Pretreatment method and application of mirabegron resin compound

Abstract

The invention discloses a pretreatment method and application of a mirabegron resin compound, and relates to the pretreatment method of the mirabegron resin compound, which comprises the following steps: extracting the mirabegron resin compound by an extraction solvent to obtain a sample to be detected for detection; wherein the extraction solvent comprises an aprotic solvent, an ionized solvent and a counter-ion solvent. According to the method, a multi-factor synergistic strategy is adopted, the extraction time of mirabegron in the mirabegron resin compound is remarkably shortened, the medicine extraction efficiency is remarkably improved, the extraction method is high in recovery rate, meanwhile, comprehensive optimization of quality is ensured, a foundation is laid for accurate determination of the medicine content, the consistency of the medicine effect is ensured, and the method is suitable for large-scale popularization and application. The requirements of links such as drug research and development, production and quality control are met.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a pretreatment method of mirabegron resin complex and application thereof. BACKGROUND

[0002] Ion-exchange Resin (IER) is a water-insoluble polymer containing acidic or basic functional groups. It forms a reversible weak ionic bond with counter-charged drugs through ion exchange, and can release free drugs according to the ion environment. When the drug repeatedly contacts the resin, the drug is loaded on the resin, and then the drug is released by the charged ions in the gastrointestinal tract. At the same time, IER cannot be absorbed by the human body, so there is no food safety problem for oral administration. In recent decades, ion-exchange resins have been widely studied for the delivery of oral drugs, mainly to mask the bitter taste of drugs, stabilize sensitive drugs, and control drug release.

[0003] Taking mirabegron sustained-release dry suspension as an example, mirabegron belongs to β3-adrenergic receptor agonists. There are β3-adrenergic receptors in the human bladder detrusor muscle. When mirabegron binds to these receptors, it can activate the intracellular signaling pathway, relax the bladder detrusor muscle, and help improve urinary control and improve symptoms such as urgency incontinence. However, the short half-life and low bioavailability of mirabegron reduce its clinical efficacy, so in the development of mirabegron preparations, ion exchange resin is used as the core excipient to prepare mirabegron-resin complex through ion exchange reaction to form mirabegron sustained-release preparation. This sustained-release preparation achieves sustained release of the drug through ion exchange in body fluids, ultimately achieving the purpose of reducing the frequency of drug administration and improving efficacy. After the mirabegron-resin complex enters the human body, it relies on ions in the body fluid (such as sodium ions and hydrogen ions) to exchange ions to release the drug. Its working principle is as follows:

[0004]

[0005] The drug-resin complex has a porous structure due to the ion exchange resin, and the diffusion speed of drug ions in these pores is relatively slow. When the complex is in contact with the surrounding medium, the drug ions first diffuse in the pores inside the resin particles, and then are released from the surface of the resin to the external medium. The diffusion speed of drug ions depends on factors such as the pore size of the resin, the size and properties of the drug ions, and the properties of the surrounding medium. By adjusting the pore structure of the resin and the binding mode of the drug and the resin, the diffusion speed of the drug ions can be controlled, and thus the sustained-release effect of the drug can be achieved. At the same time, the network structure of the resin and the charge distribution on its surface can hinder the release of drug ions. Therefore, through the synergy of ion exchange, diffusion, and barrier, the ion exchange resin complex can achieve the release of the target drug.

[0006] Therefore, in the quality control of the drug-resin complex preparation, the ion exchange reaction has a bidirectional nature, and when the drug is extracted, the drug ions that have been separated from the resin can be recombined with the resin in reverse, greatly hindering the complete extraction of the drug. Furthermore, the ion exchange resin is composed of a cross-linked polymer skeleton and active groups, and its complex structure, pores and self-barrier hinder the diffusion of drug ions, and the charge distribution and steric hindrance further reduce the displacement rate.

[0007] Therefore, the drug extraction problem needs to be overcome in the quality control of the drug-resin complex preparation. Otherwise, problems such as inaccurate drug quantification and unsatisfactory drug quality and safety can easily occur. For example, the target drug content is lower than the labeled amount, the drug is difficult to reach the effective blood drug concentration, and the expected therapeutic effect cannot be achieved, which delays the patient's condition; and the target drug content is higher than the specified amount, the blood drug concentration is too high, the risk of adverse reactions such as organ damage and allergy is greatly increased, and the life safety is endangered. Therefore, it is necessary to develop an efficient and accurate drug extraction method. SUMMARY

[0008] The present application aims to at least solve one of the above-mentioned technical problems in the prior art. To this end, the purpose of the present application is to provide a pretreatment method for mirabegron resin complex and its application.

