CN118453513A - A preparation process of a liquid preparation of a β-lactamase inhibitor - Google Patents

Abstract

The present invention discloses a preparation process of a liquid preparation of a β-lactamase inhibitor. The preparation process disclosed in the present invention comprises preparing a liquid preparation of a β-lactamase inhibitor by high-pressure homogenization of a suspension of a β-lactamase inhibitor, wherein the pressure of the high-pressure homogenization is 1-30K psi; the high-pressure homogenization cycle is 3-57 times; and the equipment for the high-pressure homogenization is a high-pressure homogenizer or a microfluidizer. The liquid preparation of the β-lactamase inhibitor obtained by the preparation process of the present invention is placed under natural light conditions at 25°C for 24 hours, and there is no significant change in concentration and total impurity content.

Description

A preparation process of a liquid preparation of a β-lactamase inhibitor

Technical Field

The invention relates to a preparation process of a beta-lactamase inhibitor liquid preparation.

Background Art

β-lactam antibiotics have always been the first choice of antibacterial agents in clinical practice, but the efficacy of related antibiotics is currently affected by bacterial β-lactamases, which can cause resistance to penicillins, extended-spectrum cephalosporins, monolactams and carbapenems. In order to address β-lactamase-mediated resistance, β-lactamase inhibitors have been introduced into clinical practice, greatly enhancing the efficacy of β-lactams in the treatment of bacterial infections (Clin Microbiol Rev. 2010 Jan; 23(1): 160-201). Antibiotic resistance caused by β-lactamases poses more challenges to the efficacy of β-lactam drugs and the types of antibiotics used in clinical practice. In the past three decades, only a few β-lactamase inhibitors have been introduced to the market (Medchemcomm. 2018 Aug17; 9(9): 1439-1456). β-lactamase inhibitors are clinically available as single-dose and multiple-dose injections, and can also be used in combination with other antimicrobial drugs. However, the β-lactamase inhibitors shown in the following general formula are poorly soluble small molecule drugs, and the drugs are easily precipitated during the storage and use of the injection solution, and have poor stability, which is not conducive to combined use with other antibacterial drugs.

The dissolution strategy of poorly soluble drugs is an important issue that needs to be considered in the application of the pharmaceutical industry. Researchers and professionals have explored many methods to try to solve such problems. For example, the dissolution of nateglinide (a lipophilic insoluble drug) is improved by nanoparticle and blending technology (Int J Pharm. 2013 Sep 15; 454 (1): 562-7); by freezing liquid into spray micro powder products, the physical stability is enhanced to improve the solubility of insoluble drugs (Pharm Dev Technol. 2003; 8 (2): 187-97), etc. Although these methods have been proven to increase the solubility of drugs, these methods currently have great limitations: they can only be applied to small-dose production, the process methods are relatively complex, and the time cycle for developing formulations is long. At present, it is still necessary to consider relatively mature preparation processes to better solve such problems.

High-pressure homogenization technology is mainly used in the biological and pharmaceutical industries. It is a process in which a homogenizer is used to break up the solid substances in nanoemulsions, liposomes, and nanosuspensions to make the solid particles ultrafine and form a uniform suspended emulsion. Generally, through the mechanical forces such as high-speed shearing, high-frequency oscillation, cavitation, and convection impact and the corresponding thermal effects, the solubility of insoluble compounds is improved, and the materials are well evenly distributed.

The forces commonly used in homogenization processes are mainly shear force and pressure. The homogenizers commonly used in the pharmaceutical and biological industries are mainly high-pressure homogenizers and micro-jet homogenizers. High-pressure homogenizers mainly use the high pressure generated by the pressure system to cause cavitation and turbulence effects to squeeze, extend, impact and crush materials. The disadvantages of high-pressure homogenizers are: the homogenization valve has a large design gap, the homogenization pressure is low, it is easy to be damaged when homogenizing high-hardness particles, and it is difficult to repair. The advantage is that the price is relatively low. High-pressure homogenizers are suitable for processing soft and semi-soft granular materials. Micro-jet homogenizers use channels of about 100 microns to form supersonic jets, and the jets collide with each other to perform extremely strong shearing. The advantage is that it will produce a better particle size distribution effect. The disadvantage is that the flow rate is small and the cost is relatively high. Among them, the high-pressure homogenization chamber is the core component, and the internal unique geometric structure also affects the homogenization effect of the final product.

