CN113750063A

CN113750063A - Solid preparation of piperazine isethionate cetirizine and preparation method thereof

Info

Publication number: CN113750063A
Application number: CN202111086209.0A
Authority: CN
Inventors: 王静; 孙嘉怡; 杨猛
Original assignee: Jiangsu Food and Pharmaceutical Science College
Current assignee: Jiangsu Food and Pharmaceutical Science College
Priority date: 2021-09-16
Filing date: 2021-09-16
Publication date: 2021-12-07

Abstract

The invention relates to the technical field of pharmaceutical preparations, and discloses a solid preparation of piparide isethionate and a preparation method thereof, wherein the solid preparation is a tablet of piparide isethionate, and is prepared by dry granulation and tabletting, and the angle of repose of the dry granulated particles is less than 45 degrees; the preparation auxiliary materials of the piperacillin hydrochloride isethionate tablet comprise a filler, a disintegrant, a glidant and a lubricant. The optimized product of the invention takes the piparide isethionate as a raw material medicine, and improves the dosage form into piparide isethionate tablets. The invention establishes and optimizes a set of complete preparation process of the pipera cily isethionate tablet, finally obtains the optimal prescription and preparation process of the pipera cily isethionate tablet, can solve the problems of poor solubility and large hygroscopicity, meets the requirements of quality and stability, and can be popularized in production.

Description

Solid preparation of piperazine isethionate cetirizine and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, relates to a solid preparation of piperacillin isethionate and a preparation method thereof, and particularly relates to a prescription of piperacillin isethionate and a preparation process thereof.

Background

Piparib (Palbociclib) is the first worldwide CDK4/6 kinase inhibitor approved by the us FDA for marketing on day 3/2 of 2015, developed, manufactured and sold by Pfizer. First line therapy, approved as an endocrine foundation with letrozole, treats menopausal women with androgen receptor (ER) positive, human epidermal growth factor receptor 2(HER2) negative advanced breast cancer patients.

The piparixiline has good curative effect in treating ER positive and HER2 negative locally advanced or metastatic breast cancer, and has good curative effect when used together with an aromatase inhibitor as initial endocrine treatment for postmenopausal female patients; since 2015 time of U.S. marketing, hundreds of countries and regions are marketed worldwide. The pfeiffei Capsules (Palbociclib Capsules) developed by the company pfeiri, with a trade name: IBRANCER; the raw material medicine is piparixilline free alkali.

However, the pipera cypress cily capsule product has the defects of poor solubility of the raw material medicines and large hygroscopicity in the production process.

Disclosure of Invention

In view of the above, the application provides a solid preparation of piperazine mesylate occidentalis and a preparation method thereof, and the invention provides a tablet of piperazine mesylate occidentalis and a preparation process thereof.

The invention provides a solid preparation of piperazine cypress cetirizine isethionate, which is a piperazine cypress cetirizine isethionate tablet and is prepared by dry granulation and tabletting, wherein the angle of repose of the dry granulated granules is less than 45 degrees;

the preparation auxiliary materials of the piperacillin hydrochloride isethionate tablet comprise a filler, a disintegrant, a glidant and a lubricant.

Aiming at the defects of the existing product, the application develops the piperazili isethionate tablet, the active ingredient of the preparation product is piperazili isethionate, which is yellowish to orange powder, is an oral cyclin-

dependent kinase

4 and 6 inhibiting drug and plays a role mainly by regulating the cell cycle. Its advantages include low hygroscopicity, high solubility and stability. However, the prescription process in the actual production of the drug substance of pipariril isethionate still has the problems of poor fluidity and unfavorable production, so the research further improves the preparation process for the first time and optimizes the prescription.