[0009] In order to achieve the above-mentioned purpose, the technical solution adopted by the present application is:

[0010] In a first aspect of the present application, a pretreatment method for mirabegron resin complex is provided, comprising the following steps:

[0011] The extraction solvent extracts the mirabegron resin complex to obtain a sample to be tested for detection; wherein the extraction solvent comprises an aprotic solvent, an ionized solvent and a counter-ion solvent.

[0012] In some embodiments of the present application, the ionized solvent comprises ethanol and / or methanol.

[0013] In some embodiments of the present application, the aprotic solvent comprises acetonitrile.

[0014] In some embodiments of the present application, the counter-ion solvent comprises a potassium chloride solution.

[0015] In some embodiments of the present application, in the extraction solvent, the volume ratio of the ionized solvent is 10% to 15%.

[0016] In some embodiments of the present application, the volume ratio of the aprotic solvent, the ionized solvent and the counter-ion solvent is (4-6):(1-1.5):(3.5-5).

[0017] In some embodiments of the present application, the concentration of the potassium chloride solution is 0.8-1.6 mol / L.

[0018] In some embodiments of the present application, the pH of the extraction solvent is 7-9.

[0019] In some embodiments of the present application, the extraction time is ≤1 hour.

[0020] In some embodiments of the present application, the extraction of the mirabegron resin complex by the extraction solvent comprises the following steps:

[0021] The extraction solvent is added to the mirabegron resin complex to obtain a mixed solution.

[0022] The mixed solution is extracted by water bath ultrasonic to obtain a sample to be tested.

[0023] In some embodiments of the present application, the water bath temperature is 30-60℃.

[0024] In some embodiments of the present application, the frequency of the ultrasonic is 30-50 Hz.

[0025] In some embodiments of the present application, the mass-volume ratio of the mirabegron resin complex to the extraction solvent is 0.1%-0.25% (g / mL).

[0026] In a second aspect of the present application, a method for detecting the content of mirabegron in mirabegron sustained-release dry suspension is provided, comprising the following steps:

[0027] The pretreatment method of the mirabegron resin complex as described above is used.

[0028] The sample to be tested is detected by high performance liquid chromatography.

[0029] The present application has the following beneficial effects:

[0030] The present application uses the strategy of increasing the concentration of counter ions to effectively inhibit the reverse reaction in the extraction of mirabegron resin complex, ensuring the forward progress during the extraction process. At the same time, the non-protic solvent is introduced to accelerate the breaking of hydrogen bonds between mirabegron and resin, promote the rapid dissociation of the drug, and weaken the binding force between them. In addition, the ionized solvent is used to strengthen the ionization of counter ion solvent in the system, further strengthen the driving force of ion exchange forward reaction, thereby greatly improving the dissociation efficiency of mirabegron. In this way, through the synergistic effect of multiple media, the complete extraction of mirabegron from the mirabegron resin complex is realized, and the extraction quality is significantly improved.

[0031] The application adopts a multi-factor synergistic strategy, significantly reduces the extraction time of milabegron in the milabegron resin complex, significantly improves the drug extraction efficiency, has high recovery rate of the extraction method, simultaneously ensures overall optimization of quality, lays a foundation for accurate determination of drug content, ensures consistency of drug efficacy, and meets the needs of drug research and development, production and quality control and the like. DETAILED DESCRIPTION

[0032] The content of the application is further described in detail through specific examples. The raw materials, reagents or devices used in the examples and comparative examples can be obtained from conventional commercial channels or can be obtained by prior art methods, unless otherwise specified. Unless otherwise specified, the test or test method is a conventional method in the art.

[0033] In the application, when a numerical range is involved, the above numerical range is considered to be continuous and includes the minimum value and the maximum value of the range and each value between the minimum value and the maximum value, unless otherwise specified. Further, when the range refers to an integer, each integer between the minimum value and the maximum value of the range is included. In addition, when multiple ranges are provided to describe a feature or a characteristic, the ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all sub-ranges incorporated therein.

[0034] In a first aspect of the application, a pretreatment method of a milabegron resin complex is provided, comprising the following steps:

[0035] The extraction solvent extracts the milabegron resin complex to obtain a sample to be tested for detection; wherein the extraction solvent comprises an aprotic solvent, an ionized solvent and a counter-ion solvent.

