees, 19.461 degrees, 19.818 degrees, 20.407 degrees, 21.225 degrees, 22.099 degrees, 23.263 degrees, 24.672 degrees, 25.304 degrees, 26.305 degrees, 27.909 degrees, 29.356 degrees, 29.898 degrees, 32.171 degrees, 33.353 degrees, 35.015 degrees, 35.296 degrees, 36.160 degrees, 39.510 degrees, 40.426 degrees, 44.955 degrees, 54.213 degrees and 59.310 degrees.
Preferably, the particle size of the pamoic acid lurasidone nanocrystal is 250-500 nm.
The invention also provides a preparation method of the pamoic acid lurasidone crystal, which comprises the following steps:
(1) dissolving lurasidone and pamoic acid in tetrahydrofuran to obtain a first mixed solution;
(2) adding ethyl acetate into the first mixed solution, stirring, heating for reaction, and cooling to room temperature to obtain a second mixed solution;
(3) and (3) adding ethyl acetate after the second mixed solution is dried in a spinning mode, crystallizing by using dichloromethane, separating out crystals, and filtering to obtain the pamoic acid lurasidone crystals.
Preferably, the molar ratio of lurasidone to pamoic acid in step (1) is 1: 1-1.2.
Preferably, the reaction is carried out for 2-3h in the step (2) by heating to 55-60 ℃.
The invention also provides a preparation method of the pamoic acid lurasidone nanocrystal, which comprises the following steps:
(a) preparing a lurasidone pamoate crystal according to the method;
(b) dissolving a stabilizer in purified water, adding the lurasidone pamoate crystal, and stirring to obtain a premixed suspension;
(c) and adding the premixed suspension into a high-pressure homogenizer, and circulating under the pressurization of 200-1000bar to obtain the pamoic acid lurasidone nanocrystal suspension.
Preferably, the method further comprises:
(d) adding a freeze-drying protective agent into the pamoic acid lurasidone nanocrystal suspension, and then placing the suspension in a low-temperature refrigerator for freezing;
(e) and (3) placing the frozen sample in a freeze dryer, and freeze-drying to obtain the pamoic acid lurasidone nanocrystal.
Preferably, the stabilizer is at least one of poloxamer 188, povidone K12, sodium lauryl sulfate and sodium lauryl sulfate.
Preferably, the mass concentration of poloxamer 188 is 0.1% (W/V).
Preferably, the pressure for high-pressure homogenization in the step (c) is 400-800 bar.
Preferably, the lyoprotectant is mannitol, more preferably 3-6% by weight mannitol.
Preferably, the temperature in the low temperature refrigerator in step (d) is-80 ± 5 ℃.
The invention also provides a pharmaceutical composition which contains the pamoic acid lurasidone crystal or the pamoic acid lurasidone nano crystal and pharmaceutically acceptable auxiliary materials.
Preferably, the pharmaceutical composition is a pamoic acid lurasidone injection.
The invention also provides application of the pamoic acid lurasidone crystal or the pamoic acid lurasidone nano crystal in preparation of medicines for treating schizophrenia.
Compared with the prior art, the technical scheme of the invention has the following advantages:
(1) the equilibrium solubility of the pamoic acid lurasidone crystal is 0.12-73 mu g/ml at pH2.0-7.8, the absolute change value of the solubility is small, the general trend is stable, the influence of pH value is avoided, and the pH dependency is avoided.
(2) The pamoic acid lurasidone crystal has the equilibrium solubility of 46-73 mu g/ml at the pH value of 7.0-7.8 (the pH value of human blood is 7.1-7.4), and the absolute change value of the solubility is smaller and the influence of the pH value is small.
(3) The pamoic acid lurasidone crystal has small solubility at pH7.0-7.8, and the maximum solubility is only 73 mu g/ml, has the property of preparing long-acting injection, and creates a prerequisite for the long-acting lurasidone injection.
(4) The pamoic acid lurasidone nanocrystal can improve the solubility of the pamoic acid lurasidone and increase the drug loading rate of a drug; the injection prepared by applying the prepared pamoic acid lurasidone nano-crystal has a slow release function.
