WO2017020841A1 - Pharmaceutical composition containing lcz696 and preparation method thereof - Google Patents

Abstract

Disclosed is a pharmaceutical composition containing a specific crystalline powder of LCZ696. The crystalline powder of LCZ696 having a specific powdery feature satisfies a requirement of a preparation process and can be used to produce a pharmaceutical composition satisfying a clinic drug use requirement while realizing a scaling up of the pharmaceutical composition.

Description

Pharmaceutical composition containing LCZ696 and preparation method thereof Technical field

The invention belongs to the field of medicine, and particularly relates to a pharmaceutical composition containing LCZ696 which can be used for the treatment of heart failure and a preparation method thereof.

Background technique

Heart failure (referred to as heart failure) is a complex clinical syndrome in which ventricular filling or impaired ejection capacity is impaired by any abnormal cardiac structure or function. The main clinical manifestations of heart failure are dyspnea and fatigue (limited activity tolerance), as well as fluid retention (pulmonary congestion and peripheral edema). Heart failure is a serious and terminal stage of various heart diseases, and its incidence is high. It is one of the most important cardiovascular diseases today (Guide to Diagnosis and Treatment of Heart Failure in China 2014).

Since 2005, due to the prevalence of cardiovascular risk factors, the number of cardiovascular diseases in China has continued to increase. According to statistics, there are about 290 million cardiovascular patients in China, and there are about 4.5 million patients with central failure (China Cardiovascular Disease Report 2013). Angiotensin-converting enzyme inhibitor (ACEI) is the first class of drugs that have been shown to reduce mortality in patients with heart failure. It is also the drug with the highest accumulation of evidence-based medicine. It is recognized as the drug of choice for the treatment of heart failure, enalapril. It is one of the ACEI commonly used in the treatment of clinical heart failure.

LCZ696 (CAS: 936623-90-4) is an anti-heart failure drug developed by Novartis, which has dual roles of angiotensin receptor blockade and neutral endopeptidase inhibition, and its structure was first disclosed in patent WO2007056546 ( The following formula). This compound is a supramolecular complex (complex) trisodium salt containing 2.5 water of crystallization, which is formed by combining non-covalent bonds of valsartan and AHU377.

The published clinical trial results show that LCZ696 reduces the hospitalization rate of heart failure by 21% compared with the enalapril-treated group, and reduces the symptoms and physical limitations of heart failure, in reducing heart failure patients. Mortality and hospitalization rates are superior to enalapril (N Engl J Med, 2014, 371(1): 993-1004). It can be seen that LCZ696 is a market-leading anti-heart failure drug, and the product was approved for marketing in the second half of 2015.

Because LCZ696 is a special drug with special bonding and salt formation methods, it is unstable to moisture and heat, and dissociation occurs in the solution system. Therefore, even in the conventional production environment, LCZ696 will still Because of moisture absorption The quality is degraded by other reasons. Therefore, in the production and preparation of LCZ696 clinical drugs, the contact time with air should be shortened as much as possible, and the use of heat-receiving processes (such as crushing) should be avoided.

Patent Example WO2007056546, Examples 1 to 3 disclose a preparation method of LCZ696. The LCZ696 prepared according to the method has a very fine powder shape, so that the filtration rate in the post-treatment process is extremely slow, especially in the amplification reaction. Obviously, even if nitrogen gas is used in the whole process of suction filtration, the obtained product still has the possibility of the product becoming sticky due to moisture absorption, thereby affecting the process stability. In addition, the extremely fine powder is not conducive to the preparation of the preparation product by the subsequent preparation process.

Patent WO2009061713 discloses a series of preparations of LCZ696, which have the characteristics of good dissolution performance and high stability, but in the field of preparation, for a specific product having multiple specifications at the same time, from the perspective of clinical drug use and process simplification. The prescribed prescriptions and processes need to achieve equal magnification/reduction at the same time, that is, under the premise of not changing the prescription and the process, the preparation specifications are doubled/reduced, and the dissolution performance of the preparation still meets the requirements for clinical use, and the dissolution performance of the preparation is not Excessive fluctuations, while the patent WO2009061713 shows that the various specifications of the formulation have not achieved equal magnification, and the prior art does not disclose a solution to achieve a proportional enlargement/reduction of the LCZ696 formulation.

In summary, the prior art does not provide the LCZ696 crystalline powder obtained by direct synthesis, which is advantageous for the synthesis and preparation process, and does not optimize the formulation and process of the LCZ696 formulation. Therefore, it is necessary to find a LCZ696 crystalline powder and realize the formulation of the LCZ696 formulation. The optimization of the process is a technical problem that is not solved by the prior art.

Summary of the invention

A first object of the present invention is to overcome the deficiencies of the prior art. For the first time, a crystalline powder of LCZ696 prepared by direct synthesis is provided, which has the characteristics of being easy to be suctioned and filtered during the synthesis process, and can be directly used for preparation. In the process, the pulverization process before the preparation can be avoided, and the preparation process is simplified (such as material mixing, etc.), and the obtained preparation can achieve equal ratio enlargement/reduction while optimizing various performances (such as dissolution performance) of the preparation.

The above advantageous effects of the present invention are achieved by the following technical solutions:

A crystalline powder of LCZ696 characterized in that the crystalline powder is 20 μm ≤ D ₉₀ ≤ ₁₀₀ μm.

Specifically, unless otherwise specified, the powder properties (such as D ₉₀ , D _{50 ,} etc.) of all the LCZ696 crystalline powders in the present invention are measured after passing the dried powder through an 80 mesh sieve (pore size of about 200 μm). The purpose of the screen is to remove a small amount of LCZ696 product that agglomerates during the drying process. In the synthesis process, the powder with too low particle size is not conducive to product filtration, and moisture absorption is easy to occur in the filtration and drying process, while the product with too high particle size corresponds to a relatively long crystallization time, which does not conform to the synthesis process. The optimal requirements, and products with too high particle size, also have the problem of inhomogeneous enlargement/reduction in the formulation; when the LCZ696 crystalline powder is 20 μm ≤ D ₉₀ ≤ ₁₀₀ μm, preferably 25 μm ≤ D ₉₀ ≤ 75 μm, it can be realized. Rapid filtration to avoid product moisture and viscosity due to excessive contact with air, affecting product quality; at the same time, avoiding product drying in the post-treatment process for a long time, and the product obtained after drying is agglomerated; more preferred The LCZ696 crystalline powder is 30 μm ≤ D ₉₀ ≤ 60 μm. Further, the LCZ696 crystalline powder simultaneously satisfies ₅ μm ≤ D ₅₀ ≤ ₅₀ μm, preferably 8 μm ≤ D ₅₀ ≤ 30 μm.

A second object of the present invention is to provide a method for preparing a crystalline powder of the above LCZ696, which can stably prepare a crystalline powder of LCZ696 having the foregoing powder properties, and the obtained crystalline powder can be directly used for subsequent processing without pulverization. In the agent process, the method is suitable for industrial scale production, which uses the process route shown below.

The method comprises the following preparation steps:

1) Dissolving free AHU377 and valsartan in a mixed solution of solvent A/solvent B at a temperature lower than 30 ° C;

2) slowly dropping an aqueous sodium hydroxide solution at a temperature lower than 30 ° C, and heating to 50-55 ° C for 20-30 min;

3) cooling to 40 ~ 45 ° C, adding 0.1 to 5.0 wt% of valsartan LCZ696 seed crystal, the solution becomes cloudy, and then cooled to a temperature of 30 ° C ~ 35 ° C at a rate of 0.5 ~ 1.5 ° C / 10 min;

4) The reaction solution is moved to 5 to 25 ° C and stirred for 1 to 5 hours;

5) Filtration and drying in vacuo gave LCZ696 crystalline powder.