[0036] In the application, the counter-ion solvent can continuously exchange in the detection system and inhibit the reverse operation of the ion reaction; the aprotic solvent can promote the breaking of the hydrogen bond between milabegron and resin in the drug resin complex, promote the rapid dissociation of milabegron, and weaken the binding force of the two; and the ionized solvent can effectively promote the ionization of the counter-ion solvent in the system, so that the milabegron continuously dissociates.

[0037] According to some embodiments of the present application, the concentration of the counter-ion solvent is 0.8-1.6 mol / L, such as 0.9-1.5 mol / L, 1.0-1.4 mol / L, 1.0-1.2 mol / L, etc. If the concentration of the counter-ion solvent is too low, the counter-ion is replaced into the resin in the later stage of ion exchange, resulting in the concentration of cations in the resin being greater than the concentration of anions in the solution, and the exchange reaction proceeds in the reverse direction, so as to reach the ion concentration balance, leading to incomplete extraction of mirabegron; when the concentration of the counter-ion solvent is even lower, the reverse exchange capacity is lost, which will also cause incomplete extraction of mirabegron. When the concentration of the counter-ion is too high, the counter-ion preferentially combines with the active sites of the resin, resulting in a decrease in the extraction rate of mirabegron; in addition, in the process of ion exchange, the counter-ion needs to diffuse from the solution bulk to the surface of the resin (liquid film diffusion), and then diffuse to the inside of the resin (pore diffusion); when the concentration of the counter-ion is too high, the total ion concentration in the solution increases, leading to an increase in the viscosity of the solution, a decrease in the Brownian motion of the ions, a decrease in the liquid film diffusion rate, and thus a slowdown of the overall exchange rate.

[0038] According to some embodiments of the present application, the ionized solvent comprises ethanol and / or methanol.

[0039] According to some embodiments of the present application, in the extraction solvent, the volume ratio of the ionized solvent is 10%-15%. In the present application, when the concentration of the ionized solvent is too low, the counter-ion in the counter-ion solvent cannot be in an ionized state in the extraction solvent, which is not conducive to the dissociation of mirabegron. When the concentration of the ionized solvent is too high, the ionic strength in the system increases, which easily leads to compression of the double electric layer on the surface of the resin, thereby affecting the adsorption of ions and reducing the exchange efficiency.

[0040] According to some embodiments of the present application, the ionized solvent can comprise methanol or ethanol alone; or can comprise both methanol and ethanol, and the volume ratio of the two is not limited, such as 0.1%-99.9%, 1%-99%, 10%-90%, 20%-80%, 30%-70%, 40%-60%, 50%, etc.

[0041] According to some embodiments of the present application, the aprotic solvent comprises acetonitrile.

[0042] According to some embodiments of the present application, the counter-ion solvent comprises a potassium chloride solution.

[0043] According to some embodiments of the present application, the volume ratio of the aprotic solvent, the ionized solvent and the counter-ion solvent is (4-6):(1-1.5):(3.5-5).

[0044] According to some embodiments of the present application, the volume percentage of the aprotic solvent in the extraction solvent is 40% to 60%, such as 40% to 55%, 45% to 55%, etc. In the present application, too low a content of the aprotic solvent cannot promote the breaking of the hydrogen bond between mirabegron and the resin, reducing the extraction efficiency; too high a content of the aprotic solvent can inhibit the ionization of the counter ion in the system, causing incomplete extraction of mirabegron.

[0045] According to some embodiments of the present application, the pH of the extraction solvent is 7 to 9; such as 7.5, 8.0, 8.5, etc. In the present application, the pH of the extraction solvent affects the direction of the ion exchange reaction, and a pH of 7 to 9 can inhibit the reverse of the ion exchange reaction. In the later stage of the dissociation reaction of the drug-resin complex, the complex dissociates into mirabegron and a blank resin, and the reaction will displace a large amount of hydrogen ions, causing mirabegron to recombine with the resin, which can easily cause incomplete extraction of mirabegron; in an alkaline or neutral environment, the hydroxyl ion will undergo a neutralization reaction with the displaced hydrogen ion, effectively reducing the hydrogen ion concentration in the system, thereby inhibiting the reverse of the ion exchange reaction and ensuring the effective extraction of the drug.

[0046] According to some embodiments of the present application, an alkali can be used to adjust the pH of the extraction solvent to 7 to 9; the alkali includes inorganic alkali and / or alkali salt; the inorganic alkali is, for example, sodium hydroxide, potassium hydroxide, ammonia, etc.; the alkaline salt is, for example, sodium carbonate, potassium carbonate, sodium bicarbonate, etc.

