Preparation process of inositol nicotinate tablets

Abstract

The invention relates to the technical field of medicine preparation processes, discloses a preparation process of inositol nicotinate tablets, and aims to improve uniform distribution and particle stability of medicine components. The process comprises the following steps: premixing a filling agent and a disintegrating agent to form a first auxiliary material mixture; mixing inositol nicotinate with a first auxiliary material, and screening to obtain a second raw material mixture; dry inositol nicotinate particles are obtained through wet granulation and staged drying; optimizing a particle screening process by adopting an airflow screening model to obtain target particles; and finally, mixing with a lubricant and pressing into tablets. Through application of the airflow screening model and segmented temperature control drying based on the dissolution rate, the uniformity, the dissolution performance and the production efficiency of the product are remarkably improved.

Description

Technical Field

[0001] The present invention relates to the technical field of drug preparation technology, and more specifically, to a preparation process of inositol nicotinate tablets. Background Art

[0002] Inositol nicotinate tablets are a commonly used drug for treating hyperlipidemia. At present, there are many patent applications for inositol nicotinate tablets preparations and preparation methods at home and abroad.

[0003] The Chinese patent application with publication number CN114681417A discloses an inositol nicotinate orally disintegrating tablet and a preparation method thereof. The inositol nicotinate orally disintegrating tablet provided by the technical solution has the advantages of increasing the absorption of the drug through the mucosal tissue, rapid disintegration, excellent taste, no gritty feeling, good compliance, etc. However, the technical solution does not explain in detail how to optimize the granulation and drying process to further improve the product quality.

[0004] The Chinese patent application with publication number CN107737113A discloses an inositol nicotinate tablet and a preparation method thereof. The technical solution sets a coating layer on the outer layer of the tablet to ensure the stability of the drug quality and prolong the shelf life. However, the technical solution does not involve how to improve the uniformity and stability of the particles through the granulation and screening process.

[0005] In summary, conventional drying methods in the prior art easily lead to hardening of the particle surface, affecting drug dissolution; and the screening process lacks quantitative model guidance, making it difficult to obtain the optimal particle size distribution. Summary of the invention

[0006] In order to overcome the above-mentioned defects of the prior art, the present invention provides a preparation process of inositol nicotinate tablets, the core of which is to significantly improve the uniformity, stability and dissolution performance of the preparation through optimized wet granulation, segmented temperature controlled drying and a screening method based on an airflow screening model.

[0007] To achieve the above object, the present invention provides the following technical solutions:

[0008] A preparation process of inositol nicotinate tablets, comprising:

[0009] Premixing the filler and the disintegrant to form a first auxiliary material mixture; mixing inositol nicotinate with the first auxiliary material mixture to form a first raw material mixture; pouring the first raw material mixture into a vibrating screen for sieving to obtain a second raw material mixture;

[0010] The second raw material mixture is placed in a high-efficiency wet granulator, a binder is added, and wet granulation is performed to generate inositol nicotinate wet granules;

[0011] Placing the wet inositol nicotinate granules in a fluidized bed dryer and drying them by a staged drying method until the moisture content is 1.0-5.0%, thereby obtaining dry inositol nicotinate granules;

[0012] The inositol nicotinate dry particles are transferred to a swing granulator for particle screening, airflow is introduced during the screening process, an airflow screening model is constructed, and the mesh size and screening time of the particle screening process are determined according to the airflow screening model to obtain inositol nicotinate particles;

[0013] mixing inositol nicotinate particles with a lubricant to form raw material mixed particles;

[0014] The raw material mixed granules are compressed into tablets using a tablet press.

[0015] Furthermore, the adhesive is one or more of starch slurry, sucrose syrup, and water;

[0016] The filler is one or more of starch, pregelatinized starch, and sucrose; the starch in the filler includes corn starch;

[0017] The disintegrant is one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl cellulose;

[0018] The lubricant is one or more of magnesium stearate, talc and silicon dioxide.

[0019] Furthermore, the filler and disintegrant are premixed by: mixing sucrose, pregelatinized starch and low-substituted hydroxypropyl cellulose evenly, and then mixing with corn starch;

[0020] The mixing parameters of mixing inositol nicotinate with the first auxiliary material mixture are a stirring speed of 120 r / min, a chopping speed of 1500 r / min, and mixing for 5 minutes;

[0021] The screening parameters for pouring the first raw material mixture into the vibrating screen for screening include the number of screen meshes and the optimal screening time.

[0022] Furthermore, the mesh size of the sieve in the sieving parameters is 40 meshes, and the optimal sieving time is 2-5 minutes.