In recent years, nanosuspensions have attracted widespread attention as a form of injection. Improving the dissolution rate of nanoparticles-nanosuspensions can solve the problem of poor drug solubility. Nanosuspensions have a large surface area, which not only increases the dissolution rate, but also increases the saturation of the solution and improves bioavailability. Therefore, commercial nanosuspension products such as Rapamune and Emend have been rapidly adopted by the pharmaceutical industry. (Pharmaceutical development and technology, 24(10), 1278–1286).

Given that the liquid preparations of β-lactamase inhibitors prepared by the preparation method shown in Figure 1 have high impurity content and poor drug solubility, β-lactamase inhibitors urgently need to develop new liquid preparation processes to improve solubility, reduce impurity content, and stabilize storage. Considering that high-pressure homogenization technology has matured and the preparation development method of β-lactamase inhibitors using this technology has not been applied, the high-pressure homogenization process can be used to prepare β-lactamase inhibitors with broad-spectrum antibacterial and poorly soluble small molecule compounds.

Summary of the invention

In order to overcome the high impurity content and poor drug solubility of the liquid preparation of β-lactamase inhibitors in the prior art, a preparation process of a liquid preparation of a β-lactamase inhibitor is provided. The β-lactamase inhibitor prepared by the preparation process of the present invention is placed under natural light at 25°C for 24 hours, and the concentration and total impurity content do not change significantly.

The present invention provides a process for preparing a liquid preparation of a β-lactamase inhibitor, which comprises preparing a liquid preparation of the β-lactamase inhibitor by high-pressure homogenization of a suspension of the β-lactamase inhibitor,

The pressure of the high pressure homogenization is 1-30K psi;

The high pressure homogenization cycle is 3-57 times;

The high-pressure homogenization equipment is a high-pressure homogenizer or a microfluidizer.

In one embodiment, the flow rate of the high pressure homogenization is 50-200 ml/min, for example 100 ml/min.

In a certain embodiment, the pressure of the high-pressure homogenization may be 5-25K psi, such as 5K psi, 10K psi, 20K psi or 25K psi.

In one embodiment, the high pressure homogenization cycle is 3 times, 18 times, 24 times, 27 times, 30 times, 35 times or 57 times.

In one embodiment, when the pressure of the high-pressure homogenization is 5K psi, the high-pressure homogenization cycle is 3 times.

In one embodiment, when the pressure of the high-pressure homogenization is 10K psi, the high-pressure homogenization cycle is 3 times.

In one embodiment, when the pressure of the high-pressure homogenization is 20K psi, the high-pressure homogenization cycle is 3 times or 18 times.

In one embodiment, when the pressure of the high-pressure homogenization is 20K psi, the high-pressure homogenization cycle is 24 or 35 times.

In one embodiment, when the pressure of the high-pressure homogenization is 25K psi, the high-pressure homogenization cycle is 27, 30 or 57 times.

In one embodiment, the high-pressure homogenization cycle is 3 high-pressure homogenization cycles at 5K psi homogenization pressure, 3 high-pressure homogenization cycles at 10K psi homogenization pressure, and then increasing the homogenization pressure to 20K psi for 35 high-pressure homogenization cycles.

In one embodiment, the high-pressure homogenization cycle is 3 high-pressure homogenization cycles at 5K psi homogenization pressure, 3 high-pressure homogenization cycles at 20K psi pressure, and 27 high-pressure homogenization cycles with the homogenization pressure increased to 25K psi.

In one embodiment, the high-pressure homogenization cycle is 3 cycles of high-pressure homogenization at 5K psi pressure, 3 cycles of high-pressure homogenization at 10K psi pressure, and finally 24 cycles of high-pressure homogenization at 20K psi pressure.

In a certain embodiment, the high-pressure homogenization cycle is 3 cycles of 5K psi homogenization pressure, 3 cycles of 10K psi homogenization pressure, and 18 cycles of increasing the homogenization pressure to 20K psi.

In the present invention, the time of high-pressure homogenization is the conventional homogenization time in the art. Preferably, the time of high-pressure homogenization is related to the pressure and number of high-pressure homogenization; preferably, it is 4.5-52 min, for example, 4.5 min, 27 min, 36 min, 40 min and 52 min.