[0047] According to some embodiments of the present application, the extraction time is ≤1 hour, such as 45 min.

[0048] According to some embodiments of the present application, the mass-volume ratio of the mirabegron-resin complex to the extraction solvent is 0.1% to 0.25% (g / mL).

[0049] According to some embodiments of the present application, the mirabegron-resin complex comprises mirabegron and an ion exchange resin. The ion exchange resin comprises a pharmacologically inert organic and / or inorganic matrix containing ionized or ionizable functional groups under appropriate pH conditions. The organic matrix can be synthetic, such as but not limited to: homopolymers or copolymers of acrylic acid, methacrylic acid, sulfonated styrene, sulfonated divinylbenzene; or partially synthetic, such as but not limited to: modified cellulose and dextran. The inorganic matrix includes but is not limited to silica gel modified by the addition of ionic groups. The covalently bound ionic groups can be strongly acidic (such as sulfonic acid, phosphoric acid), weakly acidic (such as carboxylic acid), or acidic and basic groups. The ion exchange resin of the present application is a cation exchange resin, specifically, the cation exchange resin has a polymer matrix with anionic functional groups.

[0050] According to some embodiments of the present invention, a cation exchange resin is used to complex with the active agent. The cation exchange resin may be sodium polystyrene sulfonate or calcium polystyrene sulfonate.

[0051] According to some embodiments of the present invention, the mirabegron resin complex is a mirabegron-sodium polystyrene sulfonate complex or a mirabegron-calcium polystyrene sulfonate complex.

[0052] According to some embodiments of the present invention, in the mirabegron resin complex, the mass ratio of mirabegron to ion exchange resin is 1:(2-3), such as 1:2, 1:2.2, 1:2.4, 1:2.6, 1:2.8, or 1:3.

[0053] According to some embodiments of the present invention, the extraction solvent extracts the mirabegron resin complex, comprising the following steps:

[0054] adding the extraction solvent to the mirabegron resin complex to obtain a mixed solution;

[0055] The mixed solution was extracted by water bath ultrasound to obtain the sample to be tested.

[0056] In the present invention, the extraction solvent can effectively and fully extract mirabegron from the drug-resin complex for subsequent mirabegron content detection. Ultrasound has a certain energy, which not only accelerates the diffusion rate of drug ions in the solution, but also imparts a certain amount of energy to the ions, breaking some of the bonds in the resin complex and promoting the dissociation of mirabegron. Furthermore, the mechanical vibration caused by ultrasound can accelerate the relative motion between the ion exchange complex and the extraction solvent, thereby accelerating the diffusion rate of drug ions in the solution.

[0057] According to some embodiments of the present invention, the water bath temperature is 30° C. to 60° C., such as 40° C. to 60° C. In the present invention, ultrasonic extraction at this temperature can accelerate the thermal motion of mirabegron ions, enhance their detachment kinetic energy, increase their diffusion coefficient, and promote ion dissociation.

[0058] According to some embodiments of the present invention, the frequency of the ultrasound is 30 Hz to 50 Hz, such as 40 Hz; and the ultrasound power is 90% to 100%.

[0059] According to some embodiments of the present invention, the detection method includes at least one of high performance liquid chromatography (HPLC), ultraviolet-visible spectrophotometry, gas chromatography, mass spectrometry, titration, capillary electrophoresis, near-infrared spectroscopy, Raman spectroscopy, and biotitration.

[0060] The second aspect of the present invention provides a method for detecting the content of mirabegron in a mirabegron sustained-release dry suspension, comprising the following steps:

[0061] The pretreatment method of mirabegron resin complex is as described above.

[0062] The sample to be detected is detected by high performance liquid chromatography.

[0063] According to some embodiments of the present application, in the high performance liquid chromatography detection, the conditions of high performance liquid chromatography include:

[0064] Chromatographic column: octadecylsilane bonded silica gel column;

[0065] Mobile phase: buffer solution as mobile phase A, acetonitrile as mobile phase B; the volume ratio of mobile phase A to mobile phase B is (70-90):(10-30); the pH of the buffer solution is 1.0-2.5 (such as 1.0-1.5); the buffer solution includes perchloric acid and sodium hydroxide;

[0066] Elution mode: isocratic elution;

[0067] Column temperature: 35-45℃;

[0068] Flow rate: 0.8-1.2 mL / min;

[0069] Injection volume: 8-50 μL;

[0070] Detection wavelength: 230-270 nm.