In the embodiment of the invention, the solubility of the drug substance is examined according to the solubility measuring method by respectively putting the drug substance of the piparide isethionate in four media, namely water, a hydrochloric acid solution with pH1.0, a phosphate buffer solution with pH6.8 and an acetate buffer solution with pH 4.5. The results are as follows:

as is clear from Table 1, the solubility of piparide isethionate in hydrochloric acid solution at pH1.0 is the best, and the solubility in phosphate buffer solution at pH6.8 is the worst, so that the solubility of piparide isethionate has a certain pH dependence.

TABLE 1 solubility of piperazine isethionate cetirizine in different media

In the prescription, the preparation auxiliary materials of the piperacillin hydrochloride isethionate tablet comprise pharmaceutically acceptable auxiliary material types of a filler, a disintegrant, a glidant and a lubricant. For the specific types of the auxiliary materials, the auxiliary materials with good compatibility with the pipera cypress isethionate are adopted in the embodiment of the invention. In a preferred embodiment of the invention, the filler is selected from one or both of microcrystalline cellulose and lactose, in particular microcrystalline cellulose and lactose (lactose monohydrate). The mass ratio of the filler to the pipera cypress cetirizine isethionate tablet can be 54-56%; the mass ratio of the microcrystalline cellulose to the lactose is (1-3): 1, preferably 2: 1.

in a preferred embodiment of the present invention, the disintegrant is selected from crospovidone (PVPP), which is commercially available from companies such as Pasteur, Hubei Gekko Furan, etc. In the selection of raw and auxiliary materials, because the impurities of the disintegrant (sodium carboxymethyl starch) in the original grinding product have a growing trend in the compatibility result of the raw and auxiliary materials, and in the prescription screening, the recovery rate of the prescription containing the sodium carboxymethyl starch is low; in the invention, the disintegrant crospovidone is preferably used as a key functional auxiliary material in the prescription. Specifically, the mass ratio of the disintegrant in the pipera occidentalis isethionate tablet can be 4% -8%, preferably 5% -7%, and more preferably 6%.

In a preferred embodiment of the present invention, the glidant is colloidal silicon dioxide (or called colloidal silicon dioxide) which mainly reduces the friction between particles, thereby improving the powder flowability; the lubricant is magnesium stearate, so that the friction force between the material and the die can be reduced. The invention uses auxiliary materials with different lubrication mechanisms; the mass ratio of the lubricant to the pipera cypress cetirizine isethionate tablet can be 1-3%, preferably 2%, which is beneficial to flowability and the like. And the dosage proportion of the glidant can be 1-2%.

Through prescription screening, microcrystalline cellulose, lactose monohydrate, crospovidone, colloidal silicon dioxide and magnesium stearate are optimally selected to serve as auxiliary materials of the piperacillin hydrochloride isethionate tablet. In the embodiment of the invention, different prescription compositions are designed, the use amounts of the filling agent, the disintegrating agent and the lubricant are considered by taking the flowability, the fillability, the dissolution behavior and the like of the powder intermediate as indexes, and the use amounts of the auxiliary materials in the prescription are gradually adjusted, so that the composition of the auxiliary materials in the prescription is determined.

In the optimal formula of the embodiment of the invention, the mass ratio of the microcrystalline cellulose as the filler to the lactose as the filler is 2:1, 6 percent of disintegrant crospovidone and 2 percent of magnesium stearate serving as a lubricant. And the specification of the piperacillin hydrochloride isethionate tablet is 125mg dosage mg/granule.

Accordingly, the present embodiments provide a method for preparing a solid formulation of piparix isethionate as described hereinbefore, comprising the steps of:

sieving the raw material drug of the pipera cypress xili isethionate, mixing with auxiliary materials, carrying out dry granulation, wherein the angle of repose of granules is less than 45 degrees, and then carrying out tabletting to obtain the pipera cypress xili isethionate tablet.