In the present invention, the single time of the high-pressure homogenization cycle is 1.5 minutes.

In the present invention, the β-lactamase inhibitor may be a compound as shown in (A);

In the present invention, the pH value of the suspension is a conventional pH value in the art, for example, 4-5, such as 4.5 or 4.6.

In the present invention, the temperature of the high pressure homogenization is a conventional temperature in the art, which may be less than or equal to 55°C, for example, 20°C, 27°C, 30°C, 33°C, 35°C, 38°C, 40°C, 48°C, 50°C or 51°C.

In the present invention, the particle size of the β-lactamase inhibitor is a conventional particle size in the art, which may be less than or equal to 500 μm, 10-200 μm, or 60-100 μm, such as 31.78 μm, 60.33 μm or 100 μm.

In the present invention, the suspension further comprises sodium sulfobutyl cyclodextrin, citric acid and a base, wherein the base is preferably NaOH.

In the present invention, the content of the β-lactamase inhibitor liquid preparation in the suspension is the conventional content in the art, which may be less than or equal to 15 mg/mL; for example, 5.26 mg/mL, 10.mg/mL or 12 mg/mL.

In the present invention, in the suspension, the content of citric acid is a conventional content in the art, such as 0.77 mg/mL.

In the present invention, in the suspension, the content of the sodium sulfobutyl cyclodextrin is a conventional content in the art, such as 50.00 mg/mL.

In the present invention, the content of the base in the suspension is a conventional content in the art, for example, 6.53 mg/mL.

In the present invention, the homogenizing chamber of the microfluidizer is Y-shaped or Z-shaped, preferably Y-shaped.

In the present invention, in the preparation process, the high-pressure homogenization further includes centrifugation and/or filtration.

In the present invention, the specification of the filtering filter is 0.22 μm.

The present invention also provides an application of high-pressure homogenization in the preparation of a liquid preparation of a β-lactamase inhibitor, wherein the application conditions are as described in the above-mentioned preparation process.

The present invention also provides a liquid preparation of a β-lactamase inhibitor, which is prepared by the above-mentioned preparation process.

Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

The reagents and raw materials used in the present invention are commercially available.

The positive improvement effect of the present invention is that the liquid preparation of the β-lactamase inhibitor prepared by the preparation process of the present invention is placed under natural light at 25° C. for 24 hours, and the concentration and total impurity content do not change significantly.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a process flow chart of the original liquid preparation.

FIG. 2 is a result of a liquid placement stability test prepared in Example 1.

FIG3 is a time-varying curve of the total impurity content (RP-HPLC) of the liquid prepared in Example 1.

FIG4 is a diagram of the high pressure homogenization process (high pressure homogenizer) in Example 2 for preparing a liquid formulation of Compound A.

FIG. 5 shows the effect of the high pressure homogenization process (microfluidizer) on the solubility of compound A in Example 3.

FIG. 6 is a study on liquid stability after homogenization in Example 3.

FIG. 7 is a comparison of the appearance of the homogenized liquid of compound A prepared by the Y-shaped and Z-shaped homogenizing chambers of Example 4.

FIG8 and FIG9 show the effect of the microfluidization homogenization process with different homogenization chambers (Y-type and Z-type) on the solubility of compound A in Example 4.

FIG. 10 and FIG. 11 are the solubility results of compound A of different particle sizes/concentrations after microfluidization homogenization in Example 5.

DETAILED DESCRIPTION

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

The meaning of scientific and technological terms in this application is consistent with the general understanding of those skilled in the art, unless otherwise specified. In this application, "one" or its combination with various quantifiers includes both singular and plural meanings, unless otherwise specified. In this application, for the same parameter or variable, when multiple values, numerical ranges, or combinations thereof are given for description, it is equivalent to also specifically revealing these values, range ends, and numerical ranges formed by any combination thereof. In this application, any numerical value, whether or not it is accompanied by an approximate modifier such as "about", shall cover an approximate range that can be understood by those skilled in the art, such as a range of plus or minus 10%, 5%, etc. In this article, any "implementation method" refers to and covers the implementation methods of various methods and systems of this application equally. In this application, one or more technical features in any implementation method can be freely combined with one or more technical features in any one or more other implementation methods, and the implementation methods obtained thereby also belong to the content disclosed in this application. The weight volume percentage (%, w/v) herein represents the number of grams (g) per hundred milliliters (100mL). Molar concentration (M, mol/L) indicates the number of moles (mol) of solute contained in each liter (L) of solution. When the dispersed substance is uniformly dispersed in the dispersion medium in the form of molecules, atoms or ions (particle diameter d < 1nm), the system formed is called a true solution. A true solution is dispersed in the form of small molecules or ions, a homogeneous clear solution, and a stable system, also known as a solution, in which the particle size is < 1nm.