[0071] The following examples and comparative examples use commercially available mirabegron sustained-release dry suspension (manufacturer: Astellas Pharma US, Inc., specification: 8 mg / mL, 100 mL / bottle / box), the core excipient of which is a cation exchange resin-polystyrene sodium sulfonate, and the API mirabegron and the polystyrene sodium sulfonate form a mirabegron resin complex through ion exchange reaction.

[0072] Example 1

[0073] In this embodiment, mirabegron sustained-release dry suspension is pretreated, and the specific process is as follows:

[0074] S1: Mix acetonitrile, ethanol and 1.6 M potassium chloride solution according to the volume ratio of 45%, 10% and 45%, and adjust the pH to 8.0 with sodium hydroxide solution to prepare an extraction solvent.

[0075] S2: Weigh 50 mg of mirabegron sustained-release dry suspension into a 50 mL volumetric flask, add 40% of the volume of the extraction solvent, and then ultrasonicate at 40℃ (ultrasonic frequency is 40 Hz, power is 100%) for 1 h. After cooling to room temperature, dilute to the mark with the extraction solvent, shake well, and then obtain a solution containing 0.1 mg / mL of mirabegron.

[0076] Example 2

[0077] The pre-treatment of mirabegron sustained-release dry suspension is carried out in this example, and the difference from example 1 is that the volume ratio of acetonitrile, ethanol, 1.6M potassium chloride solution is 40%, 10%, 50%, and the rest is carried out according to example 1.

[0078] Example 3

[0079] The pre-treatment of mirabegron sustained-release dry suspension is carried out in this example, and the difference from example 1 is that the volume ratio of acetonitrile, ethanol, 1.6M potassium chloride solution is 55%, 10%, 35%, and the rest is carried out according to example 1.

[0080] Example 4

[0081] The pre-treatment of mirabegron sustained-release dry suspension is carried out in this example, and the difference from example 1 is that the volume ratio of acetonitrile, ethanol, 1.6M potassium chloride solution is 45%, 12%, 43%, and the rest is carried out according to example 1.

[0082] Example 5

[0083] The pre-treatment of mirabegron sustained-release dry suspension is carried out in this example, and the difference from example 1 is that the volume ratio of acetonitrile, ethanol, 1.6M potassium chloride solution is 40%, 15%, 45%, and the rest is carried out according to example 1.

[0084] Example 6

[0085] The pre-treatment of mirabegron sustained-release dry suspension is carried out in this example, and the difference from example 1 is that the concentration of potassium chloride solution is 0.8M, and the rest is carried out according to example 1.

[0086] Example 7

[0087] The pre-treatment of mirabegron sustained-release dry suspension is carried out in this example, and the difference from example 1 is that ethanol is replaced by methanol, and the rest is carried out according to example 1.

[0088] Example 8

[0089] The pre-treatment of mirabegron sustained-release dry suspension is carried out in this example, and the difference from example 1 is that the pH is 7.0, and the rest is carried out according to example 1.

[0090] Example 9

[0091] The pre-treatment of mirabegron sustained-release dry suspension is carried out in this example, and the difference from example 1 is that the pH is 9.0, and the rest is carried out according to example 1.

[0092] Example 10

[0093] The mirabegron sustained-release dry suspension is pretreated in this example, and the difference from Example 1 is that the extraction solvent volume in the extraction process is 60%, and the rest is carried out according to Example 1.

[0094] Example 11

[0095] The mirabegron sustained-release dry suspension is pretreated in this example, and the difference from Example 1 is that the constant temperature in the extraction process is 60°C, and the rest is carried out according to Example 1.

[0096] Example 12

[0097] The mirabegron sustained-release dry suspension is pretreated in this example, and the difference from Example 1 is that the constant temperature in the extraction process is 30°C, and the rest is carried out according to Example 1.

[0098] Example 13

[0099] The mirabegron sustained-release dry suspension is pretreated in this example, and the difference from Example 1 is that the ultrasonic time in the extraction process is 45 min, and the rest is carried out according to Example 1.

[0100] Comparative Example 1

[0101] The mirabegron sustained-release dry suspension is pretreated in this example, and the specific process is:

[0102] 50 mg of mirabegron sustained-release dry suspension is weighed into a 50 mL volumetric flask, 50% of the volumetric flask volume of 0.1 M hydrochloric acid is added, and then ultrasonic treatment (ultrasonic frequency is 40 Hz, power is 100%) is carried out for 1 h. After cooling to room temperature, the extraction solvent is diluted to the mark, and then shaken uniformly to obtain the product.