Drawings
Fig. 1 shows an equilibrium solubility curve of a pamoic acid lurasidone crystal.
Fig. 2 shows an equilibrium solubility curve of lurasidone hydrochloride.
FIG. 3 shows an X-ray powder diffraction pattern of a crystal of pamoic acid lurasidone.
FIG. 4 shows an X-ray powder diffraction pattern of the pamoic acid lurasidone nanocrystals.
FIG. 5 is a differential scanning calorimetry diagram of a crystal of pamoic acid lurasidone.
FIG. 6 shows a differential scanning calorimetry diagram of a lurasidone pamoate nanocrystal.
FIG. 7 is a graph showing the particle size of a lurasidone pamoate nanocrystal.
FIG. 8 shows in vitro release profiles of lumasidone pamoate and lumasidone nanocrystals.
Detailed Description
The following describes in detail specific embodiments of the present invention. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
The pamoic acid lurasidone crystal is radiated by Cu-K α, and an X-ray powder diffraction spectrum expressed by 2 theta has diffraction peaks at 9.327 degrees, 10.961 degrees, 15.296 degrees, 18.354 degrees, 18.801 degrees, 19.152 degrees, 21.185 degrees, 21.968 degrees, 23.096 degrees, 24.893 degrees, 25.989 degrees, 29.564 degrees and 33.771 degrees.
In a preferred case, the solubility of the lurasidone pamoate crystals is 0.12-73. mu.g/ml at a pH of 2-7.8, and specifically, for example, 0.12. mu.g/ml, 0.25. mu.g/ml, 1.6. mu.g/ml, 2.3. mu.g/ml, 4. mu.g/ml, 5. mu.g/ml, 6. mu.g/ml, 8. mu.g/ml, 11. mu.g/ml, 18. mu.g/ml, 20. mu.g/ml, 25. mu.g/ml, 30. mu.g/ml, 35. mu.g/ml, 40. mu.g/ml, 46. mu.g/ml, 50. mu.g/ml, 55. mu.g/ml, 60. mu.g/ml, 68. mu.g/ml, 70. mu.g/ml or 73. mu.g/ml. Further preferably, the solubility of the pamoic acid lurasidone crystal is 46-73 μ g/ml between pH 7-7.4.
In a more preferred embodiment, the pamoic acid lurasidone crystals are pamoic acid lurasidone nanocrystals that have diffraction peaks at 9.696 °, 15.610 °, 17.274 °, 19.184 °, 19.461 °, 19.818 °, 20.407 °, 21.225 °, 22.099 °, 23.263 °, 24.672 °, 25.304 °, 26.305 °, 27.909 °, 29.356 °, 29.898 °, 32.171 °, 33.353 °, 35.015 °, 35.296 °, 36.160 °, 39.510 °, 40.426 °, 44.955 °, 54.213 °, 59.310 ° in an X-ray powder diffraction spectrum expressed in 2 θ irradiated with Cu-K α.
Further preferably, the particle size of the pamoic acid lurasidone nanocrystal is 250-500nm, and specifically, the particle size can be 250nm, 260nm, 270nm, 280nm, 290nm, 300nm, 310nm, 320nm, 330nm, 350nm, 380nm, 400nm, 420nm, 460nm, 480nm or 500 nm.
The preparation method of the pamoic acid lurasidone crystal comprises the following steps:
(1) dissolving lurasidone and pamoic acid in tetrahydrofuran to obtain a first mixed solution;
(2) adding ethyl acetate into the first mixed solution, stirring, heating for reaction, and cooling to room temperature to obtain a second mixed solution;
(3) and (3) adding ethyl acetate after the second mixed solution is dried in a spinning mode, crystallizing by using dichloromethane, separating out crystals, and filtering to obtain the pamoic acid lurasidone crystals.
In step (1), the molar ratio of lurasidone to pamoic acid may be 1: 1-1.2, most preferably 1: 1.
in step (2), preferably, heating to 55-60 ℃ for reaction for 2-3 h.