The room temperature referred to in the present invention is 20 ± 5 ° C unless otherwise specified. The molar ratio of free AHU377 to valsartan in reaction step 1) follows the conventional principle of setting the ratio of such reaction in the art. Preferably, the molar ratio of free AHU377 to valsartan is 1:0.95 to 1.05. The free AHU377 and valsartan used preferably have a purity of ≥99.0%. The free AHU377 can be obtained by freeing the AHU377 salt, and the AHU377 salt (M) can be a common metal salt or a non-metal salt such as a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a zinc salt, an ammonium salt, or the like. The ethylamine salt, the diethylamine salt and the like are preferably a calcium salt. In a preferred embodiment of the present invention, the free AHU377 is obtained by the following steps:

a) AHU377 salt and isopropyl acetate (IPAC) were placed in the reactor, 2N HCl was added dropwise at a temperature below 30 ° C, and stirred until clarification;

b) Dispensing and collecting the organic phase, washing, drying, and desolvation to obtain free AHU377.

For different active ingredients, there are differences in the conditions affecting the habit, and for LCZ696, LCZ696 crystalline powder (such as D ₉₀ and/or D _50, etc.) having the aforementioned powder properties can be obtained by the above method. The technical key of the preparation step is the kind and proportion of the solvent in the mixed solution in the step 1), one of which is a good solvent with respect to LCZ696, the other is a poor solvent, and a certain proportion of the mixed solvent is controlled, and the temperature is decrystallized by cooling. The method obtains the product, the ratio of the good solvent is increased, and/or the slow cooling and crystallization is favorable for obtaining the crystal powder having a larger particle diameter, and the ratio of the poor solvent is increased and/or the room temperature crystallization is favorable for obtaining the crystal powder having a smaller particle diameter. Specifically, the solvent A is a poor solvent selected from any one of acetone, tetrahydrofuran, acetonitrile, etc., and the solvent B is a good solvent selected from the group consisting of isopropanol, n-butanol, isobutanol and the like. In one case, the solvent A is preferably acetone having relatively low toxicity; in order to maximize the yield while ensuring that the particle size of the product meets the requirements, the volume-mass ratio of the solvent A to the valsartan in the mixed solution is 6～10:1ml: 1g, the purpose of this step is to dissolve AHU377 and valsartan, and to ensure a certain solvent saturation to facilitate crystal precipitation. Preferably, the volume of solvent A and valsartan in the mixed solution The mass ratio is 7-9:1 ml: 1 g; in the mixed solution of step 1), the volume ratio of the solvent A to the solvent B is V _A : V _B =1-7:1, and similarly, a specific ratio of the solvent can be A certain solvent saturation is ensured to facilitate crystal precipitation. Preferably, the volume ratio of the solvent A to the solvent B is V _A : V _B = 4-6:1.

In order to precipitate LCZ696 as much as possible from the system, the solvent A can be prepared in the subsequent process to achieve the purpose of improving the yield. Specifically, in step 4), the solvent A in which the volume of the solvent A in the mixed solution is 1.0 to 3.0 times is added, so that the LCZ696 can be further precipitated from the solvent system, and the purpose of improving the yield can be achieved. Preferably, the step 4) can be further optimized: the reaction solution is moved to 5 to 25 ° C and stirred for 0.5 to 3 hours, and the solvent A is further added and stirring is continued for 0.5 to 2 hours.

Said step 5) is preferably filtered under the protection of an inert gas, preferably nitrogen.

The study found that within the scope of the above method, the product only has fluctuations in particle size, and the impurity content fluctuates less. Therefore, the above method can ensure that LCZ696 is uniformly precipitated in a specific physical form, and the product yield and powder properties are also controlled optimally. In the state, the speed of the LCZ696 powder in the suction filtration process is obvious, and it shows a more obvious speed advantage in mass production. The faster filtration rate can effectively prevent the product from sticking due to moisture absorption during the preparation process, avoiding longer drying time, and avoiding product stagnation, avoiding the conventional pulverization process before preparation.

A third object of the present invention is to further optimize on the basis of the foregoing method, to control the obtained LCZ696 crystalline powder to be within a specific particle size range, and to control the hydrolysis impurities to a very low range. Specifically, the hydrolysis impurity is a hydrolysis impurity of AHU377, and the structure thereof is as follows:

Excessive hydrolysis of impurities may cause adverse drug reactions, so hydrolysis of impurities is one of the impurities that need to be controlled in the production process. Further stability experiments found that there is a certain correlation between the content of hydrolyzed impurities and its growth rate. Specifically, for the LCZ696 preparation, when the accelerated experiment (40 ° C ± 2 ° C, 75% ± 5% RH) 30 days, the hydrolysis impurity increased by more than 0.1%. At the time, the stability of the preparation was considered to be poor. Through experiments, we found that when the hydrolysis impurities in the preparation are controlled below 1.0%, the increment is relatively slow. The accelerated experiment (40 °C ± 2 °C, 75% ± 5% RH) has a low increase in hydrolysis impurities within 30 days. At 0.1%, the obtained preparation has high stability and meets the requirements for clinical use.

Specifically, the method for preparing the low-hydrolysis impurity content LCZ696 of the present invention achieves the purpose of controlling the content of the hydrolyzed impurities by controlling the amount and concentration of the sodium hydroxide. Specifically, the amount of sodium hydroxide does not affect the powder form of the LCZ696 crystalline powder, but it affects the product yield and impurity content. Under the aforementioned solvent system and preparation steps, when the valsartan and the sodium hydroxide used are molar When the ratio is 1:2.5-3.0 and the concentration of the aqueous sodium hydroxide solution is in the range of 0.5-1.0 g/ml, the quality of the hydrolyzed impurities can be controlled to be within 1.0%. Specifically, there is technical difficulty in further controlling the content of hydrolyzed impurities on the basis of ensuring the properties of the crystal powder of the aforementioned LCZ696. When the amount of sodium hydroxide used is too large, the content of hydrolyzed impurities is increased; when the amount of sodium hydroxide used is too small, the final product is caused. The decrease in yield also affects the precipitation of crystals. Therefore, the overall yield and the influence factor of the impurity content, preferably, the molar ratio of valsartan to the sodium hydroxide used is 1:2.70-2.95, more preferably, when valsartan and sodium hydroxide used When the molar ratio is 1:2.80-2.90, the reaction yield and impurity content can be optimized. In addition, the concentration of sodium hydroxide has a certain influence, and the lower concentration in the above concentration range corresponds to a relatively low yield.

The LCZ696 crystalline powder of the present invention can be directly used in the formulation process without pulverization due to its advantages in powder form and quality. Specifically, for the preparation of a conventional product, it is usually necessary to pretreat the drug substance to a desired state according to the formulation process, the formulation requirements, and the product characteristics before the preparation, and the pretreatment usually includes a step of pulverizing and sieving. For the LCZ696 product, because it is unstable to moisture and heat, it needs to avoid the pulverization process in the preparation process, and the raw material medicine without pretreatment is easy to cause fluctuations in the preparation process and product quality. Specifically, the particle size Too coarse results in poor material mixing uniformity, which may cause a large difference in tablet weight when the tablet is pressed. The particle size is too fine, resulting in poor fluidity of the material, easy sticking, and the sheet weight difference may be large when the tablet is pressed, and the sheet surface is slightly deep.

The inventors have surprisingly found that the LCZ696 crystalline powder in the particle size range of the present invention is more favorable to the dry granulation process than the crystalline powder outside the particle size range. Specifically, the LCZ696 crystalline powder has simple pretreatment and uniform particle size. The process is stable, the difference between the batches is small, and the like, and more importantly, the prescription ratio can be enlarged/reduced, that is, the prescription and the process can be enlarged/reduced without changing the prescription and the process. The realization of the prescription equalization enlargement/reduction is conducive to the conversion of various specifications in the production, and is the embodiment of the prescription technology content.

Based on the above, a fourth object of the present invention is to provide a LCZ696 pharmaceutical composition comprising the LCZ696 crystalline powder of the present invention.