[0023] Furthermore, the wet granulation process firstly performs low-speed granulation for 2 minutes, with a stirring speed of 80 r / min and a chopping speed of 1000 r / min, and adds a binder; and then performs high-speed granulation for 3 minutes, with a stirring speed of 120 r / min and a chopping speed of 1500 r / min.

[0024] Furthermore, the staged drying method is:

[0025] Place the wet granules of inositol nicotinate in a fluidized bed dryer and set the drying parameters: drying temperature 45°C, hot air flow rate 40-60m 3 / h, drying for 30-40min, drying to a moisture content of 8.0-10.0% to obtain pre-dried particles;

[0026] The pre-dried granules were taken out, their solubility was measured, recorded as Q1, and the drying parameters were adjusted: when Q1<60%, the drying temperature was adjusted to 55°C; when 60%≤Q1<75%, the drying temperature was adjusted to 50°C; when Q1≥75%, the drying temperature was adjusted to 45°C; the hot air flow rate remained unchanged, and the drying was continued for 20-30 minutes to obtain medium-dried granules;

[0027] Take out the dried granules, measure their solubility, record it as Q2, and adjust the drying parameters: when the difference between Q2 and Q1 |Q2-Q1|<10%, maintain the existing drying temperature unchanged; when |Q2-Q1|≥10% and Q2<85%, reduce the drying temperature by 5-10℃; when |Q2-Q1|≥10% and Q2≥85%, reduce the drying temperature by 10-15℃; reduce the hot air flow rate to 30-40m 3 / h, and dried to a moisture content of 1.0-5.0% to obtain inositol nicotinate dry particles.

[0028] Further, the airflow screening model includes an airflow screening first sub-model, an airflow screening second sub-model and an airflow screening third sub-model;

[0029] The first sub-model of airflow screening is:

[0030]

[0031] The second sub-model of airflow screening is:

[0032]

[0033] The third sub-model of airflow screening is:

[0034]

[0035] Where d is the particle diameter, ρ g is the gas density, v is the air velocity, C d is the drag coefficient, g is the acceleration due to gravity, ρ p is the particle density, M is the mesh size, k is the first proportional coefficient, α' is the second proportional coefficient, t' is the screening time, and L is the screen surface diameter.

[0036] Furthermore, the mesh size of the particle screening process obtained according to the airflow screening model is 14 meshes, and the screening time is 8 minutes.

[0037] Furthermore, the parameters of the wet granulation process are stirring speed 80-120r / min, chopping speed 1000-1500r / min, and granulation for 5 minutes;

[0038] In the drying process using the staged drying method, the drying temperature is 30-70°C, the drying time is 50-100 minutes, and the hot air flow rate is 30-60m 3 / h;

[0039] During the mixing of the inositol nicotinate particles and the lubricant, the mixing speed is 8 r / min and the mixing time is 10 min;

[0040] In the process of using the tablet press to press the raw material mixed particles into tablets, the tablet hardness is controlled at 50-100 N. Compared with the prior art, the beneficial effects of the present invention are:

[0041] Through multi-stage premixing and optimized wet granulation process, the uniform distribution of drug ingredients in the mixture is ensured, which significantly improves the uniformity of the drug and reduces the fluctuation of drug content in tablets; the airflow screening model is used to optimize the particle screening process, so that the screened particles have better stability and size consistency, thereby improving the quality of tableting and drug release characteristics; the segmented temperature control during the drying process is based on dissolution, which can effectively shorten the drying time and prevent the hardening of the particle surface, thereby improving the dissolution performance of the drug and ensuring the rapid effect of the drug; by precisely controlling the parameters of each step, such as stirring speed, chopping speed, drying temperature, etc., the quality consistency of each batch of products is ensured and the differences between batches are reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0043] Figure 1 The present invention is a method flow chart of a preparation process of inositol nicotinate tablets;

[0044] Figure 2 The present invention is a flow chart of a method for premixing a filler and a disintegrant in a preparation process of an inositol nicotinate tablet of the present invention;

[0045] Figure 3 The present invention is a flow chart showing the principle of a staged drying method in a wet granulation process of a preparation process of inositol nicotinate tablets. DETAILED DESCRIPTION

[0046] In order to facilitate the understanding of the present invention, the present invention will be described more fully below with reference to the relevant drawings. Several embodiments of the present invention are given in the drawings. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present invention more thorough and comprehensive.