The preparation method of the pamoic acid lurasidone nanocrystal comprises the following steps:
(a) preparing a lurasidone pamoate crystal according to the method;
(b) dissolving a stabilizer in purified water, adding the lurasidone pamoate crystal, and stirring to obtain a premixed suspension;
(c) and adding the premixed suspension into a high-pressure homogenizer, and circulating under the pressurization of 200-1000bar to obtain the pamoic acid lurasidone nanocrystal suspension.
In a more preferred embodiment, the method further comprises:
(d) adding a freeze-drying protective agent into the pamoic acid lurasidone nanocrystal suspension, and then placing the suspension in a low-temperature refrigerator for freezing;
(e) and (3) placing the frozen sample in a freeze dryer, and freeze-drying to obtain the pamoic acid lurasidone nanocrystal.
In the present invention, the stabilizer may be a conventional choice in the art. Preferably, the stabilizer is at least one of poloxamer 188, povidone K12, sodium lauryl sulfate and sodium lauryl sulfate. When poloxamer 188 is selected as the stabilizing agent, preferably, the mass concentration of poloxamer 188 is 0.1% (W/V).
In the step (c), the pressure for high-pressure homogenization may be 400-800bar, specifically, 400bar, 450bar, 500bar, 550bar, 600bar, 650bar, 700bar, 750bar or 800 bar.
In step (d) above, the lyoprotectant used is preferably mannitol. More preferably, mannitol is used at a concentration of 3-6 wt.%, most preferably at a concentration of 5 wt.%.
In the above step (d), the temperature in the low temperature refrigerator may be-80 ± 5 ℃, most preferably-80 ℃.
The pharmaceutical composition contains the pamoic acid lurasidone crystal or the pamoic acid lurasidone nano crystal and pharmaceutically acceptable auxiliary materials. The pharmaceutically acceptable excipients are conventional choices in the art.
The dosage form of the pharmaceutical composition is not particularly limited, and may be various dosage forms well known in the art. In a specific embodiment, the pharmaceutical composition is a pamoic acid lurasidone injection.
The pamoic acid lurasidone crystal or the pamoic acid lurasidone nanocrystal can be used for treating schizophrenia. Therefore, the pamoic acid lurasidone crystal or the pamoic acid lurasidone nanocrystal can be used for preparing a medicine for treating schizophrenia.
The following examples are intended only to further illustrate the present invention and should not be construed as limiting the invention. Modifications or substitutions to methods, procedures, or conditions of the invention may be made without departing from the spirit and scope of the invention.
The raw materials used in the examples of the present invention and the comparative examples are commercially available products.
Example 1
This example illustrates the preparation of a crystal of lurasidone pamoate.
1g lurasidone and 788mg pamoic acid are dissolved in 20ml tetrahydrofuran, then 20ml ethyl acetate is added, and after 2h reaction at 60 ℃, spin-drying is carried out. 10ml of ethyl acetate and 5ml of dichloromethane are added, and after crystallization, the product pamoic acid lurasidone A1 is obtained by filtration.
Example 2
This example illustrates the preparation of a crystal of lurasidone pamoate.
1g lurasidone and 788mg pamoic acid are dissolved in 30ml tetrahydrofuran, 10ml ethyl acetate are added, reaction is carried out at 55 ℃ for 3h, and then spin-drying is carried out. Adding 15ml of ethyl acetate and 8ml of dichloromethane, and filtering after crystallization to obtain the product pamoic acid lurasidone A2. The product was dried under vacuum at 50 ℃ and stored in a glass bottle at room temperature, dry and protected from light.
Example 3
This example illustrates the preparation of nanoparticles of lurasidone pamoate.
Weighing 0.1g of poloxamer 188, dissolving the poloxamer 188 in 100ml of purified water, adding 55mg of pamoic acid lurasidone A1, and stirring to obtain a premixed suspension; and adding the premixed suspension into a high-pressure homogenizer, and circulating for 18 times under the pressure of 400bar to obtain the pamoic acid lurasidone nanocrystal suspension.