In this application, "homogenizer" includes various types of equipment with homogenization function known in the art, such as high-pressure homogenizer and microfluidizer. High-pressure homogenizer is a commonly used equipment in pharmaceutical, food and chemical industries, and the selection and use of its model belongs to the skills of those skilled in the art.

In the present application, "homogenization chamber" includes components of various model parameters and different internal structures, which belong to the core components of the high-pressure homogenizer, such as the Y/Z type homogenization chamber. In the present application, "liquid preparation" refers to a liquid dispersion system composed of a drug or a drug and other ingredients dispersed in a liquid solvent in a certain form. "Compound A" refers to: one of the compounds of β-lactamase inhibitors (BLI). "API" refers to the active pharmaceutical ingredient (Active pharmaceutical ingredient), any substance or mixture of substances used in the manufacture of drugs, which has pharmacological activity or other direct effects or can affect the function or structure of the body, but cannot be taken directly. Generally, it is made into a drug that can be used directly after adding excipients and processing. "Placebo" refers to: tablets, pills or injections made of substances with no medicinal effect and no toxic side effects, such as citric acid and sulfobutyl ether-β-cyclodextrin (SBECD) used in this application.

In some embodiments, the high-pressure homogenization process for the liquid preparation of the β-lactamase inhibitor broad-spectrum antimicrobial poorly soluble small molecule compound referred to in the present application includes any device, tool or integration thereof that specifies one or a group of steps that can achieve the fact of high-concentration liquid preparation of the β-lactamase inhibitor broad-spectrum antimicrobial poorly soluble small molecule compound.

The present application will be described in detail by the following exemplary specific examples. The following examples are only used to help those skilled in the art better understand the inventions of the present application. It should be noted that the spirit of the present application and the scope of protection of the claims are not limited by the following specific examples.

The material compound A used in the examples was purchased from Chongqing Boteng Company;

The structure of compound A is as follows:

The high-pressure homogenizer (model: NATHOX Lab 3) was purchased from Nathan Technologies; the microfluidizer (model: M-110EH30) and its accessories Y/Z-type homogenization chamber were purchased from Microfluidics; the constant temperature water bath (model: HWCL-3) was purchased from Greatwall; the dynamic light scattering instrument (model: Malvern ZEN3600) was purchased from Malvern; and the clarity detector (model YB-2) was purchased from Tianda Tianfa.

Reverse phase high performance liquid chromatography (RP-HPLC): chromatographic column (3 μm, 150 mm×4.6 mm); Agilent high performance liquid chromatograph (model: 1260); mobile phase: A: 0.05% phosphoric acid: (980 mL H ₂ O: 5 mL methanol: 5 mL acetonitrile), B: 0.05% phosphoric acid: (500 mL methanol: 500 mL acetonitrile); flow rate: 1.0 mL/min; detection wavelength: 210 nm. Diluent: pure water.

In the following examples, the relevant substance (RP-HPLC) detection conditions are shown in Table 1 below:

Table 1:

Example 1 Preparation process of liquid preparation of compound A

This example aims to study the physicochemical properties of the liquid drug solution of Compound A prepared by the liquid dosage form preparation process, in order to evaluate the effect of the liquid dosage form preparation process on the drug solution.

Homogeneous liquid formula: 50.00 mg/mL SBECD, 0.77 mg/mL citric acid, 6.53 mg/mL 1M NaOH, compound A (batch: PS-12502-105-190002-1) feed concentration is 5.26 mg/mL.