[0047] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0048] Example 1

[0049] See also Figure 1 As shown, this embodiment provides a preparation process of inositol nicotinate tablets, comprising:

[0050] Step S10, premixing the raw materials to form a second raw material mixture;

[0051] The raw materials include inositol nicotinate and auxiliary materials, and the auxiliary materials include a binder, a disintegrant, a filler and a lubricant;

[0052] The binder is one or more of starch slurry, sucrose syrup or water;

[0053] The filler is one or more of starch, pregelatinized starch or sucrose; the starch in the filler includes corn starch;

[0054] Preferably, the starch in the filler is corn starch;

[0055] The disintegrant is one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose or sodium carboxymethyl cellulose;

[0056] The lubricant is one or more of magnesium stearate, talc or silicon dioxide.

[0057] Raw material premixing refers to mixing inositol nicotinate and excipients in a certain proportion to make them evenly distributed, laying the foundation for the subsequent granulation process. Among them, inositol nicotinate is a fat-soluble vitamin that has the effects of lowering cholesterol and improving vascular function, and is the main active ingredient of this preparation. Excipients are inert substances added for the purpose of excipient, filling, bonding, lubrication, etc., including binders, disintegrants, fillers and lubricants. Binders can improve the formability and hardness of particles, and commonly used ones include starch slurry, sucrose syrup or water; disintegrants can promote the disintegration of tablets in the gastrointestinal tract and the release of drugs, and common ones include cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose or sodium carboxymethyl cellulose; fillers can increase the volume of tablets, improve the quality of tablets, and improve tableting performance. Commonly used ones include starch, pregelatinized starch or sucrose, among which corn starch is the most widely used; lubricants can reduce the adhesion of particles to tableting molds and improve the appearance quality of tablets, and common ones include magnesium stearate, talc, silicon dioxide, etc. By premixing inositol nicotinate with these excipients, the uniformity and stability of the preparation can be significantly improved, creating favorable conditions for subsequent processes.

[0058] like Figure 2 As shown, the step S10 includes:

[0059] Step S11, premixing the filler and the disintegrant to form a first auxiliary material mixture;

[0060] Preferably, sucrose, pregelatinized starch and low-substituted hydroxypropyl cellulose are uniformly mixed, and then mixed with corn starch to form a first auxiliary material mixture;

[0061] The premixing of fillers and disintegrants refers to the mixing of two or more auxiliary material components in advance, the purpose of which is to further improve the dispersibility and uniformity of the auxiliary materials. This embodiment preferably uses sucrose and pregelatinized starch as fillers, and low-substituted hydroxypropyl cellulose as a disintegrant. Among them, sucrose is a common filler with a sweet taste, which can mask the bitter smell of the drug, and can also fill the gaps between the particles to prevent the drug from hygroscopic agglomeration; pregelatinized starch is treated with a special process, has good solubility and disintegration, can quickly replenish granulation water, and can fill the gaps between particles; low-substituted hydroxypropyl cellulose is a semi-synthetic cellulose derivative with a low degree of hydroxypropyl substitution on its molecular chain, good water absorption and swelling and disintegration, and can promote the disintegration of tablets in the gastrointestinal tract. The three auxiliary material components are mixed evenly and then mixed with the main filler corn starch to form a first auxiliary material mixture with better dispersibility and uniformity, which is beneficial to improve the overall performance of the preparation.

[0062] Step S12, mixing inositol nicotinate with the first auxiliary material mixture to form a first raw material mixture, the mixing parameters are stirring speed 100-150 r / min, chopping speed 1200-2000 r / min, and mixing for 1-5 minutes;

[0063] Preferably, the mixing parameters are a stirring speed of 120 r / min, a chopping speed of 1500 r / min, and mixing for 5 minutes;

[0064] Mixing inositol nicotinate with the first auxiliary material mixture is to form a uniformly dispersed mixture of the drug and the auxiliary material. High-speed mixing can make inositol nicotinate fully dispersed in the auxiliary material matrix, prevent the local drug concentration from being too high or too low, and improve the uniformity of the preparation. The stirring speed is controlled at 100-150r / min, the chopping speed is controlled at 1200-2000r / min, and the mixing time is 1-5 minutes, so that a uniform mixture can be obtained in a short time. Among them, a lower stirring speed is conducive to the uniformity of the mixture, and a higher chopping speed is conducive to crushing the drug particles to prevent the occurrence of large particles or agglomeration. If the mixing time is too short, the mixing is insufficient; if the mixing time is too long, the mixture may be stratified or sticky, and the production efficiency will also be reduced. The preferred mixing parameters of this embodiment are a stirring speed of 120r / min, a chopping speed of 1500r / min, and mixing for 5 minutes. On the basis of taking into account the mixing uniformity and production efficiency, a first raw material mixture with stable performance is obtained, creating good material conditions for wet granulation.