Example 4
This example was used to prepare a pamoic acid lurasidone injection.
The formula for preparing the pamoic acid lurasidone injection is shown in table 1.
TABLE 1
| Pamoic acid lurasidone crystal A1 | 10g |
| |
1g |
| Polyethylene glycol 4000 | 3g |
| Citric acid | 0.5g |
| Disodium hydrogen phosphate | 0.5g |
| Sodium hydroxide | Adjusting pH to 6.8 |
| Water for injection | To 100ml |
The preparation method comprises the following steps:
dissolving 1g polysorbate 80 in 20ml water for injection, transferring the solution through a 0.2 μm sterile filter into a sterilized stainless steel container; dispersing 10g of the lurasidone pamoate crystal into 40ml of water for injection, grinding for 4 hours, and filtering the suspension into a stainless steel container through a 40-micron sterile filter; taking 20ml of water for injection, sequentially adding 0.5g of citric acid, 0.5g of disodium hydrogen phosphate and 3g of polyethylene glycol 4000, uniformly mixing, filtering the solution into a stainless steel container through a sterile filter of 0.2 mu m, uniformly mixing, adjusting the pH to 6.8 by using a sterile NaOH solution, adding the water for injection to 100ml, and finally, aseptically filling into a sterile syringe.
Examples of the experiments
Experimental example 1
X-ray powder diffraction analysis of pamoic acid lurasidone crystal
The measuring method comprises the steps of measuring by using a Cu-K α target of an X-ray diffractometer, wherein the current is 40mA, the voltage is 40kV, the scanning speed is 10 DEG/min, the step size is 0.02 DEG, the scanning range is 3-60 DEG, and the characteristic peak is expressed by the angle of 2 theta.
And (3) measuring results: characteristic peaks are found at 9.327 °, 10.961 °, 15.296 °, 18.354 °, 18.801 °, 19.152 °, 21.185 °, 21.968 °, 23.096 °, 24.893 °, 25.989 °, 29.564 °, 33.771 °. The resulting X-ray powder diffractogram is shown in FIG. 3.
The X-ray powder diffraction analysis result shows that the pamoic acid lurasidone is in a crystalline state.
Experimental example 2
X-ray powder diffraction analysis of pamoic acid lurasidone nanocrystals
The measuring method comprises the steps of measuring by using a Cu-K α target of an X-ray diffractometer, wherein the current is 40mA, the voltage is 40kV, the scanning speed is 10 DEG/min, the step size is 0.02 DEG, the scanning range is 3-60 DEG, and the characteristic peak is expressed by the angle of 2 theta.
And (3) measuring results: characteristic peaks are found at 9.696 °, 15.610 °, 17.274 °, 19.184 °, 19.461 °, 19.818 °, 20.407 °, 21.225 °, 22.099 °, 23.263 °, 24.672 °, 25.304 °, 26.305 °, 27.909 °, 29.356 °, 29.898 °, 32.171 °, 33.353 °, 35.015 °, 35.296 °, 36.160 °, 39.510 °, 40.426 °, 44.955 °, 54.213 °, 59.310 °. The resulting X-ray powder diffractogram is shown in FIG. 4.
Experimental example 3
Differential scanning calorimetry analysis of lurasidone pamoate crystals
The determination method comprises the following steps: and (2) putting the 2mg of the pamoic acid lurasidone crystal into an aluminum pot, wherein the scanning speed is 10 ℃/min, the nitrogen flow rate is 20mL/min, and the scanning temperature range is 25-400 ℃.
And (3) measuring results: the pimaric acid lurasidone crystal has an exothermic peak at 365 ℃. Differential scanning calorimetry analysis results show that the pamoic acid lurasidone crystals exist in a crystal form. The differential scanning calorimetry analysis map is shown in FIG. 5.
Experimental example 4
Differential scanning calorimetry analysis of pamoic acid lurasidone nanocrystals
The determination method comprises the following steps: and (2) putting the 2mg of the pamoic acid lurasidone crystal into an aluminum pot, wherein the scanning speed is 10 ℃/min, the nitrogen flow rate is 20mL/min, and the scanning temperature range is 25-400 ℃.