The preparation process of the tablet can be divided into four modes of wet granulation and tabletting, dry granulation and tabletting, direct powder tabletting and semi-dry granule tabletting. Different processes and preparation methods have certain influence on the dissolution of the product. The powder prepared by the direct compression process has the advantages of providing disintegration and dissolution, reducing production cost, having good repeatability and the like, but has certain limitation on raw and auxiliary materials, and the preparation method meets the following requirements: the material has good fluidity and compressibility; secondly, the product is stable to air, moisture and heat; the tablet can be compatible with various medicines, has larger 'holding capacity' (namely can be matched with medicines with higher percentage without influencing the tabletting performance), and does not influence the bioavailability of main medicines; fourthly, the granularity is similar to that of most medicines, etc. The dry granulation process has the advantages similar to the powder direct compression process, but the process has more steps of sieving, mixing, briquetting, crushing, granule finishing and the like than the powder direct compression process, so that the problems of unstable dissolution and the like caused by uneven mixing in the powder direct compression process are solved.

The specific process for preparing the piperacillin hydrochloride tablet for isethionic acid in some embodiments of the invention is as follows:

sieving the raw materials with a 40 mesh sieve, and removing hard blocks for later use. Sieving colloidal silicon dioxide and lactose with 80 mesh sieve, and removing hard blocks.

Weighing the microcrystalline cellulose with the prescription amount and the raw material drug of the pipera cypress cetirizine isethionate, sieving the mixture by a 40-mesh sieve, and mixing the sieved mixture. Weighing lactose monohydrate and crospovidone according to the prescription amount, sieving the lactose monohydrate and the crospovidone with the materials obtained in the step for 3 times through a 40-mesh sieve, and uniformly mixing in a self-sealing bag. Granulating by adopting a dry granulating machine; adding colloidal silicon dioxide and magnesium stearate according to the weight of the dry granules, mixing in a self-sealing bag, shaking by hand for 5 minutes, and tabletting to obtain the tablet.

The dry granulation process is adopted in the research, and the main reasons are as follows: (1) the raw material medicines are unstable when meeting water and heated, and wet granulation needs water adding and drying processes, so that the impurities of the product are out of limit, and the wet granulation process is eliminated firstly; (2) tests show that the powder has a lower flowability under direct compression than dry granulation (angle of repose ratio, 45.9 DEG: 36.9 ℃), and that the powder has a significantly lower dissolution rate under direct compression in four different dissolution media than dry granulation. In the screening process of the preparation prescription, all factors are comprehensively considered, the optimal scheme of raw materials and auxiliary materials is creatively obtained in the actual screening process, and the production is facilitated.

According to the prescription, the research mainly inspects briquetting and granulating in the dry granulation process. The results show that the process parameters in the actual production play a crucial role in the production process, wherein the industrial production or the product quality is influenced by the over-high or over-low feeding speed, pressure and the rotating speed of the compression roller.

In a specific embodiment of the invention, the feeding speed of the dry granulation is 4-8rpm, preferably 5-6 rpm; the rotation speed of the press roll is 2-6 rpm. And, the compression roller pressure of the dry granulation may be 20 to 50kg/cm³Preferably 30 to 40kg/cm³。

In a specific embodiment of the present invention, the dry granulation employs a two-stage whole particle screen, preferably: the primary size grading sieve is 2.0mm, and the secondary size grading sieve is 1.0 mm.

In a specific embodiment of the invention, the dry granulation may have a granule angle of repose of from 32 ° to 44 °; the dry granulation may have a bulk density of 0.4-0.6g/cm³The tap density is 0.5-0.8g/cm³. In addition, the invention has no special limitation on the tabletting process parameters and can be carried out by adopting conventional operation.

The angle of repose is an index commonly used to measure the flowability of a particle, and can reflect the ease of powder flow, with good flowability when the angle of repose is small. It is generally considered that the fluidity is good when the angle of repose α is less than 30 ℃ and the fluidity is poor when α is greater than 45 ℃. In the examples of the present application, the angle of repose was determined using a flow analyzer conventional in the art.