[0065] Step S13, pouring the first raw material mixture into a vibrating screen with a mesh size of 20-60, and sieving for 2-5 minutes to obtain a second raw material mixture; preferably, the mesh size of the screen is 40 mesh.

[0066] The first raw material mixture is granulated by a vibrating screen, the purpose of which is to remove large particles and agglomerates in the mixture, control the particle size distribution of the mixture, and improve the uniformity and formability of granulation. The mesh number of the screen is selected to be 20-60 mesh, which is mainly determined according to the particle size distribution characteristics of inositol nicotinate and excipients. If the mesh number of the screen is too large, large particles in the mixture are difficult to remove; if the mesh number of the screen is too small, the degree of crushing of the mixture is too high, which is not conducive to granulation. In this embodiment, the preferred mesh number of the screen is 40 mesh, which is equivalent to a sieve hole diameter of 0.425 mm, which can effectively remove a small amount of large particles in the mixture and retain most of the qualified fine particles, reduce the powder degree of the mixture, and improve the granulation efficiency. The screening time is controlled at 2-5 minutes, which is mainly determined based on factors such as the batch size of the material and the difficulty of screening. If the screening time is too short, the granulation of the mixture is not thorough; if the screening time is too long, the amount of fine powder produced increases, and the particle size distribution of the mixture becomes wider. The second raw material mixture obtained after screening has the characteristics of uniform particle size distribution, appropriate fineness, good fluidity, etc., and can significantly improve the controllability and reproducibility of the granulation process.

[0067] Step S20, placing the second raw material mixture into a high-efficiency wet granulator for wet granulation; starting stirring, with a stirring speed of 80-150 r / min and a chopping speed of 1200-2000 r / min, slowly adding a binder during the stirring process, and granulating for 1-5 minutes until the material is spherical and no dust is flying, thereby generating inositol nicotinate wet granules;

[0068] Preferably, the stirring speed is 100 r / min, the chopping speed is 1200 r / min, and the granulation time is 5 minutes;

[0069] High-efficiency wet granulation is a process of mixing drugs, excipients and adhesives and liquid granulation under high-speed stirring and chopping. It has the advantages of simple operation, uniform mixing, rapid sphering, etc., and is the most widely used granulation method in the production of tablets and capsules. In the granulation process, the adhesive plays a vital role. It can increase the adhesion between particles and improve the sphericity, hardness and toughness of the particles. In this embodiment, starch slurry is used as an adhesive. The starch slurry has the characteristics of moderate bonding strength, low price and wide sources. In the process of slow addition, the surface of the mixture is gradually wetted, so that the dry drug and excipient particles gradually gather into balls. In the granulation process, the control of stirring and chopping speed is crucial: the stirring speed is controlled at 100-150r / min, which is conducive to the full contact between the mixture and the adhesive and the uniform dispersion of the liquid; the chopping speed is controlled at 1200-2000r / min, which can prevent the particles from growing too much and make them have a suitable particle size and sphericity. The preferred stirring speed is 100r / min, the chopping speed is 1200r / min, and the granulation time is 5 minutes. The state of the material should be closely observed during the operation. When the material is spherical and there is no dust flying, the end point is reached, and the liquid addition is stopped and the material is discharged. The inositol nicotinate wet granules obtained at this time have the characteristics of uniform particle size, high sphericity, appropriate water content, loose structure, etc. After drying, the finished granules with stable quality can be obtained.

[0070] Step S30, placing the wet granules of inositol nicotinate in a fluidized bed dryer, setting the drying parameters: drying temperature 30-70°C, drying time 50-100 minutes, hot air flow rate 30-60m 3 / h, drying to a moisture content of 1.0-5.0% to produce inositol nicotinate dry particles;

[0071] Preferably, the drying temperature is 60°C.

[0072] Fluidized bed drying is a commonly used hot air drying method. It uses the principle of suspending wet particles and quickly dehydrating them through rising hot air flow. It has the advantages of high heat and mass transfer efficiency, fast drying speed, and good particle dispersibility. During the drying process, the control of temperature and time is crucial: the drying temperature is controlled at 30-70°C, which is mainly determined based on the thermal stability of inositol nicotinate and excipients. If the temperature is too low, the drying time will be extended; if the temperature is too high, it may cause drug decomposition or excipient denaturation. Moisture content is also an important quality control indicator and should be controlled at 1.0-5.0%. Too high a moisture content may cause hygroscopic adhesion of the particles and reduce the stability of the preparation; too low a moisture content may cause electrostatic aggregation or brittle crushing of the particles. The preferred drying temperature in this embodiment is 60°C, which can not only ensure the thoroughness and efficiency of drying, but also prevent the hardening of the particle surface or the decomposition of the drug. The inositol nicotinate dry particles obtained after fluidized bed drying have the characteristics of appropriate moisture content, uniform appearance, looseness, no powdering and less stickiness, and can be directly used in subsequent granulation and mixing processes.