And (3) measuring results: two exothermic peaks of the pamoic acid lurasidone nanocrystal at 166 ℃ and 365 ℃ are measured. The differential scanning calorimetry analysis map is shown in FIG. 6.
Experimental example 5
Infrared spectroscopic analysis of lurasidone pamoate crystals
The determination method comprises the following steps: respectively taking a small amount of pamoic acid lurasidone nanocrystals, grinding, fully mixing with KBr, grinding, tabletting, and placing in a spectrometer for scanning infrared absorption. The infrared spectrum is 400-4000cm-1In the wavelength range of 4cm-1The resolution of (2).
And (3) measuring results: infrared spectrum at 3282cm-1the-NH bond stretching vibration peak appeared nearby. 2961cm-1-CH bond stretching vibration peak. 1250-1140 cm-1The absorption peak is C-C skeleton vibration peak. 1680cm-1The absorption peak at (b) is a C ═ 0 (amide) stretching vibration peak. 1600cm-1、1500cm-1The absorption peak is the stretching vibration of the aromatic ring skeleton. 1300-900 cm-1The absorption peak is C-S single bond stretching vibration peak. 860-800 cm-1The absorption peak is a para-disubstituted structure of aromatic ring, 770cm-1The absorption peak is ortho-disubstituted structure of aromatic ring. 900-860 cm-1，810～750cm-1，710～690cm-1The absorption peak is the meta-disubstituted structure of the aromatic ring. Absorption peak 1651cm-1The peak is the free carboxylic acid C ═ O stretching vibration peak in pamoic acid, 1561cm-1A stretching vibration peak of carboxylate C ═ O can be observed. The pamoic acid lurasidone nano crystal is a novel lurasidone crystal.
Experimental example 6
Nuclear magnetic resonance analysis of lurasidone pamoate crystals
The determination method comprises the following steps: dissolving appropriate amount of lurasidone moxanolate nanocrystal in DMSO-d6And then measured by a 300MHz nuclear magnetic instrument.
And (3) measuring results: the pimaric acid lurasidone crystal has a methyl proton peak at delta-0.9, a six-membered ring methylene proton peak at delta-1.89, a methylene unsaturated carbon-carbon double bond proton peak at delta-2.7-3.9, a benzene ring proton peak at delta-6.5-8, and a six-membered ring amide proton peak at delta-8.2. The peak is the characteristic proton peak of pamoic acid methylene at the position of delta-4.7. δ ═ 8.35 is the proton peak of the primary amine salt, and no chemical shifts were observed for the free carboxyl proton peak and the free primary amino proton peak. The pamoic acid lurasidone nano crystal is a novel lurasidone crystal.
Experimental example 7
Determination of equilibrium solubility of pamoic acid lurasidone crystal
10mg of the pamoic acid lurasidone crystals are precisely weighed each time and respectively placed in a glass bottle filled with 10ml of phosphate buffer solution with pH of 2.0, 3.0, 3.8, 4.5, 5.0, 5.5, 6.0, 6.8, 7.4 and 7.8, so as to obtain a 1mg/ml pamoic acid lurasidone solution. The solution is placed in a water bath kettle at 37 ℃ to be stirred, and a sample is taken out after 24 hours of dissolution and balance and is filtered by a 0.22 mu m filter membrane. And (3) diluting the filtrate, and measuring the absorbance value of the filtrate, wherein the measurement wavelength is 235 nm.
The measured solubility (. mu.g/ml) of the lurasidone pamoate crystals in solutions with different pH values are shown in Table 2 below. The equilibrium solubility curve of the pamoic acid lurasidone crystal is shown in figure 1.
TABLE 2
The result shows that the solubility of the pamoic acid lurasidone is slightly increased along with the increase of the pH value, the maximum solubility is about 73 mu g/ml, and the general trend is stable; the pamoic acid lurasidone is extremely difficult to dissolve, the equilibrium solubility is 46-73 mu g/ml at the pH value of 7.0-7.8, the absolute change value of the solubility is about 27 mu g/ml, and the influence of the pH value is small.