The particle size range of LCZ696 crystal powder is the key to achieve the above beneficial effects. Specifically, for LCZ696 products of 50mg, 100mg, 200mg and 400mg specifications, it is required to achieve dissolution of more than 70% in 15 minutes in accordance with clinical drug requirements. Compared with the enlargement/reduction, it adopts the same prescription and process to achieve the dissolution of more than 70% of the products of all specifications in 15 minutes, and the dissolution performance fluctuates less. Through experiments, we were surprised to find that when the control drug substance is 20μm≤D ₉₀ ≤100μm, LCZ696 products of 50mg, 100mg, 200mg and 400mg can achieve more than 70% dissolution in 15min, and the dissolution performance is less fluctuating. The particle size of the drug substance is 25 μm ≤ D ₉₀ ≤ 75 μm. More preferably, when the particle size of the drug substance is 30 μm ≤ D ₉₀ ≤ 60 μm, the LCZ696 products of 50 mg, 100 mg, 200 mg and 400 mg can be achieved in 15 minutes. More than 70% of the dissolution, while the dissolution performance fluctuations are minimal.

The LCZ696 pharmaceutical composition contains a filler, a disintegrant, a binder, and the kind and amount of the adjuvant also contribute to the realization of the above-mentioned beneficial effects of the LCZ696 crystalline powder.

Specifically, the filler is selected from the group consisting of microcrystalline cellulose, lactose, starch, pregelatinized starch, mannitol, calcium hydrogen phosphate, sorbitol, or a mixture of two or more thereof, preferably microcrystalline cellulose, mannose Alcohol, calcium hydrogen phosphate, sorbitol; when the amount of LCZ696 is 1 part by mass, the filler is used in an amount of 0.2 to 0.8 parts, preferably 0.3 to 0.7 parts.

The disintegrant is selected from the group consisting of crospovidone, sodium carboxymethyl starch, croscarmellose sodium, carboxymethylcellulose calcium, or a mixture of two or more thereof, preferably crosslinked carboxymethyl The base cellulose sodium and the crospovidone, when the LCZ696 parts by mass is 1 part, the disintegrant is used in an amount of 0.04 to 0.4 parts, preferably 0.05 to 0.3 parts; the disintegrant may be selected to be added, plus And the method of adding the inside and the outside, preferably the method of adding the inside and the outside; when the method is internal and external, that is, the pharmaceutical composition comprises the inner phase particles and the external auxiliary material, the inner phase particles comprise the crystal powder of the LCZ696, the filler, the disintegrating agent, and the sticking When the mixture is mixed, the mass ratio of the internally added disintegrant to the additional disintegrant is from 0.4 to 3.8:1.

The binder is selected from one or a mixture of two or more of low-substituted hydroxypropylcellulose, hypromellose, sodium carboxymethylcellulose, povidone, ethylcellulose, preferably carboxymethyl Cellulose sodium, low-substituted hydroxypropylcellulose, when the amount of LCZ696 is 1 part by mass, the binder is used in an amount of 0.05 to 0.5 part, preferably 0.1 to 0.4 part.

The LCZ696 pharmaceutical composition may further comprise a glidant selected from the group consisting of one or a mixture of two or more of silica, talc, and the flow aid when the LCZ 696 parts by mass is 1 part. The dosage of the agent is from 0.002 to 0.05 parts.

The LCZ696 pharmaceutical composition may further comprise a lubricant selected from one or more of magnesium stearate, hydrogenated vegetable oil, polyethylene glycol, stearic acid, palmitic acid, carnauba wax. The mixture is used in an amount of 0.01 to 0.1 parts when the LCZ 696 parts by mass is 1 part.

The LCZ696 pharmaceutical composition includes, but is not limited to, tablets, granules, capsules, powders, and the like, which are common in the art. The LCZ696 pharmaceutical composition may also be subjected to further coating treatment as needed, and the coating may be a coating type commonly used in the art such as a film coating, a sugar coating, etc., and the coating may be made of a coating which is common in the art. Materials such as hypromellose, powdered sugar, hydroxypropylcellulose, etc., can also be used in conventional commercial coating materials, such as Opadry.

The use of a crystalline powder having specific powder properties, with the aid of the above formulation, allows the pharmaceutical composition to be more optimized for proportional enlargement/reduction, that is, when the ratio of raw materials is increased/decreased by equal ratios to obtain different specifications. In the preparation of the preparation, the dissolution properties of the obtained preparation tend to be uniform, and are not affected by the increase/decrease in the ratio of the raw materials.

In a preferred embodiment of the present invention, the LCZ696 formulation uses the LCZ696 crystalline powder of the present invention, and the prescription is:

In a preferred embodiment of the present invention, the LCZ696 formulation uses the LCZ696 crystalline powder of the present invention, and the prescription is:

In a preferred embodiment of the present invention, the LCZ696 formulation uses the LCZ696 crystalline powder of the present invention, and the prescription is:

A fifth object of the present invention is to provide a method for preparing the LCZ696 pharmaceutical composition of the present invention. Specifically, when the LCZ696 pharmaceutical composition is a tablet, the preparation method comprises the following steps:

(1) Passing the original and auxiliary materials through a 40 mesh sieve for use;

(2) pre-mixing the added components in the prescription, pressing the pre-mixed mixture using a dry granulator, and obtaining the inner phase particles after the granulation;

(3) The inner phase particles were mixed with the external auxiliary materials, and after mixing, the resulting mixture was tableted to obtain a LCZ696 core.

The obtained LCZ696 core may be coated by a coating material and a coating method which are commonly used in the art, and the coating may be made of a coating material commonly used in the art, such as hypromellose. Sugar powder, hydroxypropyl cellulose, etc., can also be used in conventional commercial coating materials, such as Opadry

In summary, the present invention is advantageous in realizing the optimization of LCZ696 synthesis and preparation process, based on the fact that the LCZ696 bulk drug is unstable under wet and hot conditions, through the two technical fields of serial composition synthesis and preparation of active ingredient, through synthesis. Preparation of a specific particle size active ingredient, and optimization of the formulation process by the obtained specific particle size active ingredient. It can be seen that the present invention has the following technical features and advantages compared with the prior art:

1. For the first time, a crystalline powder of LCZ696 prepared by direct synthesis is provided. The crystalline powder has specific powder properties, and has the characteristics of being convenient for suction filtration and avoiding moisture absorption during the synthesis process, and the obtained product has almost no agglomeration. In the preparation process, the pulverization process can be avoided, which is beneficial to optimize the performance of the preparation (such as dissolution performance);

2. A method for preparing a crystalline powder of LCZ696, which can stably prepare the crystalline powder of LCZ696 having specific powder properties, and the obtained crystalline powder can be directly used in a subsequent preparation process, and the method is applicable to the LCZ696. Industrial production of crystalline powders;

3. Providing a method for preparing a crystalline powder of LCZ696 having a low hydrolyzed impurity content, wherein the LCZ696 crystalline powder is further controlled by controlling the amount of sodium hydroxide to further control the hydrolyzed impurities in the crystal powder of the obtained LCZ696 in a relative manner. Lower range ensures product quality;

4. Providing a LCZ696 pharmaceutical composition comprising the LCZ696 crystalline powder of the present invention, wherein the LCZ696 crystalline powder used in the LCZ696 pharmaceutical composition has specific powder characteristics, so that it meets the formulation process requirements and is produced in accordance with Simultaneous amplification of the pharmaceutical composition can be achieved while the pharmaceutical composition is required for clinical use.

5. A method of preparing a pharmaceutical composition of the LCZ696 of the present invention, which provides for the preparation of a tablet containing LCZ696.

DRAWINGS

Figure 1 shows the particle size distribution of the LCZ696 crystalline powder obtained in Example 1 before sieving.

Figure 2 is a particle size distribution diagram of the LCZ696 crystal powder obtained in Example 1 after passing through a 80 mesh sieve.

Figure 3 is an appearance of the LCZ696 crystal powder obtained in Example 1 after passing through a 80 mesh sieve.

Figure 4 is a particle size distribution of the LCZ696 crystalline powder obtained in Example 2 before sieving.

Figure 5 shows the particle size distribution of the LCZ696 crystal powder obtained in Example 2 after passing through a 80 mesh sieve.