[0073] Step S40, transferring the inositol nicotinate dry particles to a swing-type granulator, performing particle screening, determining the mesh size and screening time of the particle screening process, and obtaining inositol nicotinate particles;

[0074] The particle screening process has a screen mesh size of 12-18 meshes and a screening time of 5-10 minutes;

[0075] Swinging granulation is a process that uses the vibration and swinging motion of the screen to make the particles roll and grade on the screen surface. The purpose is to further optimize the particle size distribution of the particles, remove fine particles or powder, and improve the uniformity and fluidity of the particles. The selection of the mesh size of the screen is mainly determined according to the particle size distribution characteristics of each component in the formulation. A mesh size that is too large will allow some fine particles to pass through, affecting the quality of the formulation; a mesh size that is too small will reduce the efficiency of granulation and increase the amount of powder. The screening time is controlled within 5-10 minutes, which is mainly determined based on factors such as the batch size of the material and the difficulty of screening. If the screening time is too short, the granulation is not thorough, and if it is too long, it will cause pulverization and affect the quality of the particles. In addition, during the screening process, the amplitude and frequency of the screen should be controlled so that the particles do not jump or accumulate on the screen surface, and the screen should be cleaned in time to prevent clogging. The inositol nicotinate granules obtained after swinging granulation have uniform particle size distribution, no fine powder, regular particle shape, good fluidity and compressibility, and can significantly improve the quality and production efficiency of tablets.

[0076] Step S50, mixing the inositol nicotinate particles with a lubricant at a mixing speed of 8-10 r / min and a mixing time of 5-30 min to generate raw material mixed particles;

[0077] Preferably, the mixing speed is 8r / min and the mixing time is 10min;

[0078] Lubricants are excipients added in the last step of preparation production, the purpose of which is to reduce the friction between the particles and the stamping die or between the tablets and the stamping die after stamping, thereby improving the tableting performance and the appearance quality of the tablets. Common lubricants include magnesium stearate, calcium stearate, talcum powder, etc. In this embodiment, magnesium stearate is preferably used as a lubricant. Magnesium stearate is a magnesium salt of a higher fatty acid with excellent lubricity and anti-stickiness, and is widely used in pharmaceutical excipients. The amount of lubricant is usually low. In order to prevent the uneven distribution of the lubricant in the mixture, a low-speed mixing method is required. The mixing speed is controlled at 8-10r / min, which is mainly determined according to the characteristics of the mixing equipment and the properties of the material. If the speed is too low, the mixing uniformity is difficult to ensure; if the speed is too high, the mixture is prone to stratification or agglomeration. The preferred mixing speed is 8r / min, which minimizes the effect of the lubricant on the surface properties of the particles while ensuring the mixing uniformity. The mixing time is controlled at 5-30min, which mainly depends on the efficiency of the mixing equipment and the amount of the material. If the time is too short, the lubricant and the inositol nicotinate granules are not fully mixed; if the time is too long, the production efficiency will be reduced and the lubricant may be enriched on the surface of the granules. The preferred mixing time is 10 minutes, and evenly distributed mixed granules can be obtained in a relatively short time. The raw material mixed granules obtained after mixing with the lubricant have the characteristics of smooth surface, good fluidity, excellent compression molding, etc., which can significantly improve the production efficiency and quality of the tablets, especially the tablet weight uniformity, hardness uniformity, appearance quality and other indicators.

[0079] Step S60, using a tablet press to press the raw material mixed particles into tablets, and the tablet hardness is controlled at 30-150N;

[0080] Preferably, the tableting hardness is controlled at 50-100N;

[0081] Tableting is the process of applying a certain pressure to the prepared raw material mixed particles in the tableting mold to shape them and have a certain mechanical strength. The key parameter of the tableting process is the tableting hardness, that is, the minimum force required for the tablet to resist crushing. If the tableting hardness is too low, the tablet is easily damaged, affecting the appearance quality; if the tableting hardness is too high, the tablet disintegration time is prolonged, affecting the release of the drug. In this embodiment, the tableting hardness is controlled at 30-150N, which is mainly set according to the specifications of the tablet and the release characteristics of the drug. For tablets with lighter weight and rapid drug release, a lower tableting hardness should be selected; for tablets with heavier weight, slow drug release or enteric-coated tablets, a higher hardness is required. The preferred tableting hardness is 50-100N, which can take into account the mechanical strength of the tablet and the release performance of the drug. The shape and size of the tableting mold will also affect the performance of the tablet, and should be reasonably designed according to the requirements of the preparation process and GMP specifications. The mold surface should be smooth and flat, the cross-sectional shape should be regular, and the punching gap should be uniform to ensure the appearance quality and weight uniformity of the tablet. The tableting process should be continuous and smooth, with uniform pressure, and avoid shock or vibration to prevent defects such as cracks and defects in the tablets. In order to improve production efficiency, a high-speed tablet press can be used for production, but the uniformity of the material and the consistency of the tableting parameters should be strictly controlled.