[0103] Comparative Example 2

[0104] The mirabegron sustained-release dry suspension is pretreated in this example, and the specific process is:

[0105] 50 mg of mirabegron sustained-release dry suspension is weighed into a 50 mL volumetric flask, 50% of the volumetric flask volume of 0.1 M hydrochloric acid is added, and then ultrasonic treatment (ultrasonic frequency is 40 Hz, power is 100%) is carried out for 1 h. After cooling to room temperature, the extraction solvent is diluted to the mark, and then shaken uniformly to obtain the product.

[0106] Comparative Example 3

[0107] The mirabegron sustained-release dry suspension is pretreated in this example, and the specific process is:

[0108] Take 50 mg of mirabegron sustained-release dry suspension in a 50 mL volumetric flask, add 50% of the volume of the extraction solvent (acetonitrile, 0.4M sodium chloride solution, the volume ratio is 50%, 50%) in the volumetric flask, ultrasonic (ultrasonic frequency is 40 Hz, power is 100%) in the ultrasonic instrument for 1h, cool to room temperature, dilute to the mark with the extraction solvent, shake well, then get.

[0109] Comparative Example 4

[0110] The comparative example pretreats the mirabegron sustained-release dry suspension, and the specific process is as follows:

[0111] Take 50 mg of mirabegron sustained-release dry suspension in a 50 mL volumetric flask, add 50% of the volume of the extraction solvent (acetonitrile, 0.4M sodium chloride solution, the volume ratio is 50%, 50%) in the volumetric flask, ultrasonic (ultrasonic frequency is 40 Hz, power is 100%) in the ultrasonic instrument for 1h, cool to room temperature, dilute to the mark with the extraction solvent, shake well, then get.

[0112] Comparative Example 5

[0113] The example pretreats the mirabegron sustained-release dry suspension, and the specific process is as follows:

[0114] Take 50 mg of mirabegron sustained-release dry suspension in a 50 mL volumetric flask, add 50% of the volume of the extraction solvent (acetonitrile, 0.4M sodium chloride solution, the volume ratio is 50%, 50%) in the volumetric flask, ultrasonic (ultrasonic frequency is 40 Hz, power is 100%) in the ultrasonic instrument for 1h, cool to room temperature, dilute to the mark with the extraction solvent, shake well, then get.

[0115] Comparative Example 6

[0116] The comparative example pretreats the mirabegron sustained-release dry suspension, and the specific process is as follows:

[0117] Take 50 mg of mirabegron sustained-release dry suspension in a 50 mL volumetric flask, add 50% of the volume of the extraction solvent (acetonitrile, 0.4M sodium chloride solution, the volume ratio is 50%, 50%) in the volumetric flask, ultrasonic (ultrasonic frequency is 40 Hz, power is 100%) in the ultrasonic instrument for 1h, cool to room temperature, dilute to the mark with the extraction solvent, shake well, then get.

[0118] Comparative Example 7

[0119] The comparative example pretreats the mirabegron sustained-release dry suspension, and the specific process is as follows:

[0120] Take 50 mg of mirabegron sustained-release dry suspension in a 50 mL volumetric flask, add 50% of the volume of the extraction solvent (acetonitrile, methanol, 1.6M potassium chloride solution, the volume ratio is 30%, 10%, 60%, pH = 7.0) to the volumetric flask, and then ultrasonic (ultrasonic frequency is 40 Hz, power is 100%) in a constant temperature ultrasonic instrument at 40°C for 1 h. After cooling to room temperature, dilute to the mark with the extraction solvent, shake well, and then obtain.

[0121] Comparative Example 8

[0122] In this comparative example, mirabegron sustained-release dry suspension was pretreated, and the specific process was as follows:

[0123] Take 50 mg of mirabegron sustained-release dry suspension in a 50 mL volumetric flask, add 50% of the volume of the extraction solvent (acetonitrile, methanol, 1.6M potassium chloride solution, the volume ratio is 30%, 10%, 60%, pH = 7.0) to the volumetric flask, and then ultrasonic (ultrasonic frequency is 40 Hz, power is 100%) in a constant temperature ultrasonic instrument at 40°C for 1 h. After cooling to room temperature, dilute to the mark with the extraction solvent, shake well, and then obtain.