Homogenization process: a high-pressure homogenizer (Nathan Technologies, model: NATHOX Lab 3) was used; the temperature was not controlled during the homogenization process; the freshly prepared compound A suspension (150 ml) was homogenized at 5K psi pressure for 3 cycles, with a total cycle time of 4.5 min; the homogenization pressure was increased to 20K psi and homogenized for 18 cycles, with a total cycle time of 27 min.

According to the liquid storage stability research plan shown in Table 2, the liquid formulation was stored at 2-8°C and 25°C for 24 hours after preparation. The liquid storage stability test includes appearance, pH value, insoluble particles, concentration and related substances (RP-HPLC). The specific plan is shown in Table 2 below.

Table 2 Study plan for the liquid storage stability of compound A

X = appearance, pH, insoluble particles, concentration and related substances (RP-HPLC)

The results of the storage stability test of Compound A liquid preparation are shown in Figure 2. The results show that after being stored at 2-8°C and 25°C for 24 hours, there is no significant change in appearance, pH value, insoluble particles, and concentration; there is no significant increase in total impurities, and the time change curve of the total impurity content (RP-HPLC) of the prepared liquid is shown in Figure 3.

Example 2 Preparation of Compound A Liquid Preparation by High-Pressure Homogenization Process (High-Pressure Homogenizer)

In this example, a NATHOX Lab 3 high-pressure homogenizer from Nathan Technologies was used to develop a high-pressure homogenization preparation process for the liquid formulation of Compound A.

A homogeneous liquid formula was selected: 50.00 mg/mL SBECD (sodium sulfobutyl cyclodextrin), 0.77 mg/mL citric acid, 6.53 mg/mL 1M NaOH, and a feed concentration of 5.26 mg/mL of compound A (batch: PS-12502-105-190002-1).

The homogenization process adopts the cooling circulating water cooling method to control the homogenization liquid temperature ≤ 50°C; the freshly prepared compound A suspension (150ml) is sampled in a series of homogenization pressures and different homogenization cycle times using a high-pressure homogenizer: 5K psi homogenization pressure cycle 3 times, total cycle time 4.5min, 10K psi homogenization pressure cycle 3 times, total cycle time 4.5min, and increase the homogenization pressure to 20K psi homogenization cycle 18 times, total cycle time 27min. After homogenization, some samples are placed at 70°C for 45min. The samples are taken to test the appearance under a clarity detector. The specific high-pressure homogenization process scheme is detailed in Table 3 below.

Table 3 High-pressure homogenization process (high-pressure homogenizer) for preparing liquid formulations of compound A

X = concentration and related substances (RP-HPLC); Y = temperature; () indicates selected measurement

"/" means the data does not exist

The results are summarized in Figure 4. The concentrations of the samples after high-pressure homogenization (homogenization pressure to 20K psi, 18 cycles, cycle time 27min) and after high-pressure homogenization (homogenization pressure to 20K psi, 18 cycles, cycle time 27min) and incubated at 70°C for 45min are very similar, 5.01mg/mL and 4.98mg/mL respectively; however, the results show that the total impurity content of the former is significantly lower. This shows that in order to ensure that the impurity content of the drug solution is at a low level, the high-temperature heating link should be avoided as much as possible in the liquid preparation process of Compound A.

Example 3 Preparation of Compound A Solution by High-Pressure Homogenization Process (Microfluidizer) and Evaluation of High-Pressure Homogenization Process

This example uses the Microfluidics M-110EH microfluidizer to develop a high-pressure homogenization preparation process for the liquid preparation of compound A. The effect of this process on the solubility of compound A is investigated, and the stability of the liquid after homogenization is also investigated. It can also be used to guide and compare the stability differences between the homogenization process and the original liquid preparation (Example 1).

A homogeneous liquid formula was selected: 50.00 mg/mL SBECD, 0.77 mg/mL citric acid, 6.53 mg/mL 1M NaOH, and a compound A solution (batch: DP3ES001101901) with a feed concentration of 10.00 mg/mL.

High-pressure homogenization process: use a microfluidizer and a Y-shaped homogenization chamber; control the homogenization process temperature ≤ 50°C; first homogenize the freshly prepared compound A suspension (150ml) at 5K psi pressure for 3 cycles, with a cycle time of 4.5min, then at 10Kpsi pressure for 3 cycles, with a cycle time of 4.5min, and finally increase the homogenization pressure to 20K psi for 24 cycles, with a cycle time of 36min. Take the last homogenized liquid and filter it with a 0.22μm filter, and place it under natural light at 2-8°C and 25°C for 24 hours. The specific scheme is shown in Table 4 below.