Experimental example 8
Determination of lurasidone hydrochloride equilibrium solubility
Precisely weighing 10mg of lurasidone hydrochloride each time, and respectively placing the lurasidone hydrochloride into glass bottles filled with 10ml of phosphate buffer solution with pH of 2.0, 3.0, 3.8, 4.5, 5.0, 5.5, 6.0 and 6.8 to obtain 1mg/ml lurasidone hydrochloride solution. The solution is placed in a water bath kettle at 37 ℃ to be stirred, and a sample is taken out after 24 hours of dissolution and balance and is filtered by a 0.22 mu m filter membrane. And (4) diluting the filtrate, and measuring the absorbance value of the diluted filtrate, wherein the measurement wavelength is 258 nm.
The measured solubilities (mg/ml) of lurasidone hydrochloride in solutions of different pH values are shown in Table 3 below. The lurasidone hydrochloride equilibrium solubility curve is shown in fig. 2.
TABLE 3
| pH | 2.0 | 3.0 | 3.8 | 4.5 | 5.0 | 5.5 | 6.0 | 6.8 |
| Solubility C (mg/ml) | 0.18 | 0.51 | 0.78 | 0.61 | 0.31 | 0.25 | 0.012 | 0.007 |
The results show that the solubility of lurasidone hydrochloride is the greatest in the range of pH 2.0-6.8 and at pH 3.8; the lurasidone hydrochloride has pH dependency, and the solubility is smaller and smaller along with the increase of the pH value when the pH value is more than 3.8.
Experimental example 9
Particle size and potential analysis of pamoic acid lurasidone nanocrystals
The determination method comprises the following steps: the prepared pamoic acid nanocrystal suspension is diluted to a proper concentration by using distilled water, and the average particle size, the polydispersity index and the Zeta potential are measured by using a Malvern particle sizer. The average particle size, polydispersity and Zeta potential were determined by the same method as described above after redissolving the nanocrystal lyophilized powder.
The measured properties of the pamoic acid lurasidone nanocrystals are shown in table 4.
TABLE 4
| Parameter(s) | Nanocrystal suspensions | After re-dissolving the nano crystal freeze-dried powder |
| Average particle diameter (nm) | 298.2 | 310.4 |
| PDI | 0.257 | 0.231 |
| Zeta potential (mv) | -25.3 | -26.3 |
The particle size of the prepared pamoic acid lurasidone nano crystal is about 298.2 nm. The distribution is uniform and narrow, and the PDI is less than 0.3. The potential measurement result shows that the surface of the nano crystal has negative charges, the absolute value of the potential is more than 25mv, and the potential of the system is relatively stable. The particle size of the nanocrystal lyophilized powder after reconstitution is slightly increased, and other parameters are not obviously changed. The particle size diagram of the pamoic acid lurasidone nanocrystals is shown in fig. 7.
Experimental example 10
Stability investigation test of pamoic acid lurasidone nanocrystal
The particle size is taken as an evaluation index, the physical stability of the pamoic acid lurasidone nano suspension at 4 ℃ is examined, and the storage form of the pamoic acid lurasidone long-acting injection is preliminarily determined. Meanwhile, the physical stability of the pamoic acid lurasidone nanosuspension at 37 ℃ is examined to predict the in vitro release stability of the pamoic acid lurasidone long-acting injection, and the results are shown in the following table 5.
Table 5: the change of the particle size and the character of the pamoic acid lurasidone under different storage conditions
The experimental result shows that the physical stability of the pamoic acid lurasidone nanosuspension is good when the pamoic acid lurasidone nanosuspension is stored for 30 days at the temperature of 4 ℃, and the particle size is slightly increased along with the increase of the standing time. Compared with the particle size of 0, the pamoic acid lurasidone nano suspension stored for 30 days at 37 ℃, has the advantages that the average particle size is increased by about 50nm, the physical stability is good, the redispersibility is good, and the more stable drug release degree can be obtained.