The optimal process of the embodiment of the invention adopts a dry granulation process, and the process parameters comprise: the feeding speed is 6rpm, the press roll rotating speed is 4rpm, and the press roll pressure isIs 30kg/cm³The primary size grading sieve is 2.0mm, and the secondary size grading sieve is 1.0 mm.

The embodiment of the invention establishes the optimal prescription and preparation process of the pipera occidentalis tablet isethionate, meets the requirements of quality and stability, and successfully solves the defects of the preparation and production processes of the original preparation.

Drawings

FIG. 1 shows the dissolution results of different filler ratio formulations of example 1 of the present invention;

FIG. 2 shows the dissolution results of different formulations of disintegrant in example 2 of the present invention;

FIG. 3 shows the dissolution results of the disintegrant formulations of different manufacturers of example 3 of the present invention;

FIG. 4 shows the dissolution results for lubricant formulations of example 4 of the present invention in various proportions;

FIG. 5 shows the dissolution results of example 6 of the present invention at different feeding speeds and at different roll speeds;

FIG. 6 shows the results of dissolution in example 7 of the present invention under different nip pressure;

FIG. 7 shows the results of dissolution in different size sieves of example 8 of the present invention;

figure 8 is the dissolution results of the batches with the optimum process parameters of example 9 of the present invention in four different dissolution media.

Detailed Description

The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

For further understanding of the present application, the present application is specifically described below with reference to examples.

In the following examples, the sources and specifications of the raw materials and excipients are as follows: the raw material medicine is from Beijing Bailingwei science and technology limited, and the auxiliary materials are all conventional commercial products.

Example 1

In order to examine the ratio of microcrystalline cellulose and lactose as fillers, the following 3 prescriptions were prepared, and acetate buffer solution with pH4.5 was selected as the medium for prescription screening, and the index of the dissolution was measured at 15 minutes in medium with pH4.5 (according to pharmacopoeia for dissolution measurement of tablets), which is detailed in Table 2 below.

TABLE 2 formulation composition of different Filler proportions

The results of the filler ratio study are as follows:

as can be seen from the dissolution data in fig. 1, the change in the ratio of the filler microcrystalline cellulose to lactose had no significant effect on the dissolution, and microcrystalline cellulose was empirically selected: lactose is used in a ratio of 2: 1.

Example 2

Formulations were prepared for 4%, 6%, 8% proportions of disintegrant and the dissolution of different proportions of disintegrant in medium ph4.5 was examined for 15 minutes, as detailed in table 3 below.

TABLE 3 preparation of different disintegrant dosage formulations

The results of the study of the amount of disintegrant were as follows:

as can be seen from the dissolution data in FIG. 2, the 4% ratio of the disintegrant was less than 85% in 15 minutes, and the 6% and 8% ratios of the disintegrant were not significantly different, so the 6% ratio of the disintegrant was selected as the optimum ratio.

Example 3

The disintegrant crospovidone is taken as a key functional auxiliary material in the prescription, disintegrants of different manufacturers are selected for screening, the prescription is prepared, and the dissolution behavior in acetate buffer solution with the PH of 4.5 is inspected, which is specifically shown in table 4.

TABLE 4 preparation of disintegrant formulations from different manufacturers

The results of the investigation of different manufacturers of disintegrants are as follows:

from the dissolution data in figure 3, it can be seen that there was no significant difference in the dissolution of the disintegrant between the two manufacturers, and the study selected imported crospovidone from basf, germany as the disintegrant in the formulation.

Example 4

To examine the effect of the amount of magnesium stearate on the flowability, dissolution behavior, etc., lubricants were prepared in different proportions and the flowability and dissolution of the intermediate granules in acetate at PH4.5 were examined, as detailed in table 5.