[0082] In the preparation process of the inositol nicotinate tablets provided in this embodiment, the wet granulation adopts efficient mixing and an appropriate amount of binder, and can obtain inositol nicotinate wet granules with uniform particle size distribution and good fluidity, thereby improving the granulation yield and drying efficiency; the drying process adopts fluidized bed drying, the hot air is in full contact with the material, the drying speed is fast and uniform, the quality problems caused by local overheating can be avoided, and the loose porous structure of the particles can be maintained to the maximum extent, which is conducive to the rapid disintegration and release of the drug; the low-speed mixing of the lubricant can improve the surface properties of the raw material mixed particles, reduce the adhesion to the tableting mold, thereby improving the quality uniformity and production efficiency of the tablets; reasonable tableting hardness control can ensure the mechanical strength of the tablets while achieving timely release of the drug, avoiding appearance defects such as scratches or cracks, and improving the overall quality of the tablets; the entire preparation process is simple, the process parameters are easy to control, the difference between product batches is small, the stability is good, and the production efficiency and clinical safety of inositol nicotinate tablets can be significantly improved.

[0083] Example 2

[0084] This embodiment provides a preparation process of inositol nicotinate tablets based on embodiment 1, comprising:

[0085] Step S20, putting the second raw material mixture into a high-efficiency wet granulator, starting stirring, first granulating at a low speed for 2 minutes, with a stirring speed of 80 r / min and a chopping speed of 1000 r / min, and slowly adding 50% of the binder; then granulating at a high speed for 3 minutes, with a stirring speed of 120 r / min and a chopping speed of 1500 r / min, and slowly adding the remaining binder until the material is spherical and the particle size is 1-2 mm, to obtain inositol nicotinate wet granules.

[0086] This step adopts a staged wet granulation method, first low-speed granulation, then high-speed granulation, the purpose is to make the binder more evenly distributed in the mixture and control the growth rate of the particles. The stirring speed in the low-speed stage is 80r / min, the chopping speed is 1000r / min, the mixing strength is low, and the amount of binder added is 50% of the total amount, so that the mixture is fully moistened and initially spherical; the stirring speed in the high-speed stage is increased to 120r / min, the chopping speed is increased to 1500r / min, the mixing strength is increased, and the amount of binder added is the remaining 50%, which further promotes the growth and densification of the particles until the material is spherical, and the particle size is controlled at 1-2mm. Slow-speed granulation is conducive to improving the liquid dispersibility and water content uniformity in the early stage of granulation, and high-speed granulation is conducive to improving the spherical rate and particle strength in the later stage of granulation. The combination of the two can obtain wet granules of inositol nicotinate with uniform particle size, high sphericity and suitable hardness. It is worth noting that the binder should be added slowly to avoid deformation or wall sticking of particles caused by local over-wetting; the particle size should be controlled within a reasonable range. If the particles are too small, dust will be easily generated, affecting the granulation efficiency; if the particles are too large, holes will be easily generated, affecting the drying quality. Staged wet granulation can significantly improve the controllability of the granulation process, improve the quality uniformity of the particles, reduce drying energy consumption, and lay a good foundation for subsequent processes.

[0087] Step S30, placing the wet inositol nicotinate granules in a fluidized bed dryer for drying, using a staged drying method to generate inositol nicotinate dry granules;

[0088] like Figure 3 As shown, the staged drying method is:

[0089] Place the wet granules of inositol nicotinate in a fluidized bed dryer and set the drying parameters: drying temperature 45°C, hot air flow rate 40-60m 3 / h, drying for 30-40min, drying to a moisture content of 8.0-10.0% to obtain pre-dried particles;

[0090] The pre-dried granules were taken out, their solubility was measured, recorded as Q1, and the drying parameters were adjusted: when Q1<60%, the drying temperature was adjusted to 55°C; when 60%≤Q1<75%, the drying temperature was adjusted to 50°C; when Q1≥75%, the drying temperature was adjusted to 45°C; the hot air flow rate remained unchanged, and the drying was continued for 20-30 minutes to obtain medium-dried granules;

[0091] Take out the dried granules, measure their solubility, record it as Q2, and adjust the drying parameters: when the difference between Q2 and Q1 |Q2-Q1|<10%, maintain the existing drying temperature unchanged; when |Q2-Q1|≥10% and Q2<85%, reduce the drying temperature by 5-10℃; when |Q2-Q1|≥10% and Q2≥85%, reduce the drying temperature by 10-15℃; reduce the hot air flow rate to 30-40m 3 / h, and dried to a moisture content of 1.0-5.0% to obtain inositol nicotinate dry particles.