Table 4 Effect of high pressure homogenization process (microfluidizer) on the solubility of compound A and the study plan of liquid stability after homogenization

X = pH, DLS (after filtration), concentration and related substances (RP-HPLC);

Y = sample temperature

The research results are summarized in Figures 5 and 6. Using a microfluidizer, the microfluidization temperature was controlled at ≤50°C, and the feed concentration of compound A was increased to 10.00 mg/mL. The concentration of compound A continued to increase with the increase of homogenization pressure and homogenization cycle number. The homogenization pressure was increased to 20K psi, the homogenization cycle was 24 times, the cycle time was 36min, and the concentration was increased to 9.32 mg/mL; compared with heating at 70°C after high-pressure homogenization, the total impurity content was significantly reduced. During the homogenization process, the pH of the selected homogenized sample solutions did not change significantly; the particle size detection (DLS) results showed that the homogenized solution of compound A was a true solution after filtration through a 0.22μm filter.

The results of the liquid stability experiment of Compound A after homogenization showed that after the homogenous liquid of Compound A was filtered through a 0.22μm filter and placed under natural light conditions at 5℃ for 24 hours, there was no significant change in concentration and total impurity content; after being placed under natural light conditions at 25℃ for 24 hours, there was no significant change in concentration and total impurity content.

In addition, in this example, when the homogenization pressure was 20K psi and the homogenization cycle was 24 times, the cycle time was 36 minutes, and the total impurities were significantly reduced by 1.03% compared with the results of the original liquid preparation in Example 1; when placed under natural light conditions at 25°C for 24 hours, the total impurities were also significantly reduced by 1.51%.

Example 4 Effect of different homogenization chambers (Y-type and Z-type) microfluidization homogenization process on the solubility of compound A

This example uses the M-110EH microfluidizer produced by Microfluidics, and on this basis uses two types of homogenization chambers, Y-type and Z-type; the effect of different homogenization chamber process conditions on the solubility of compound A is investigated.

Homogeneous liquid formula: 50.00 mg/mL SBECD, 0.77 mg/mL citric acid, 6.53 mg/mL 1M NaOH, feed concentration of 12.00 mg/mL compound A (batch: D153-2019208-0029-01).

High-pressure homogenization process: microfluidizer; use Y-type and Z-type homogenization chambers respectively; control the temperature of the homogenization process to ≤45°C; homogenize the freshly prepared compound A suspension (150 ml) at 5K psi homogenization pressure for 3 times, with a cycle time of 4.5 min, homogenize at 20K psi pressure for 3 times, increase the homogenization pressure to 25K psi for 27 times, and cycle time of 40 min. The specific scheme is shown in Table 5 below.

Table 5 Effect of microfluidization homogenization process with different homogenization chambers (Y-type and Z-type) on the solubility of compound A

X = pH, sample temperature, DLS (after filtration), concentration and related substances (RP-HPLC);

The appearance results are shown in Figure 7. Under the same compound A feed concentration (12.00 mg/mL) and other homogenization conditions, when the homogenized liquid reaches a relatively clear state: as shown in Figures 8 and 9, the Z-type homogenization chamber needs to be homogenized to 25K-57 (homogenization pressure (psi)-homogenization cycle (times)), while the Y-type homogenization chamber only needs to be homogenized to 25K-30 (homogenization pressure (psi)-homogenization cycle (times)).

The effect of different homogenization chambers (Y-type and Z-type) on the solubility of compound A is shown in Figures 8 and 9. Compared with the Z-type homogenization chamber, the concentration of the liquid preparation of compound A prepared by the microfluidic high-pressure homogenization process using the Y-type homogenization chamber is significantly higher and the total impurity content is significantly lower. The particle size detection (DLS) results show that the homogenized solutions of compound A prepared using the two homogenization chambers are all true solutions after filtering through a 0.22μm filter.

In summary, for compound A, the microfluidization homogenization process using a Y-shaped homogenization chamber has a better homogenization effect.