Figure 6 is a comparison of the appearance of the LCZ696 product obtained in Example 1 before sieving.

Figure 7 is a comparison of the particle size distribution of the LCZ696 product obtained in Example 1 after passing through a 80 mesh sieve.

Figure 8 is a particle size distribution diagram of the LCZ696 crystal powder obtained in Example 4 after passing through a 80 mesh sieve.

Figure 9 is a particle size distribution diagram of the LCZ696 crystal powder obtained in Example 5 after passing through a 80 mesh sieve.

detailed description

The present invention will be further described in detail below with reference to the embodiments and drawings, but the embodiments of the invention are not limited thereto.

First, the synthesis research part

By adjusting the solvent system, feed ratio, reaction conditions and other process parameters, the effects of solvent system and feed ratio on the powder properties and hydrolysis impurities content of the product were studied.

Example 1

Preparation of AHU377 free acid:

100 g of AHU377 calcium salt, 1000 ml of isopropyl acetate were added to a 2 L three-necked flask, 240 ml of 2 mol/L hydrochloric acid was added dropwise under ice bath; the solution was dissolved; the organic layer was collected, and washed twice with 600 ml of water; Decomposition under reduced pressure at 38 ° C to obtain AHU377 free acid;

Preparation of LCZ696:

At room temperature, AHU377 free acid, 100g valsartan and 880ml acetone, 220ml isopropanol were added to a 3L three-necked flask, and dissolved; and a 2.78-equivalent aqueous solution of 0.9 g/ml of valsartan was added dropwise at room temperature. , heat up to 50 ° C The reaction was carried out for 20 min; the temperature was lowered to 45 ° C, about 2.0 g of seed crystals were added, the solution was turbid after stirring, and then the external temperature was lowered to 35 ° C at a rate of 1.0 ° C / 10 min, and then the reaction solution was moved to a temperature of 15 ° C and stirred for 2 h; Then, 1120 ml of acetone was added dropwise to the system, and the mixture was stirred at 15 ° C for 2 h. Under a nitrogen atmosphere, the mixture was filtered through a Buchner funnel to obtain a white solid. The mixture was dried under vacuum at 35 ° C for 8 h, and dried to obtain a solid 188.0 g. The purity of HPLC was 99.91%. The hydrolyzed impurity content is 0.02%, and the particle size distribution thereof is shown in FIG.

The obtained product was passed through an 80 mesh sieve to obtain 184.2 g of a crystalline powder having a D ₉₀ of 43.90 μm and a D ₅₀ of 10.14 μm. The particle size distribution of the obtained crystalline powder is shown in Fig. 2, and the external appearance is shown in Fig. 3.

Example 2

Preparation of AHU377 free acid:

100 g of AHU377 calcium salt, 1000 ml of isopropyl acetate were added to a 2 L three-necked flask, 230 ml of 2 mol/L hydrochloric acid was added dropwise under ice bath; the solution was dissolved and dissolved; the organic layer was separated, and washed twice with 600 ml of water; Decomposition under reduced pressure at 38 ° C to obtain AHU377 free acid, dissolved in 250 ml of isopropanol, and then decomposed again under reduced pressure and repeated once;

Preparation of LCZ696:

At room temperature, AHU377 free acid, 100g valsartan and 800ml of acetone, 220ml of isopropanol were added to a 3L three-necked flask, and dissolved; and a 2.95-equivalent aqueous solution of sodium hydroxide at a concentration of 0.85 g/ml relative to valsartan was added dropwise at room temperature. , the temperature is raised to 53 ° C for 30 min; then the external temperature is reduced to 30 ° C at a rate of 1.0 ° C / 10 min, about 1.0 g of seed crystals are added, the reaction solution is moved to a temperature of 20 ° C for 2 h; then dropped into the system 1200ml of acetone was added, and the temperature was stirred for 2 hours. Under vacuum protection, the mixture was filtered through a Buchner funnel to obtain a white solid. The mixture was dried under vacuum at 35 ° C for 8 hours, and dried to obtain a solid 191.3 g. The yield was 85.6%. The purity by HPLC was 99.33%. The impurity content was 0.58%, and the particle size distribution was as shown in FIG.

The obtained product was passed through an 80 mesh sieve to obtain 188.0 g of a crystalline powder having a D ₉₀ of 48.07 μm and a D ₅₀ of 10.26 μm. The particle size distribution of the obtained crystalline powder is shown in Fig. 5 .

Example 3

Since the crystal powders obtained in Example 1 and Example 2 have a moderate particle size morphology, rapid filtration can be achieved during the reaction. In order to reflect its advantages compared with the prior art in filtration, the reaction scales of Example 1 and Example 2 are magnified 20 times, and it is combined with Patent CN200680001733.0 Example 3 (hereinafter referred to as "contrast implementation" Example 1") relative ratio, the results are as follows:

project	Deliberation time (min)	D90 (μm)
Example 1	About 20min	44.68
Example 2	<20min	47.36
Comparative Example 1	About 55min	16.80

In particular, the crystalline powder obtained in Comparative Example 1 had a more serious agglomeration due to moisture absorption during the filtration process (appearance is shown in FIG. 6), and the passage rate through the 80 mesh sieve was only about 25%. The particle size distribution of the crystalline powder is shown in Fig. 7.

In contrast, the products of Example 1 and Example 2 can achieve faster filtration, which is more obvious in larger scale production.

Example 4

At 25 ° C, AHU377 free acid (10g AHU377 calcium salt free), 10g valsartan and 80ml acetone, 15ml isobutanol was added to the reaction flask; 2.9 equivalents relative to valsartan was added at room temperature, the concentration was 0.85 G/ml aqueous sodium hydroxide solution, the temperature is raised to 50 ° C for 25 min; the temperature is lowered to 45 ° C, about 0.3 g of seed crystals are added, the solution is turbid after stirring, and then the external temperature is lowered to 30 ° C at a rate of 1.5 ° C / 10 min. The reaction solution was stirred to a temperature of 15 ° C and stirred for 3 h; then 120 ml of acetone was added dropwise to the system, and the temperature was stirred for 2 h; filtered under a nitrogen atmosphere through a Buchner funnel to obtain a white solid, which was vacuum dried at 40 ° C for 8 h and dried. The solid was 19.2 g, the purity was 99.83%, and the hydrolysis impurity content was 0.12%.

The obtained product was passed through an 80 mesh sieve to obtain 18.5 g of a crystalline powder having a D ₉₀ of 31.60 μm and a D ₅₀ of 8.40 μm. The particle size distribution of the obtained crystalline powder is shown in Fig. 8 .

Example 5

At 25 ° C, AHU377 free acid (10g AHU377 calcium salt free), 10g valsartan and 85ml tetrahydrofuran, 17ml isopropanol was added to the reaction bottle and stirred to dissolve; at room temperature, 2.9 equivalent concentration relative to valsartan was added dropwise It is 0.85 g/ml sodium hydroxide aqueous solution, the temperature is raised to 50 ° C for 25 min; the temperature is lowered to 45 ° C, about 0.3 g of seed crystals are added, the solution is turbid after stirring, and then the external temperature is lowered to 30 at a rate of 1.5 ° C/10 min. °C, the reaction solution was stirred to a temperature of 20 ° C for 3 h; then 135 ml of THF was added dropwise to the system, and the temperature was stirred for 2 h; under a nitrogen atmosphere, suction filtration through a Buchner funnel to obtain a white solid, and vacuum drying at 40 ° C for 8 h. Drying gave a solid of 18.9 g, a purity of 99.83%, and a hydrolyzed impurity content of 0.12%.

The obtained product was passed through an 80 mesh sieve to obtain 18.1 g of a crystalline powder having a D ₉₀ of 32.95 μm and a D ₅₀ of 8.71 μm. The particle size distribution of the obtained crystalline powder is shown in Fig. 9 .