[0092] The staged drying method achieves real-time optimization control of the drying process by adjusting parameters such as drying temperature and hot air flow rate based on the dissolution test results. Compared with traditional constant temperature and humidity drying, the staged drying method can effectively shorten the drying time, improve the dissolution performance of the particles, and improve the drying efficiency and product quality.

[0093] The staged drying method mainly includes three stages: pre-drying, intermediate drying and post-drying. In the pre-drying stage, the wet particles are dried at a lower temperature (45°C) and a higher hot air velocity (40-60m / s). 3 / h) for 30-40min to remove free water on the surface of the particles and make the moisture content reach 8.0-10.0%. The drying temperature at this stage should not be too high to avoid decomposition of the drug or melting of the excipients; the hot air flow rate is relatively high, which is conducive to the rapid evaporation of water and prevents the surface of the particles from forming a skin. The particles obtained after pre-drying are called pre-dried particles.

[0094] In the intermediate drying stage, the pre-dried granules are taken out, their dissolution Q1 is measured, and the drying temperature is adjusted according to the size of Q1: when Q1 < 60%, it means that the drug dissolution is slow, and the drying temperature needs to be increased to 55°C to accelerate the evaporation of the solvent; when 60% ≤ Q1 < 75%, it means that the drug dissolution is moderate, and the drying temperature is adjusted to 50°C; when Q1 ≥ 75%, it means that the drug has basically reached the expected dissolution requirements, and the drying temperature can be maintained at 45°C. The hot air flow rate in the intermediate drying stage is the same as that in the pre-drying stage, and the drying time is 20-30min. The granules obtained after intermediate drying are called intermediate drying granules. Dissolution refers to the percentage of drug dissolved in a solid preparation per unit time under specified conditions (generally the dissolution medium is water or a buffer solution of a specific pH, the dissolution container is a basket method or a tank method, and a certain rotation speed or flow rate). It is an important indicator for evaluating the in vitro drug release performance of the preparation.

[0095] In the post-drying stage, take out the medium-dried granules again, measure their solubility Q2, compare the difference between Q2 and Q1, and adjust the drying temperature and hot air flow rate accordingly. When |Q2-Q1|<10%, it means that the drug dissolution has not changed much and the existing drying temperature can be maintained; when |Q2-Q1|≥10% and Q2<85%, it means that the drug dissolution has changed greatly but has not yet met the expected requirements, and the drying temperature needs to be reduced by 5-10°C; when |Q2-Q1|≥10% and Q2≥85%, it means that the drug dissolution has basically stabilized and met the requirements, and the drying temperature can be appropriately reduced by 10-15°C. At the same time, the hot air flow rate is reduced to 30-40m in the post-drying stage. 3 / h, in order to prevent the drug from being over-dried and causing a decrease in solubility. When the moisture content is dried to 1.0-5.0%, the finished inositol nicotinate dry granules are obtained.

[0096] The temperature setting of the staged drying method is mainly based on the physical and chemical properties and stability of the drug, as well as the compatibility of excipients and other factors. Generally speaking, for every 10°C increase in temperature, the chemical reaction rate increases by 1 times, and the drying rate will also increase significantly. However, excessively high temperatures may cause problems such as drug decomposition, excipient melting or discoloration. The melting point of inositol nicotinate is 64°C, so the drying temperature should not exceed 60°C. The pre-drying uses a lower temperature of 45°C in order to avoid local overheating of the drug while slowly removing moisture; the intermediate drying adjusts the temperature within the range of 45-55°C according to the solubility, taking into account the drying rate and the quality of the finished product; the post-drying further cools the temperature to below 40°C, mainly to stabilize the dissolution properties of the drug.

[0097] The setting of hot air flow rate mainly considers factors such as the density and specific surface area of ​​the material. The wet particles are loose and have a large specific surface area, so the hot air flow rate can be increased accordingly, such as 40-60m in the pre-drying and intermediate drying stages. 3 / h; in the subsequent drying stage, the particles are basically formed and the volume shrinks, so the hot air flow rate can be reduced to 30-40m 3 Although too high a hot air flow rate can speed up drying, it may cause drug dust to fly and increase losses; too low a hot air flow rate will prolong the drying time and affect production efficiency.