[0124] Comparative Example 9

[0125] In this comparative example, mirabegron sustained-release dry suspension was pretreated, and the specific process was as follows:

[0126] Take 50 mg of mirabegron sustained-release dry suspension in a 50 mL volumetric flask, add 50% of the volume of the extraction solvent (acetonitrile, methanol, 1.6M potassium chloride solution, the volume ratio is 30%, 10%, 60%, pH = 7.0) to the volumetric flask, and then ultrasonic (ultrasonic frequency is 40 Hz, power is 100%) in a constant temperature ultrasonic instrument at 40°C for 1 h. After cooling to room temperature, dilute to the mark with the extraction solvent, shake well, and then obtain.

[0127] Comparative Example 10

[0128] In this comparative example, mirabegron sustained-release dry suspension was pretreated, and the specific process was as follows:

[0129] Take 50 mg of mirabegron sustained-release dry suspension in a 50 mL volumetric flask, add 50% of the volume of the extraction solvent (acetonitrile, methanol, 1.6M potassium chloride solution, the volume ratio is 30%, 10%, 60%, pH = 7.0) to the volumetric flask, and then ultrasonic (ultrasonic frequency is 40 Hz, power is 100%) in a constant temperature ultrasonic instrument at 40°C for 1 h. After cooling to room temperature, dilute to the mark with the extraction solvent, shake well, and then obtain.

[0130] The mirabegron extraction recovery rate of the pretreatment of Examples 1-13 and Comparative Examples 1-10 was detected, and the specific process was as follows:

[0131] Preparation of reference solution: 25 mg of mirabegron reference substance was precisely weighed into a 25 mL volumetric flask, 20 mL of the extraction solvent prepared in Example 1 was added to dissolve the substance under ultrasonic condition (ultrasonic frequency of 40 Hz, power of 100%), and then diluted to the mark with the extraction solvent. 1 mL of the above solution was transferred into a 10 mL volumetric flask and diluted to the mark with the extraction solvent, thus obtaining the reference solution. Two solutions were prepared in parallel. The acceptable standard for recovery rate was 95.0% to 105.0%.

[0132] Preparation of sample solution: the sample to be tested of each example and comparative example.

[0133] Detection: the reference solution and the sample solution were subjected to chromatographic detection, and the chromatographic conditions were as follows:

[0134] The chromatographic column was an octadecylsilane-bonded silica gel column (4.6 mm x 15 cm, 3 μm; packing L1), isocratic elution was performed with a buffer solution: acetonitrile (80:20, v / v) as the eluent, the column temperature was 40°C, the flow rate was 1.0 mL / min, the injection volume was 10 μL, and the detection wavelength was 250 nm. The buffer solution was prepared as follows: a solution containing 8.7 mL / L of perchloric acid and 3.0 g / L of sodium hydroxide was prepared, and the pH was adjusted to 2.0 with 1M sodium hydroxide solution.

[0135] The specific parameters and recovery results of the examples and comparative examples are shown in Table 1.

[0136] Table 1 Specific parameters and recovery results of examples and comparative examples

[0137]

[0138]

[0139] From the above results, it can be seen from Examples 1 to 3 that increasing the proportion of aprotic solvent within the scope of the present application can promote the rapid dissociation of mirabegron and weaken the binding force between the two, so that the recovery rate of mirabegron extraction is improved; as can be seen from Examples 1, 4 and 7, when the ionic solvent is replaced by ethanol or methanol, the recovery rate of mirabegron extraction is also above 99%; as can be seen from Example 5 relative to Example 1, increasing the volume of ethanol and the volume of extraction solvent, and increasing the concentration of the counterion solvent from 1.6 M to 0.8 M in Examples 1 and 6 can sufficiently inhibit the reverse operation of the ion reaction, thereby improving the recovery rate of mirabegron extraction.

[0140] The pH is 7-9, and the mirabegron extraction recovery rate is also above 99% in Example 1, Examples 8-9; as can be seen from Example 1 and Example 10, increasing the amount of the extraction solvent within the scope of the present application is conducive to the sufficient mixing of the mirabegron resin complex and the extraction solvent, thereby further improving the extraction recovery rate; the mirabegron extraction recovery rate is also above 98% in Example 1, Examples 11-12, and Example 13, which uses different extraction temperatures and an extraction time of 45 min, and the extraction recovery rate is within the extraction recovery rate range (98.02%-102.01%).

[0141] As can be seen from the above, the mirabegron resin complex in Example 1-13 is extracted by using the extraction solvent containing the aprotic solvent, the ionized solvent and the counter-ion solvent according to the present application, and the mirabegron extraction recovery rate is high, which is within the content analysis extraction recovery rate range of 98.02%-102.01%, indicating that the mirabegron in the resin complex in the mirabegron sustained-release dry suspension can be completely extracted according to the present application, and the extraction time is short, which is 45 min to 1 h, and the extraction efficiency is high.