Experimental example 11
In vitro release degree of different forms of pamoic acid lurasidone
The dialysis bag method is used for determining the in vitro release degree of the pamoic acid lurasidone. 501.1mg of the pamoic acid lurasidone (marked as LPM), 3.2g of the pamoic acid lurasidone freeze-dried powder with the particle size of 286.4nm (which is about equivalent to 513.6mg of the original pamoic acid lurasidone and marked as NCPs1) and 5.3g of the pamoic acid lurasidone freeze-dried powder with the particle size of 462.7nm (which is about equivalent to 501.8mg of the original pamoic acid lurasidone and marked as NCPs2) are precisely weighed. Placing the particles in dialysis bags with the diameter of 22mm and the length of about 10cm respectively, removing air in the bags, fastening two ends by using a cord, coiling and fixing the particles on a stirring paddle of a dissolution instrument, placing the stirring paddle at a position which is about 1.5cm away from the bottom of a dissolution cup, using 900ml of buffer solution with the pH of 7.4 as the temperature of the dissolution medium (37.0 +/-0.5) DEG C, and sampling 2ml of the stirring paddle at regular time (simultaneously adding the release medium with the same volume) at 0.5h, 1.0h, 2.0h, 4.0h, 6.0h, 8.0h, 12.0h, 24.0h, 36.0h, 48.0h, 72h, 144h and 192h when the rotation speed of the stirring paddle reaches 50r/min, filtering the samples by using a 0.45 mu m microporous filter membrane, taking continuous sample injection, recording peak areas, and calculating the cumulative release percentage of the pamoic acid lurasidone at each time. The cumulative drug release profile is plotted with release rate as ordinate and time as abscissa, as detailed in figure 8. The results of the experiments are shown in Table 6 below. The degree of release and the cumulative percent release are calculated as follows:
the release rate (Q)%, actual release total amount/drug total amount × 100%
C is the concentration of the release solution, V is the volume of the release medium, and D is the dilution multiple;
w is the weight of the medicine, and F is the mass percentage content of the active ingredients in the medicine.
Table 6: in vitro release degree results of pamoic acid lurasidone and pamoic acid lurasidone nanocrystals
The results in table 6 show that the in vitro release rate of the lurasidone pamoate nanocrystals (NCPs1) with the particle size of 286.4nm is greater than that of the lurasidone pamoate bulk drug powder (LPM) and the lurasidone pamoate nanocrystals (NCPs2) with the particle size of 462.7nm, which indicates that the solubility and dissolution rate of the drug are significantly improved due to the reduction of the particle size when the drug is prepared into a nanosuspension. And the release amount of the pamoic acid lurasidone nanocrystal freeze-dried powder with the particle size of 286.4nm in each time period is stable, and no burst release phenomenon exists. The fact that most of the pamoic acid lurasidone nanocrystals are amorphous structures and few of the pamoic acid lurasidone nanocrystals are polycrystalline structures shows that compared with a large number of the polycrystalline structures in the bulk pharmaceutical chemicals, the pamoic acid lurasidone nanocrystals have higher solubility and dissolution rate, and the difference between the solubility and the dissolution rate is caused due to different molecular spatial arrangements of different crystal forms. The polymorphic structure has a unit cell structure and higher lattice energy, and higher energy is required for changing the polymorphic structure into a molecular state, so that the polymorphic structure has low solubility and low dissolution rate. However, the amorphous microstructure is a disordered assembly of molecules or atoms and is easy to dissolve or dissolve out to become a molecular state, so that the pamoic acid lurasidone nanocrystal improves the solubility and the in vitro release rate.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (17)
1. A pamoic acid lurasidone crystal is characterized in that the pamoic acid lurasidone crystal is irradiated by Cu-K α, and an X-ray powder diffraction spectrum expressed by 2 theta has diffraction peaks at 9.327 degrees, 10.961 degrees, 15.296 degrees, 18.354 degrees, 18.801 degrees, 19.152 degrees, 21.185 degrees, 21.968 degrees, 23.096 degrees, 24.893 degrees, 25.989 degrees, 29.564 degrees and 33.771 degrees;
the solubility of the pamoic acid lurasidone crystal is 0.12-73 mu g/ml between pH 2-7.8.