TABLE 5 preparation of lubricant formulations in different proportions

The results of the lubricant dosage are as follows:

as can be seen from the dissolution data in fig. 4, the dissolution rate of the lubricant at 3% ratio is less than 85% at 15min, and the dissolution rates of the lubricants at 1% and 2% ratios are both 85%, but the angles of repose of the lubricants at different ratios are: 41.7 ° (1%), 37.1 ° (2%) and 36.2 ° (3%). The lubricant with a proportion of 1% has a slightly poorer flow, so 2% of magnesium stearate is selected as the lubricant amount.

In summary, the initial optimal recipe is as follows 6:

TABLE 6 Primary prescription of 125mg piparide isethionate tablet

Example 5

According to the types of the auxiliary materials and the using amount of the conventional auxiliary materials, the powder is respectively prepared by direct filling and dry granulation, and the flowability, the bulk density and the tap density of different preparation process prescriptions and the dissolution conditions in 4 media are inspected. See table 7 for details.

TABLE 7 direct powder fill preparation and Dry granulation preparation and investigation

The screening results of the preparation process method are as follows:

the flowability of the powder directly filled material is poor, which is not beneficial to production; the dissolution of the two preparation modes of the self-grinding tablet formula in a hydrochloric acid medium with pH1.0 can reach more than 85 percent, but the dissolution of the powder in a direct filling process with pH4.5 and a water medium is slower than that of a dry granulation process. Both formulations dissolved less than 70% in pH6.8 medium for 6 hours, probably due to the low saturation solubility of the drug in pH6.8 medium. By combining the dissolution conditions, dry granulation is selected as a preparation process of the piparide isethionate tablet. See table 8 for details.

TABLE 8 screening results of preparative procedures

Example 6

Dry granulation parameters-feeding speed and compression roller rotation speed investigation: the optimum formula is adopted, different feeding speeds and different compression roller rotating speeds are set, and the particle size distribution, the flowability, the bulk density, the tap density and the dissolution condition in a medium with the pH value of 4.5 of the material are inspected, and the details are shown in a table 9.

TABLE 9 investigation parameters for different feed rates and roll speeds

The results of the investigation of the feeding speed and the rotating speed of the press roll are as follows:

from table 10 and fig. 5, it can be seen that the feeding speed and the roll rotation speed have little influence on the dissolution, but too small a feeding speed results in a large amount of fine powder and poor flowability of the material. Therefore, the feeding speed and the rotating speed of the press roll are appropriate, so that the feeding speed is 6rpm, and the rotating speed of the press roll is 4 rpm.

TABLE 10 results of examining particle size distribution and flowability at different feeding speeds and at different roll speeds

Example 7

Earlier studies showed that the pressure was less than 20g/cm³When the powder is pressed, the powder is not flaky, the fine powder is too much, and the pressure of a press roll is 30g/cm³In addition, the powder can be pressed into tablets with proper hardness. The pressure is more than 50g/cm³In the process, the color of the pressed slice is deepened, the slice is too hard, and the rolling shaft is easy to block. Therefore, 20-50g/cm³The particle size distribution, flowability, bulk density, tap density and dissolution in pH4.5 media were examined under pressure, and are shown in Table 11.

TABLE 11 different Press roll pressure investigation parameters

The results of the roller pressure test are as follows:

as can be seen from Table 12 and FIG. 6, there was no significant difference between the different roll pressures, but the roll pressure was 50kg/cm³At pH4.5, the dissolution rate in 15 minutes is only 80.0%. Therefore, the compression roller pressure of the tentative dry granulation process was analyzed comprehensively was 30kg/cm³Left and right.

TABLE 12 particle size distribution and flowability results for different roll pressure examinations

Example 8

The size of the sieve of the whole grain influences the size of the dry particles and thus influences the flowability and dissolution behavior of the material, so different recipes are prepared according to table 13 below, and the particle size distribution, flowability, bulk density, tap density and dissolution in the ph4.5 medium are examined, as detailed in the table below.