Example 5 Solubility of Compound A with Different Particle Sizes after Microfluidization Homogenization

This example uses a microfluidizer for compound A and a Y-shaped homogenization chamber based on Example 4. The purpose is to illustrate the solubility changes of compound A with different particle sizes under the guidance of the optimized homogenization process; and to examine the solubility changes of compound A with two different concentrations and 60.33 μm particle sizes after homogenization.

Homogeneous liquid formula: 50.00 mg/mL SBECD, 0.77 mg/mL citric acid, 6.53 mg/mL 1M NaOH, three particle sizes of compound A (batch: Z-D153-20190001-01) of 31.78 μm, 60.33 μm and 100.00 μm. The feeding concentrations are shown in Table 6.

High-pressure homogenization process: microfluidics homogenizer (Microfluidics, model: M-110EH30); use a Y-shaped homogenization chamber to control the temperature during the homogenization process to ≤45°C; the freshly prepared compound A suspension (150 ml) was homogenized at 5K psi homogenization pressure for 3 cycles, with a cycle time of 4.5 min, and then at 10K psi homogenization pressure for 3 cycles with a cycle time of 4.5 min, and then the homogenization pressure was increased to 20K psi for 35 cycles, with a cycle time of 52 min. The specific scheme is shown in Table 6 below.

Table 6 Effect of microfluidization homogenization process on the solubility of compound A with different particle sizes/concentrations

X = pH, concentration and related substances (RP-HPLC);

Y＝temperature() indicates optional measurement;

The effect of microfluidization homogenization process on the solubility of compound A with different particle sizes/concentrations is shown in Figures 10 and 11. Under the premise of consistent microfluidization homogenization process (i.e., the feed concentration is 5.30 mg/mL; the homogenization pressure and the number of homogenization cycles are consistent; a Y-type homogenization chamber is used; and the homogenization temperature is controlled to be ≤45°C), the pH of the homogenized solution of compound A with three different particle sizes (31.78 μm, 60.33 μm and 100.00 μm) has no significant change. After homogenization to 20K-35 (homogenization pressure (psi)-homogenization cycle (times)) and filtration through a 0.22 μm filter, the concentration of compound A is 4.55 mg/mL; indicating that the different particle sizes in the range of 31-100 μm have little effect on the solubility of compound A. Based on the impurity results, the total impurity content of the homogenized solution of compound A with a particle size of 60.33 μm is relatively low.

60.33 μm API was selected to prepare liquid preparation of Compound A, the feed concentration was increased to 10 mg/mL, and the microfluidization homogenization process (temperature control ≤ 45 °C) was used to achieve a solubility of Compound A ≥ 5 mg/mL; using 60.33 μm X, when the feed concentration was 5.30 mg/mL, homogenization was performed to 20K psi for 35 cycles, and the cycle time was 52 min, the solubility of Compound A was 4.55 mg/mL; when the feed concentration was 10.00 mg/mL, the solubility of Compound A was 8.50 mg/mL under the same homogenization conditions.

The above are only specific application examples of the present application, and do not constitute any limitation to the protection scope of the present application. For ordinary technicians in the field, other different forms of changes or modifications can be made on the basis of the above description. It is not necessary and impossible to list and describe all the implementation methods here. Any similar technical solutions formed by equivalent transformation or equivalent replacement fall within the scope of protection of the present application.

Claims (10)

1. A process for preparing the liquid preparation of beta-lactamase inhibitor features that the liquid preparation of beta-lactamase inhibitor is prepared from the suspension of beta-lactamase inhibitor through high-pressure homogenization,

The pressure of the high-pressure homogenization is 1-30K psi;

the high-pressure homogenizing cycle is 3-57 times;

The high-pressure homogenizing equipment is a high-pressure homogenizer or a micro-jet homogenizer.

2. The preparation process according to claim 1, characterized in that it satisfies one or more of the following conditions:

(1) The flow rate of the high-pressure homogenization is 50-200ml/min,

(2) The high pressure homogenization pressure is 5-25K psi,

(3) The high pressure homogenization cycle is 3, 18, 24, 27, 30, 35, or 57 times;

(4) The particle size of the beta-lactamase inhibitor is 10-200 mu m.