2. The crystalline pamoic acid lurasidone according to claim 1, wherein the solubility of the crystalline pamoic acid lurasidone is 46-73 μ g/ml between pH 7-7.4.
3. A pamoic acid lurasidone nanocrystal is characterized in that the pamoic acid lurasidone nanocrystal is irradiated by Cu-K α, and an X-ray powder diffraction spectrum expressed by 2 theta has diffraction peaks at 9.696 degrees, 15.610 degrees, 17.274 degrees, 19.184 degrees, 19.461 degrees, 19.818 degrees, 20.407 degrees, 21.225 degrees, 22.099 degrees, 23.263 degrees, 24.672 degrees, 25.304 degrees, 26.305 degrees, 27.909 degrees, 29.356 degrees, 29.898 degrees, 32.171 degrees, 33.353 degrees, 35.015 degrees, 35.296 degrees, 36.160 degrees, 39.510 degrees, 40.426 degrees, 44.955 degrees, 54.213 degrees and 59.310 degrees;
the particle size of the pamoic acid lurasidone nanocrystal is 250-500 nm.
4. A method for preparing the crystalline lurasidone pamoate as set forth in claim 1, comprising the steps of:
(1) dissolving lurasidone and pamoic acid in tetrahydrofuran to obtain a first mixed solution;
(2) adding ethyl acetate into the first mixed solution, stirring, heating for reaction, and cooling to room temperature to obtain a second mixed solution;
(3) and (3) adding ethyl acetate after the second mixed solution is dried in a spinning mode, crystallizing by using dichloromethane, separating out crystals, and filtering to obtain the pamoic acid lurasidone crystals.
5. The process of claim 4, wherein the molar ratio of lurasidone to pamoic acid in step (1) is 1: 1-1.2.
6. The method of claim 4 or 5, wherein the heating to 55-60 ℃ in step (2) is performed for 2-3 h.
7. A method of preparing the lurasidone pamoate nanocrystals as recited in claim 3, comprising the steps of:
(a) preparing a crystal of lurasidone pamoate according to the process of any of claims 4 to 6;
(b) dissolving a stabilizer in purified water, adding the lurasidone pamoate crystal, and stirring to obtain a premixed suspension;
(c) and adding the premixed suspension into a high-pressure homogenizer, and circulating under the pressurization of 200-1000bar to obtain the pamoic acid lurasidone nanocrystal suspension.
8. The method of claim 7, further comprising:
(d) adding a freeze-drying protective agent into the pamoic acid lurasidone nanocrystal suspension, and then placing the suspension in a low-temperature refrigerator for freezing;
(e) and (3) placing the frozen sample in a freeze dryer, and freeze-drying to obtain the pamoic acid lurasidone nanocrystal.
9. The method of claim 7 or 8, wherein the stabilizer is at least one of poloxamer 188, povidone K12, sodium lauryl sulfate, and sodium lauryl sulfate.
10. The method of claim 9, wherein the poloxamer 188 is present at a mass concentration of 0.1% (W/V).
11. The method as claimed in claim 9, wherein the pressure for high-pressure homogenization in step (c) is 400-800 bar.
12. The method of claim 9, wherein the lyoprotectant is mannitol.
13. The method of claim 12, wherein the lyoprotectant is 3-6% by weight mannitol.
14. The method of claim 9, wherein the temperature in the cryogenic refrigerator in step (d) is-80 ± 5 ℃.
15. A pharmaceutical composition comprising the crystal of claim 1 or 3 and a pharmaceutically acceptable excipient.
16. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is a pamoic acid lurasidone injection.
17. Use of the lurasidone pamoate crystals as set forth in claim 1 or the lurasidone pamoate nanocrystals as set forth in claim 3 for the preparation of a medicament for the treatment of schizophrenia.
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