Example 6

At 25 ° C, AHU377 free acid (10g AHU377 calcium salt free), 10g valsartan and 70ml acetone, 12ml n-butanol was added to the reaction flask and stirred to dissolve; at room temperature, 2.9 equivalent concentration relative to valsartan was added dropwise It is 0.85 g/ml sodium hydroxide aqueous solution, the temperature is raised to 50 ° C for 25 min; the temperature is lowered to 45 ° C, about 0.3 g of seed crystals are added, the solution is turbid after stirring, and then the external temperature is lowered to 30 at a rate of 1.5 ° C/10 min. °C, the reaction solution was moved to a temperature of 25 ° C for 3 h; then 150 ml of acetone was added dropwise to the system, and the temperature was stirred for 1 h; under a nitrogen atmosphere, filtered through a Buchner funnel to obtain a white solid, which was vacuum dried at 40 ° C for 8 h. Drying gave 19.5 g of a solid with a purity of 99.78% and a hydrolyzed impurity content of 0.13%.

The obtained product was passed through an 80 mesh sieve to obtain 18.7 g of a crystalline powder having a D ₉₀ of 31.16 μm and a D ₅₀ of 8.28 μm.

Example 7

At 25 ° C, AHU377 free acid (10g AHU377 calcium salt free), 10g valsartan and 88ml acetone, 40ml isopropanol was added to the reaction flask and stirred to dissolve; at room temperature, 2.9 equivalent concentration relative to valsartan was added dropwise It is a 0.85 g/ml aqueous sodium hydroxide solution, and the temperature is raised to 50 ° C for 25 min; the temperature is lowered to 45 ° C, about 0.3 g of seed crystals are added, the solution is turbid after stirring, and then the external temperature is lowered to 30 at a rate of 0.5 ° C/10 min. °C, the reaction solution was moved to a temperature of 25 ° C for 2 h; then 120 ml of acetone was added dropwise to the system, and the temperature was stirred for 3 h; under a nitrogen atmosphere, suction filtration through a Buchner funnel to obtain a white solid, which was vacuum dried at 40 ° C for 8 h. Drying gave 18.5 g of a solid with a purity of 99.80% and a hydrolyzed impurity content of 0.12%.

The obtained product was passed through an 80 mesh sieve to obtain 17.6 g of a crystalline powder having a D ₉₀ of 87.23 μm and a D ₅₀ of 46.23 μm.

Example 8

At 25 ° C, AHU377 free acid (10g AHU377 calcium salt free), 10g valsartan and 90ml acetonitrile, 25ml isopropanol was added to the reaction flask and stirred to dissolve; at room temperature, 2.9 equivalent concentration relative to valsartan was added dropwise It is 0.85 g/ml sodium hydroxide aqueous solution, the temperature is raised to 50 ° C for 25 min; the temperature is lowered to 45 ° C, about 0.3 g of seed crystals are added, the solution is turbid after stirring, and then the external temperature is lowered to 30 at a rate of 1.0 ° C / 10 min. °C, the reaction solution was moved to a temperature of 25 ° C for 2 h; then, 130 ml of acetonitrile was added dropwise to the system, and the temperature was stirred for 2 h. Under a nitrogen atmosphere, the mixture was filtered through a Buchner funnel to obtain a white solid, which was vacuum dried at 40 ° C for 8 h. Drying gave a solid of 19.0 g, a purity of 99.81%, and a hydrolyzed impurity content of 0.10%.

The obtained product was passed through an 80 mesh sieve to obtain 18.6 g of a crystalline powder having a D ₉₀ of 50.75 μm and a D ₅₀ of 11.03 μm.

Influencing factors study 1

By using the amount of the feed of Example 1, the feed ratio, the amount of the poor solvent added, and the reaction conditions, by changing the type and/or ratio of the good solvent and the poor solvent in the mixed solvent, the crystal powder powder obtained by the different solvent systems was investigated. The results are as follows:

It can be seen that when the remaining factors are constant, the higher the proportion of poor solvent in the mixed solvent, the smaller the particle size of the obtained LCZ696 product, the decreasing the filtration rate, and the rapid decrease at about 20 μm, wherein the first group is above 60 min, and the same filtration. Under the condition, the second group was about 35 minutes. The inventors have also found that the solvent system and solvent ratio have little effect on the level of hydrolyzed impurities.

In addition, in order to achieve a large particle size product, it is necessary to prolong the crystallization time. Specifically, in the seventh group reaction, in addition to reducing the amount of the poor solvent in the mixed solvent, it is necessary to extend the crystallization time to 12 h or more after adding the poor solvent. This large particle size product can be achieved, so for LCZ696 products, it is not economical to prepare a product with too large particle size.

Example 9

At 25 ° C, AHU377 free acid (10g AHU377 calcium salt free), 10g valsartan and 90ml acetone, 20ml isopropanol was added to the reaction bottle and stirred to dissolve; at room temperature, 2.6 equivalent concentration relative to valsartan was added dropwise It is 0.9g/ml sodium hydroxide aqueous solution, the temperature is raised to 50 ° C for 25min; the temperature is lowered to 45 ° C, the seed crystal is added about 0.3g, the solution is turbid after stirring, and then the external temperature is reduced to 30 at a rate of 1.0 ° C / 10 min. °C, the reaction solution was moved to a temperature of 25 ° C for 3 h; then 120 ml of acetone was added dropwise to the system, and the temperature was stirred for 1 h; suction filtration through a Buchner funnel under nitrogen to obtain a white solid, vacuum drying at 35 ° C for 12 h Drying gave 16.5 g of solid with a purity of 99.92% and a hydrolyzed impurity content of 0.03%.

The obtained product was passed through an 80 mesh sieve to obtain 15.8 g of a crystalline powder having a D ₉₀ of 45.74 μm and a D ₅₀ of 16.34 μm.

Example 10

AHU377 free acid (10g AHU377 calcium salt free), 10g valsartan and 90ml C at 25 °C The ketone and 20 ml of n-butanol were added to the reaction flask and stirred and dissolved; a 2.8 equivalent aqueous solution of 0.9 g/ml of valsartan was added dropwise at room temperature, and the temperature was raised to 50 ° C for 25 min; the temperature was lowered to 45 ° C. Add about 0.3g of seed crystal, stir the solution after turbidity, then reduce the external temperature to 30 ° C at a rate of 1.0 ° C / 10 min, and move the reaction solution to 25 ° C for 3 h; then add 120 ml of acetone to the system. The mixture was stirred at a temperature for 1 h; filtered under suction with a Buchner funnel under nitrogen to give a white solid, which was dried under vacuum at 35 ° C for 12 h and dried to give a solid 17.8 g, a purity of 99.89% and a hydrolyzed impurity content of 0.03%.

The obtained product was passed through an 80 mesh sieve to obtain 17.0 g of a crystalline powder having a D ₉₀ of 40.86 μm and a D ₅₀ of 11.79 μm.

Example 11

At 25 ° C, AHU377 free acid (10g AHU377 calcium salt free), 10g valsartan and 90ml acetone, 20ml isobutanol was added to the reaction flask and stirred to dissolve; at room temperature, add 2.95 equivalent concentration relative to valsartan It is 0.9g/ml sodium hydroxide aqueous solution, the temperature is raised to 50 ° C for 25min; the temperature is lowered to 45 ° C, the seed crystal is added about 0.3g, the solution is turbid after stirring, and then the external temperature is reduced to 30 at a rate of 1.0 ° C / 10 min. °C, the reaction solution was moved to a temperature of 25 ° C for 2 h; then 120 ml of acetone was added dropwise to the system, and the temperature was stirred for 2 h; under a nitrogen atmosphere, suction filtration through a Buchner funnel gave a white solid, and vacuum drying at 35 ° C for 12 h. Drying gave a solid of 18.9 g, a purity of 99.38%, and a hydrolyzed impurity content of 0.53%.

The obtained product was passed through an 80 mesh sieve to obtain 18.1 g of a crystalline powder having a D ₉₀ of 44.48 μm and a D ₅₀ of 14.54 μm.