3. The preparation process according to claim 1, characterized in that it satisfies one or more of the following conditions:

(1) The flow rate of the high-pressure homogenization is 100ml/min;

(2) The high pressure homogenization pressure is 5K psi, 10K psi, 20K psi or 25K psi;

(3) The particle size of the beta-lactamase inhibitor is 60-100 mu m.

4. The preparation process according to claim 1, characterized in that it satisfies any one or more of the following:

(1) The high pressure homogenization cycle is 3 times when the pressure of the high pressure homogenization is 5K psi;

(2) The high pressure homogenization cycle is 3 times when the pressure of the high pressure homogenization is 10K psi;

(3) The high pressure homogenization cycle is 3 or 18 times when the pressure of the high pressure homogenization is 20K psi;

(4) The high pressure homogenization cycle is 24 or 35 times when the pressure of the high pressure homogenization is 20K psi;

(5) The high pressure homogenization cycle is 27, 30 or 57 times when the pressure of the high pressure homogenization is 25K psi;

(6) The particle size of the beta-lactamase inhibitor is 31.78 μm, 60.33 μm or 100 μm.

5. The preparation process according to claim 1, characterized in that it satisfies any one of the following:

(1) The high-pressure homogenizing cycle is that the high-pressure homogenizing cycle is performed for 3 times under the homogenizing pressure of 5K psi, and then the homogenizing pressure is increased to 20K psi for 35 times after the high-pressure homogenizing cycle is performed for 3 times under the homogenizing pressure of 10K psi;

(2) The high-pressure homogenizing cycle is 3 times under the homogenizing pressure of 5K psi, 3 times under the homogenizing pressure of 20Kpsi, and 27 times under the homogenizing pressure of 25K psi;

(3) The high-pressure homogenizing cycle is 3 times of high-pressure homogenizing cycle at 5K psi pressure, 3 times of high-pressure homogenizing cycle at 10K psi pressure, and 24 times of homogenizing cycle at 20K psi pressure;

(4) The high pressure homogenization cycle is 5K psi homogenization pressure cycles 3 times, 10K psi homogenization pressure cycles 3 times, and raising the homogenization pressure to 20K psi high pressure homogenization cycle 18 times.

6. The preparation process according to claim 1, characterized in that it satisfies one or more of the following conditions:

(1) The high-pressure homogenization time is 4.5-52min;

(2) The single time of the high-pressure homogenizing cycle is 1.5min;

(3) The beta-lactamase inhibitor is a compound shown in the formula (A),

(4) The pH value of the suspension is 4-5;

(5) The temperature of the high-pressure homogenization is less than or equal to 55 ℃;

(6) The particle size of the beta-lactamase inhibitor is less than or equal to 500 mu m;

(7) The suspension also includes sodium sulfobetacyclodextrin, citric acid, and a base;

(8) The homogenizing cavity of the micro-jet homogenizer is Y-shaped or Z-shaped;

(9) In the preparation process, centrifugation and/or filtration are further included after the high-pressure homogenization.

7. The preparation process according to claim 6, characterized in that it satisfies one or more of the following conditions:

(1) The high-pressure homogenization time is 4.5min, 27min, 36min, 40min and 52min;

(2) The pH value in the suspension is 4.5 or 4.6;

(3) The high-pressure homogenization temperature is 20 ℃, 27 ℃, 30 ℃, 33 ℃, 35 ℃, 38 ℃, 40 ℃, 48 ℃,50 ℃ or 51 ℃;

(4) The homogenizing cavity of the micro-jet homogenizer is Y-shaped.

8. The preparation process according to claim 6, characterized in that it satisfies one or more of the following conditions:

(1) In the suspension, the alkali is NaOH;

(2) The content of the citric acid in the suspension is 0.77mg/mL;

(3) The content of the sulfobetacyclodextrin sodium in the suspension is 50.00mg/mL;

(4) The content of the alkali in the suspension is 6.53mg/mL;

(5) In the preparation process, the specification of the filtered filter is 0.22 μm.

9. Use of high pressure homogenization for the preparation of a liquid formulation of a beta-lactamase inhibitor, wherein the conditions of said use are as defined in any one of claims 1-8.

10. A liquid formulation of a β -lactamase inhibitor, wherein the liquid formulation is prepared by the process of any one of claims 1-8.