[0142] The mirabegron extraction recovery rate is between 18.15%-54.79% in Comparative Example 1 and Comparative Example 2, which uses other counter-ion types (hydrogen ion, sodium ion) of the extraction solvent; the mirabegron extraction recovery rate is about 70% in Comparative Example 3 and Comparative Example 4, which does not contain the ionized solvent; the mirabegron extraction recovery rate is 81.37% in Comparative Example 5, which uses the extraction solvent with a pH that is too high, and the mirabegron cannot be completely extracted; the mirabegron extraction recovery rate is 57.38% in Comparative Example 6, which uses the counter-ion with a high concentration and does not contain the ionized solvent, and the counter-ion and the resin active site and the solution viscosity increase, resulting in a decrease in the mirabegron displacement rate; the mirabegron extraction recovery rate is low in Comparative Example 7, which does not contain the aprotic solvent, and the mirabegron dissociation is slow, and the binding force with the resin is also strong; the aprotic solvent accounts for a small proportion in Comparative Example 8 and Comparative Example 9, which is not conducive to the breaking of the hydrogen bond between the mirabegron and the resin, and the extraction efficiency is low; the ionized solvent accounts for a small proportion in Comparative Example 10, which cannot make the counter-ion in the counter-ion solvent present in the ionic state in the extraction solvent, and is not conducive to the dissociation of the mirabegron. In summary, the extraction solvent and the extraction method in the comparative examples cannot completely extract the mirabegron in the drug complex, thereby making it difficult to achieve the purpose of effectively detecting the mirabegron.

[0143] Therefore, the pretreatment method for the mirabegron resin complex (such as the mirabegron sustained-release dry suspension) provided by the present application can significantly improve the extraction efficiency, shorten the extraction time, and ensure complete extraction, thereby laying a foundation for the accurate determination of the content of the drug.

[0144] The above embodiments are the preferred embodiments of the present application, but the embodiments of the present application are not limited to the above embodiments, and any changes, modifications, substitutions, combinations, simplifications, etc. made without departing from the spirit and principles of the present application should be equivalent replacement manners and should be included in the protection scope of the present application.

Claims

1. A pretreatment method for a mirabegron resin complex, characterized in that: The following steps are involved: The extraction solvent is used to extract the mirabegron resin complex to obtain a test sample for detection; wherein the extraction solvent includes an aprotic solvent, an ionized solvent, and a counterion solvent.

2. The pretreatment method of the mirabegron resin complex according to claim 1, characterized in that: The ionizing solvent includes ethanol and / or methanol.

3. The pretreatment method of the mirabegron resin complex according to claim 2, characterized in that: In the extraction solvent, the volume proportion of the ionized solvent is 10% to 15%.

4. The pretreatment method of the mirabegron resin complex according to claim 3, characterized in that: The volume ratio of the aprotic solvent, the ionized solvent and the counterion solvent is (4-6): (1-1.5): (3.5-5).

5. The pretreatment method of the mirabegron resin complex according to claim 4, characterized in that: The aprotic solvent comprises acetonitrile; and / or, The counter ion solvent includes potassium chloride solution.

6. The pretreatment method of the mirabegron resin complex according to claim 5, characterized in that: The concentration of the potassium chloride solution is 0.8 to 1.6 mol / L; and / or, The pH of the extraction solvent is 7 to 9; and / or, The extraction time is ≤ 1 hour.

7. The pretreatment method of the mirabegron resin complex according to any one of claims 1 to 6, characterized in that: The extraction solvent extracts the mirabegron resin complex, comprising the following steps: adding the extraction solvent to the mirabegron resin complex to obtain a mixed solution; The mixed solution was extracted by water bath ultrasound to obtain the sample to be tested.

8. The pretreatment method of the mirabegron resin complex according to claim 7, characterized in that: The water bath temperature is 30°C to 60°C; and / or, The frequency of ultrasound is 30Hz~50Hz.

9. The pretreatment method of the mirabegron resin complex according to any one of claims 1 to 6, characterized in that: The mass volume ratio of the mirabegron resin complex to the extraction solvent is 0.1%-0.25% (g / mL).

10. A method for detecting the content of mirabegron in a mirabegron sustained-release dry suspension, comprising the following steps: The pretreatment method of the mirabegron resin complex according to any one of claims 1 to 9 is adopted; The samples were detected by high performance liquid chromatography.

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