Comparative Example 2

At 25 ° C, AHU377 free acid (10g AHU377 calcium salt free), 10g valsartan and 90ml acetone, 20ml isopropanol was added to the reaction bottle and stirred to dissolve; at room temperature, add 2.4 equivalent concentration relative to valsartan It is 0.9g/ml sodium hydroxide aqueous solution, the temperature is raised to 50 ° C for 25min; the temperature is lowered to 45 ° C, the seed crystal is added about 0.3g, the solution is turbid after stirring, and then the external temperature is reduced to 30 at a rate of 1.0 ° C / 10 min. °C, the reaction solution was moved to a temperature of 25 ° C for 3 h; then 120 ml of acetone was added dropwise to the system, and the temperature was stirred for 2 h; suction filtration through a Buchner funnel under nitrogen to obtain a white solid, vacuum drying at 35 ° C for 12 h Drying gave a solid of 12.5 g, a purity of 99.90%, and a hydrolyzed impurity content of 0.02%.

The obtained product was passed through an 80 mesh sieve to obtain only 11.8 g of a crystalline powder having a D ₉₀ of 42.35 μm and a D ₅₀ of 13.01 μm.

Comparative Example 3

At 25 ° C, AHU377 free acid (10g AHU377 calcium salt free), 10g valsartan and 90ml acetone, 20ml isopropanol was added to the reaction flask and stirred to dissolve; at room temperature, 3.1 equivalent concentration relative to valsartan was added dropwise It is 0.9g/ml sodium hydroxide aqueous solution, the temperature is raised to 50 ° C for 25min; the temperature is lowered to 45 ° C, the seed crystal is added about 0.3g, the solution is turbid after stirring, and then the external temperature is reduced to 30 at a rate of 1.0 ° C / 10 min. °C, the reaction solution was moved to a temperature of 25 ° C for 3 h; then 120 ml of acetone was added dropwise to the system, and the temperature was stirred for 2 h; suction filtration through a Buchner funnel under nitrogen to obtain a white solid, vacuum drying at 35 ° C for 12 h Drying gave 18.5 g of solid, purity of 96.75%, and hydrolysis impurity content of 1.87%, and the obtained product was pale yellow.

The obtained product was passed through an 80 mesh sieve to obtain 17.9 g of a crystalline powder having a D ₉₀ of 43.66 μm and a D ₅₀ of 12.52 μm.

Influencing factors research 2

Using the reaction conditions such as the amount of feed, the feed ratio, and the solvent system of Example 1, the amount and concentration of sodium hydroxide were used to study the effect of the amount and concentration of sodium hydroxide on the amount of hydrolyzate, as shown in the following table:

Numbering	Equivalent (relative to valsartan)	Concentration (g/ml)	Hydrolyzed impurities (%)	D 90 (μm)	Yield
1	2.90	0.6	0.13	42.67	82.5%
2	2.90	0.9	0.12	44.93	86.7%
3	3.00	0.9	0.85	43.48	87.1%
4	3.00	0.7	0.87	42.16	84.3%
5	2.60	0.9	0.02	43.73	69.8%
6	2.30	0.9	0.02	41.46	51.4%
7	3.20	0.9	2.74	42.59	84.5%

It can be seen from the above table that the amount of sodium hydroxide only affects the yield and impurity content, but has little effect on the powder morphology. Specifically, within the scope of the protection of the present invention, the yield gradually decreases with the decrease of the amount of sodium hydroxide. When the amount of sodium hydroxide is less than 2.5 equivalents, although the particle size and impurities are satisfactory, the yield is The sharp drop to below 60% can not meet the requirements of industrial production; when the amount of sodium hydroxide is more than 3.0 equivalents (relative to valsartan), the content of hydrolyzed impurities exceeds 1.0%, after the product is subsequently prepared into a preparation, Does not meet the requirements for stability of the formulation.

In addition, within the scope of the claimed invention, the concentration of sodium hydroxide has a slight effect on the preparation process, as shown by the fact that when the concentration of sodium hydroxide is lowered, with more water being introduced, the reaction yield is lowered.

It can be seen that in the synthesis process, the powder properties of the LCZ696 crystalline powder are greatly affected by the solvent system; in addition, in the synthesis process, the smaller the particle size of the crystalline powder, the longer the filtration time required. Especially in large-scale reactions, which makes the product moisture absorption caused by excessive exposure to the air for a long time, and the resulting product has a more serious compaction, which is not conducive to the subsequent preparation process; The rate and the content of hydrolyzed impurities, which are affected by the amount and concentration of sodium hydroxide; and the LCZ696 crystalline powder with specific powder properties and low hydrolyzed impurities, and the optimization of the synthesis process requires a comprehensive solvent system. A number of factors affecting the amount and concentration of sodium hydroxide.

Second, the preparation research part

Using the different batches of products prepared by the synthetic research part, through the adjustment of the properties of the raw materials, formulation and process parameters, the effects of the properties of the drug substance and the content of the hydrolysis impurities on the quality of the preparation are known.

Example 12

LCZ696 tablets (100mg)

The LCZ696 crystalline powder (D ₉₀ = 43.90 μm, hydrolyzed impurities: 0.02%) obtained by the method of Example 1 was used as a drug substance.

Preparation:

1. Pass the original and auxiliary materials through a 40 mesh sieve for use;

2. pre-mixing the internal phase particle components in the prescription, and pressing the pre-mixed mixture using a dry granulator to obtain internal phase particles after granulation;

3. The inner phase particles are mixed with the added crospovidone and magnesium stearate, and after mixing, the resulting mixture is tableted.

The resulting core was coated with an Opadry coating polymer to give a coated tablet. During the preparation process, the obtained internal phase particles have good fluidity, and the obtained tablets have a smooth surface and a small difference in tablet weight.

Example 13

LCZ696 tablets (100mg)

The LCZ696 crystalline powder (D ₉₀ = 43.07 μm, hydrolyzed impurities: 0.58%) obtained by the method of Example 1 was used as a drug substance.

The LCZ696 core was prepared in the same manner as in Example 12. The resulting core was coated with an Opadry coating polymer to give a coated tablet.

During the preparation process, the obtained internal phase particles have good fluidity, and the chip surface obtained by tableting is smooth, and the difference in tablet weight is small.

Example 14

LCZ696 tablets (100mg)

The LCZ696 crystalline powder (D ₉₀ = 31.60 μm, hydrolyzed impurities: 0.12%) obtained by the method of Example 4 was used as a drug substance.

The LCZ696 core was prepared in the same manner as in Example 12. The resulting core was coated with an Opadry coating polymer to give a coated tablet.

During the preparation process, the obtained internal phase particles have good fluidity, and the obtained tablets have a smooth surface and a small difference in tablet weight.

Example 15

LCZ696 tablets (100mg)

The LCZ696 crystalline powder (D90 = 31.60 μm, hydrolyzed impurities: 0.12%) obtained by the method of Example 4 was used as a drug substance.

The LCZ696 core was prepared in the same manner as in Example 12. The resulting core was coated with an Opadry coating polymer to give a coated tablet.

During the preparation process, the obtained internal phase particles have good fluidity, and the obtained tablets have a smooth surface and a small difference in tablet weight.

Example 16

LCZ696 tablets (100mg)

The LCZ696 crystalline powder (D ₉₀ = 87.23 μm, hydrolyzed impurities: 0.13%) obtained by the method of Example 7 was used as a drug substance.

The LCZ696 core was prepared in the same manner as in Example 12. The resulting core was coated with an Opadry coating polymer to give a coated tablet.

During the preparation process, the obtained internal phase particles have good fluidity, and the chip surface obtained by tableting is smooth, and the difference in tablet weight is small.

Example 17

LCZ696 tablets (100mg)

The LCZ696 crystalline powder (D ₉₀ = 32.95 μm hydrolyzed impurities: 0.14%) obtained by the method of Example 5 was used as a drug substance.

The LCZ696 core was prepared in the same manner as in Example 12. The resulting core was coated with an Opadry coating polymer to give a coated tablet.