TABLE 13 examination of different granulation screens

The results of the screen investigation are as follows:

as can be seen from table 14 and fig. 7, when the primary sizing screen was 1.2mm and the secondary sizing screen was 1.0mm, the amount of fine powder of the material was too large and the flowability was poor; when the first-stage whole grain screen mesh is 5.0mm and the second-stage whole grain screen mesh is 1.5mm, the content of particles with more than 20 meshes in the material is 36.86%, the large particles are too large, the weight difference of the tablets is not easy to control, and the dissolution rate is slow. Therefore, a No. 2 sieve with a first-stage whole grain sieve of 2.0mm and a second-stage whole grain sieve of 1.0mm is selected.

TABLE 14 examination of particle size distribution and flowability results for different sizing screens

Example 9

The optimum dry granulation parameters of table 15 were finally obtained by screening the feed rate, the compression roller pressure, the rotation speed and the screen. The formulations of examples 1-4 above were screened and prepared according to the optimal procedure.

TABLE 15 optimal Dry granulation parameters

3 batches were prepared according to the above optimal recipe specifications, each batch was 1000, and dissolution in 4 media was measured to investigate the stability of the recipe process, and the results are shown in FIG. 8.

According to the dissolution curve of fig. 8, the dissolution of the product of the optimal formula and process can reach more than 85% in hydrochloric acid solution and water for 10min, and about 60% in acetic acid and about 30% in phosphate.

The embodiment shows that the optimized product takes the piperacillin isethionate as a raw material drug, and the piperacillin isethionate tablet is improved to the piperacillin isethionate tablet, so that the problems of poor solubility and large hygroscopicity can be solved, the requirements on quality and stability are met, and the piperacillin isethionate tablet can be popularized in production.

The above description is only a preferred embodiment of the present invention, and it should be noted that various modifications to these embodiments can be implemented by those skilled in the art without departing from the technical principle of the present invention, and these modifications should be construed as the scope of the present invention.

Claims

1. The solid preparation of the piperacillin hydrochloride isethionate is characterized in that the piperacillin hydrochloride isethionate tablet is prepared by dry granulation and tabletting, wherein the angle of repose of the dry granulated granules is less than 45 degrees;

2. The solid preparation according to claim 1, wherein the filler is selected from one or both of microcrystalline cellulose and lactose; the disintegrant is selected from crospovidone; the glidant is colloidal silicon dioxide; the lubricant is magnesium stearate.

3. The solid formulation according to claim 2, wherein the filler is microcrystalline cellulose and lactose; the mass ratio of the microcrystalline cellulose to the lactose is (1-3): 1.

4. the solid preparation according to claim 2, wherein the mass ratio of the disintegrant to the piperacillin isethionate tablet is 4% to 8%.

5. The solid preparation according to claim 2, wherein the lubricant is present in the piperacillin isethionate tablet at a mass ratio of 1% to 3%.

6. The solid preparation according to any one of claims 2 to 5, wherein the excipients for the preparation of the piperacillin hydrochloride tablet with isethionic acid comprise: microcrystalline cellulose, lactose, crospovidone, colloidal silicon dioxide, and magnesium stearate; the mass ratio of the microcrystalline cellulose to the lactose is 2: 1; the consumption of the crospovidone is 6 percent, and the consumption of the magnesium stearate is 2 percent.

7. A process for the preparation of a solid formulation of piparide isethionate as defined in any of claims 1 to 6, comprising the steps of:

8. The method of claim 7, wherein the dry granulation is fed at a speed of 4-8rpm, preferably 5-6 rpm; the rotation speed of the press roll is 2-6rpm, and the pressure of the press roll is 20-50kg/cm³Preferably 30 to 40kg/cm³。

9. The method of claim 7, wherein the dry granulation employs a two-stage granulation screen, wherein the primary granulation screen is 2.0mm and the secondary granulation screen is 1.0 mm.

10. The method according to any one of claims 7 to 9, wherein the method comprises a step of mixing the mixture with a solventThe dry-granulated granules have an angle of repose of 32-44 DEG and a bulk density of 0.4-0.6g/cm³。