During the preparation process, due to the lack of a flow aid in the internal phase, the mixing effect of the raw materials is slightly inferior to that of the formulation with the flow aid in the formulation, so that the required mixing time is relatively longer, but the obtained internal phase particles have substantially no difference in fluidity. The tablet obtained by tableting has a smooth surface and a small difference in tablet weight.

Example 18

LCZ696 tablets (100mg)

The LCZ696 crystalline powder (D ₉₀ = 32.95 μm, hydrolyzed impurities: 0.14%) obtained by the method of Example 5 was used as a drug substance.

The LCZ696 core was prepared in the same manner as in Example 12. The resulting core was coated with an Opadry coating polymer to give a coated tablet.

During the preparation process, the obtained internal phase particles have good fluidity. Since no lubricant is added, the core of the tablet obtained by pressing is slightly burred, but the overall appearance conforms to the requirements of the pharmacopoeia.

Comparative Example 4

LCZ696 tablets (100mg)

The LCZ696 crystalline powder (D ₉₀ = 16.80 μm, hydrolyzed impurities: 0.04%) obtained in Comparative Example 1 was used as a drug substance, and the same formulation as in Example 12 was used.

The preparation method is the same as that in the embodiment 12, but in the preparation process, since the particle size of the raw material is too small, the sticking phenomenon occurs in the dry granulation process, but the subsequent process is not affected, and the surface color of the obtained core is slightly uneven, compared with the embodiment. The surface of the chip obtained in 12 to 16 was slightly darker, but the overall condition was still satisfactory.

Comparative Example 5

LCZ696 tablets (100mg)

The LCZ696 crystalline powder (D ₉₀ = 43.66 μm, hydrolyzed impurities: 1.87%) obtained in Comparative Example 3 was used as a drug substance, and the same formulation as in Example 12 was used.

The LCZ696 core was prepared in the same manner as in Example 12. The resulting core was coated with an Opadry coating polymer to give a coated tablet.

During the preparation process, the obtained internal phase particles have good fluidity, and the obtained tablets have a smooth surface and a small difference in tablet weight. However, due to the high content of hydrolysis impurities in the drug substance, the core color is slightly darker and white-like.

Example 19

Dissolution test

The dissolution rate of the LCZ696 dry granulation tablets obtained in Examples 12 to 16 and Comparative Examples 4 to 5 was examined using the Chinese Pharmacopoeia (2010 edition) Appendix XC Dissolution Determination Method Second Method Paddle Method. The data obtained are shown in the following table. :

project	Particle size (μm)	15min	30min	45min
Example 12	43.90	85.50	97.37	98.87
Example 13	48.07	85.73	98.55	99.55
Example 14	31.60	86.21	97.13	99.91
Example 15	31.60	85.20	98.26	99.46
Example 16	87.23	81.62	94.50	98.91
Example 17	32.95	85.54	97.35	99.61
Example 18	32.95	86.45	98.20	99.43
Comparative Example 4	16.80	85.31	95.94	99.64
Comparative Example 5	43.66	85.53	96.50	99.97

It can be seen that the tablets obtained in Examples 12-18 and Comparative Examples 4-5 all achieved dissolution of more than 70% in 15 minutes, and nearly completely dissolved in 45 minutes of dissolution, meeting the clinical drug requirements of the LCZ696 product.

Isometric amplification test (200mg)

The amount of the raw materials used in Examples 12 to 16 and Comparative Examples 4-5 was doubled, and the tablets of 200 mg specifications were pressed using the same process parameters.

Using the Chinese Pharmacopoeia (2010 edition) Appendix XC dissolution method, the second method of paddle method, corresponding to the detection of 200mg specification tablet dissolution, the data obtained as shown below:

project	Particle size (μm)	15min	30min	45min
Example 12	43.09	83.45	96.24	99.17
Example 13	48.07	85.37	97.61	99.72
Example 14	31.60	85.80	96.72	99.45
Example 15	31.60	84.23	94.43	99.28
Example 16	87.23	74.92	93.07	99.58

Example 17	32.95	84.77	96.82	99.87
Example 18	32.95	85.54	97.34	99.50
Comparative Example 4	16.80	64.73	87.43	98.12
Comparative Example 5	43.66	83.45	96.35	98.43

It can be seen that after the preparation of the tablet of 200 mg size in a proportional enlargement, the dissolution properties of the tablets obtained in various places are reduced to some extent, and the tablets obtained by the prescriptions and processes of Examples 12-18 and Comparative Example 5 can still be realized. Dissolution of more than 70% of the active ingredient in 15 minutes, and complete dissolution in 45 minutes, in line with the clinical drug requirements of LCZ696 products, can achieve a proportional enlargement of the preparation.

However, for Comparative Example 4, since the particle size of the drug substance used was too small, the tablet obtained by the equal-amplification amplification had an active ingredient dissolution of less than 70% within 15 minutes, which did not meet the clinical drug requirements of the LCZ696 product, and the preparation could not be achieved. Zoom in.

In the further comparative reduction test, the prescriptions and processes of Examples 12-18 and Comparative Example 5 can also achieve the equal reduction of the prescription and the process, while the Comparative Example 4 is also effective because the tablet is effective within 15 minutes. The dissolution of the ingredients was less than 70%, and the ratio of the formulation was not reduced.

In the equal reduction experiments (50 mg) and further iso-amplification experiments (400 mg), we found that the formulations of Examples 12-18 and Comparative Example 5 were still able to achieve a proportional reduction/magnification.

Example 20

Stability test

The solid oral preparation (100 mg) obtained in the examples was allowed to stand under accelerated conditions (40 ° C ± 2 ° C, RH 75% ± 5%) for 30 days to examine changes in hydrolysis impurities and appearance, and the results were as follows:

It can be seen from the stability experiment that the content of the hydrolyzed impurities has a great influence on the quality of the preparation. Specifically, the hydrolysis impurities in the examples 12-18 and the comparative example 4 are less than 1.0%, and the preparation is hydrolyzed in the accelerated test. Incremental comparison Small, 60-day increment is below 0.10%, and the appearance of the preparation is still not white when the accelerated experiment is completed, and no significant change has occurred.

For Comparative Example 5, since the content of the hydrolyzed impurities is higher than 1.0%, the increase of the hydrolysis impurities during the accelerated test is large, and the 60-day increment is much higher than 0.10%, and the acceleration is increasing, and the accelerated experiment is completed. When the appearance of the preparation changed from white to pale yellow, the appearance changed significantly.

Influencing factors experiment 4

The raw material medicines with different powder properties and impurity contents were obtained by adjusting the solvent system, the feed ratio, the reaction conditions and the like, and the solid oral preparations were prepared by the same prescription and preparation process as in Example 12, respectively, using Example 17 and Examples. The method of 18 studies the effect of the powder properties and impurity content of the raw material on the enlargement/reduction of the preparation ratio and the stability of the preparation.

The results are as follows:

It can be seen from the above influencing factors that the particle size of the drug substance and the content of the hydrolyzed impurities respectively affect the proportional enlargement/reduction of the preparation and the stability of the preparation.

The specific performance is that the ratio of enlargement/reduction of the preparation is mainly related to the particle size of the drug substance. When the particle size D90 of the drug substance is 20-100 μm, the formulation and process of the preparation can be scaled up/down, when the particle size of the drug substance is D90. When the temperature is ~60 μm, the dissolution property of the obtained preparation is the best, and the effect of the enlargement/reduction ratio of the prescription is optimal.

The stability of the preparation is mainly related to the content of hydrolysis impurities in the raw material medicine. When the content of hydrolysis impurities in the preparation is less than 1.0%, the increase of hydrolysis impurities in the accelerated experiment for 30 days is less than 0.10%, which is in line with the quality requirements of LCZ696 preparation. .

In summary, when the particle size of the drug substance is controlled to be 20 to 100 μm, the problem of enlargement/reduction of the prescription ratio can be solved, and controlling the content of the hydrolysis impurity in the drug substance to be 1.0% or less is advantageous for solving the problem of improving the stability of the preparation.

Example 21

Adverse reaction investigation experiment (behavioral experiment)

Experimental sample:

Test articles: solid oral preparations obtained in Examples 12 and 13 and Comparative Example 5 (day 0); negative control: using a vehicle control substance - deionized water (laboratory preparation).

Experimental animals:

ICR mice, SPF grade, sex and number of animals used for testing, females: 25, males: 25. Body weight and age range at the time of purchase, female animals: 9.6 to 13.5 g, 3 weeks old; male animals: 10.0 to 13.0 g, 3 weeks old.

Dosage:

Vehicle control group 0mg/kg, compound 1 solid oral preparation powder, according to the active ingredient low dose group 1.0mg/kg, medium dose group 10mg/kg, high dose group 110mg/kg intragastric administration, the administration time was One week (7 days).

experiment procedure:

Climbing rod test operation: Vertically erected with a smooth metal rod (approximately 0.9 cm in diameter and approximately 72 cm in length). Before the administration and at different time points after the administration, the aerial pole reflex operation was performed after the end of the climbing rod test operation: the tail of the mouse was lifted, and the mouse was thrown after 4 rotations to observe the abnormal posture of the landing of the mouse (side or back landing) ), repeated 5 times in a row, and scored according to Irwin's behavioral grading scale. Climbing rods and aerial righting reflexes were observed at 2, 4, 8 and 24 hours before and immediately after the last dose. After the end of the experiment, the surviving animals used in this test were sacrificed by anesthesia with excess CO ₂ . Behavioral scores are expressed in terms of frequency. The above data should be statistically analyzed using SAS 9.1.

Grading criteria, Irwin’s behavioral grading scoring criteria:

Level 0: Normal standing

Level 1: 1 to 2 times out of 5 times

Level 2: 3 to 4 times out of 5 times

Level 3: 5 times all lying on the side

Level 4: 1 to 2 times out of 5 times

Level 5: 3 to 4 times out of 5 times

Level 6: 5 times all back to the ground

Level 7: carrying the ground and slowing down

Level 8: Cannot be corrected

Results and discussion:

The solid oral preparations obtained in Examples 12 and 13 showed that the content of the hydrolyzed impurities in the preparation was less than 1.0%, and the observation results of the rods and the aerial righting reflexes at the observation time points of the animals in the active ingredients of 1.0, 10 and 110 mg/kg were compared with the vehicle. There was no significant difference between the groups (0mg/kg) (P>0.05).

The results of the solid oral formulation 10 and 110 mg/kg obtained in Comparative Example 5 were distributed between Grades 3 and 5, and abnormal performance was observed in some animals.

It can be seen from the above statistical results that the solid oral preparations obtained in Examples 12 and 13 have a hydrolyzed impurity content of 1.0% or less, and the incidence of adverse reactions of the solid oral preparation is very small; and the content of the hydrolyzed impurities in the solid oral preparation obtained in Comparative Example 5 is obtained. Above 1.0%, the incidence of adverse reactions is significantly increased. However, the specific cause of the adverse reaction in mice is unknown. It is speculated that the solid oral preparation may produce other specific impurities due to excessive hydrolysis of impurities, or due to the synergistic effect between the drug and the impurities. It is known that the control of the drug substance and Impurity levels are important for reducing adverse drug reactions.

The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and combinations thereof may be made without departing from the spirit and scope of the invention. Simplifications should all be equivalent replacements and are included in the scope of the present invention.

Claims (12)

1. A pharmaceutical composition comprising LCZ696, comprising a crystalline powder of LCZ696, a filler, a disintegrant, a binder, characterized in that the crystalline composition of the LCZ696 is 20 μm ≤ D ₉₀ ≤ ₁₀₀ μm.
2. The pharmaceutical composition of LCZ696 according to claim 1, characterized in that the crystalline powder of the LCZ696 is 25 μm ≤ D ₉₀ ≤ 75 μm, preferably 30 μm ≤ D ₉₀ ≤ 60 μm.
3. The pharmaceutical composition of LCZ696 according to any one of claims 1 to 2, characterized in that the crystalline powder of the LCZ696 is ₅ μm ≤ D ₅₀ ≤ ₅₀ μm, preferably 8 μm ≤ D ₅₀ ≤ 30 μm.
4. The pharmaceutical composition of LCZ696 according to any one of claims 1 to 3, characterized in that the crystalline powder of the LCZ696 has a hydrolyzed impurity content of less than 1.0%.
5. The pharmaceutical composition of LCZ696 according to any one of claims 1 to 4, characterized in that the filler is selected from the group consisting of microcrystalline cellulose, lactose, starch, pregelatinized starch, mannitol, calcium hydrogen phosphate, sorbitol One or a mixture of two or more; when the LCZ 696 parts by mass is 1 part, the filler is used in an amount of 0.2 to 0.8 parts.
6. The pharmaceutical composition of LCZ696 according to any one of claims 1 to 5, wherein the disintegrant is selected from the group consisting of crospovidone, sodium carboxymethyl starch, croscarmellose sodium, and carboxy One or a mixture of two or more kinds of methyl cellulose calcium, when the amount of LCZ696 is 1 part by mass, the disintegrant is used in an amount of 0.04 to 0.4 parts, and the disintegrant may be added, added, and Internal and external ways.
7. The pharmaceutical composition of LCZ696 according to claim 6, wherein the pharmaceutical composition of the LCZ696 comprises internal phase particles and an additional adjuvant, the internal phase particles comprising a crystalline powder of LCZ696, a filler, a disintegrant, and a binder. In the mixture, the disintegrating agent is internally and externally added, and the external auxiliary material comprises a disintegrating agent, and the mass ratio of the internally added disintegrant to the external disintegrating agent is 0.4 to 3.8:1.
8. The pharmaceutical composition of LCZ696 according to any one of claims 1 to 7, wherein the binder is selected from the group consisting of low-substituted hydroxypropylcellulose, hypromellose, sodium carboxymethylcellulose, and polydimen One or a mixture of two or more of a ketone and an ethyl cellulose, when the LCZ 696 parts by mass is 1 part, the binder is used in an amount of 0.05 to 0.5 part.
9. The pharmaceutical composition of LCZ696 according to any one of claims 1 to 8, wherein the pharmaceutical composition of the LCZ696 is used in an amount of 0.3 to 0.7 parts, and the disintegrant is used in an amount of 0.05 to 0.3 parts. The amount of the binder used is 0.1 to 0.4 parts.
10. The pharmaceutical composition of LCZ696 according to any one of claims 1 to 9, wherein the pharmaceutical composition of the LCZ696 further comprises a glidant and/or a lubricant, the flow aid being selected from the group consisting of silica, One or a mixture of two or more kinds of talc, when the amount of LCZ696 is 1 part, the amount of the glidant is 0.002 to 0.05 parts; the lubricant is selected from magnesium stearate, hydrogenated vegetable oil, poly One or a mixture of two or more of ethylene glycol, stearic acid, palmitic acid, carnauba wax, when LCZ 696 parts by mass In the case of 1 part, the lubricant is used in an amount of 0.01 to 0.1 part.
11. The pharmaceutical composition of LCZ696 according to claim 1, wherein the pharmaceutical composition of the LCZ696 is prescribed according to any one of the following:

    Prescription 1:

    

    Prescription 2:

    

    Prescription 3:

    
12. A method of preparing a pharmaceutical composition of LCZ696 according to any one of claims 1 to 11, characterized in that the preparation method comprises the following preparation steps:

    (1) Passing the original and auxiliary materials through a 40 mesh sieve for use;

    (2) pre-mixing the added components in the prescription, pressing the pre-mixed mixture using a dry granulator, and obtaining the inner phase particles after the granulation;

    (3) mixing the inner phase particles with the external auxiliary material, and after mixing, the resulting mixture is tableted to obtain a LCZ696 core.

    The tablet is further subjected to a coating treatment using any one of hypromellose, powdered sugar, hydroxypropylcellulose or Opadry.

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