[0098] The staged drying method dynamically adjusts the drying temperature according to the dissolution rate, can monitor and feedback the dissolution changes of the drug in real time, optimize the drying process in time, avoid quality problems caused by high or low temperature, and has strong pertinence and flexibility; the combination of high-temperature rapid drying and low-temperature slow drying can ensure thorough drying while maximally maintaining the loose porous structure of the drug and reducing adverse effects such as surface hardening or solubility reduction; dissolution, as a key quality attribute of process control, can control the drying process from the source, discover and solve problems early, avoid batch differences, and thus improve the robustness of the process; staged drying dynamically adjusts process parameters according to the material properties and drying state, avoids the "one-size-fits-all" constant temperature and humidity mode, and improves drying efficiency and energy utilization; feedback adjustment based on dissolution can ensure accurate judgment of the drying endpoint, prevent overdrying, shorten drying time, reduce energy consumption, and improve production efficiency. The dissolution performance of the drug and the stability of the preparation are maintained to the greatest extent, and it has broad application prospects. This provides a high-quality material basis for subsequent mixing, tableting and other processes, and also provides a reliable guarantee for the efficacy and safety of the final product.

[0099] Step S40, transferring the inositol nicotinate dry particles to a swing-type granulator, introducing airflow during the screening process, constructing an airflow screening model, and determining the mesh size and screening time of the particle screening process according to the airflow screening model to obtain inositol nicotinate particles;

[0100] The method of constructing an airflow screening model and determining the mesh size and screening time according to the airflow screening model comprises:

[0101] Assume that the air velocity is v, the particle diameter is d, and the particle density is ρ p , the sieve aperture is D, the sieve mesh number is M, and the gas density is ρ g , the acceleration of gravity is g; among them, the mesh number M and the mesh aperture D have the following relationship:

[0102]

[0103] Where k is the first proportionality coefficient, which depends on the screen manufacturing standard; for example, for the commonly used Tyler standard screen, k is 0.149 mm 2 .

[0104] When the particles are in the air flow, they are mainly affected by gravity F g Buoyancy F b and air flow resistance F d The role of;

[0105] Gravity F g :

[0106]

[0107] Buoyancy F b :

[0108]

[0109] Air flow resistance F d :

[0110]

[0111] Where A is the windward area of ​​the particle, which is approximately C d is the drag coefficient, which is related to the Reynolds number Re.

[0112] When the forces on the particle are balanced, F g =F b +F d , substitute into various formulas and simplify to get:

[0113]

[0114] Further deformation, the relationship between particle diameter d and air flow velocity v is obtained:

[0115]

[0116] in:

[0117] d: particle diameter, unit: meter (m);

[0118] ρ g : Gas density, unit: kg / m3 (kg / m 3 ), which can be obtained by checking the physical properties handbook;

[0119] v: air velocity, unit: meter-second (m / s), obtained from the equipment operating parameters;

[0120] C d : Drag coefficient, which is related to particle shape and Reynolds number, can be estimated by looking up the drag coefficient chart;

[0121] g: acceleration due to gravity, take 9.8m / s 2 ;

[0122] ρ p : Particle density, unit: kg / m3 (kg / m 3 ), which can be obtained from the properties of the material;

[0123] Introducing the mesh number M of the sieve and considering that only particles with a diameter d smaller than the sieve hole diameter D can pass through the sieve, the critical condition can be obtained:

[0124]

[0125] Combining the above two equations, we can get the relationship between air flow velocity v, screen mesh number M and critical particle diameter d.

[0126]

[0127] Further deformation, the selection condition of the screen mesh number M is obtained:

[0128]

[0129] This inequality gives the upper limit of the mesh size M of the screen at a given air flow velocity v; only by selecting a screen smaller than this critical value can particles with a particle size greater than d be effectively retained.

[0130] In addition, the movement of particles on the screen surface is also affected by the mesh size M of the screen; assuming that the average rolling speed u of the particles on the screen surface is proportional to the screen hole diameter D, then:

[0131]

[0132] Substituting into the previous rolling time estimation formula, we can get:

[0133]

[0134] Wherein, t' is the screening time, and α' is the second proportionality coefficient, which is determined by those skilled in the art based on a large number of experiments.

[0135] In summary, the airflow screening model includes the first airflow screening sub-model, the second airflow screening sub-model and the third airflow screening sub-model;

[0136] The first sub-model of airflow screening describes the relationship between particle diameter d, screen mesh number M and airflow velocity v:

[0137]

[0138] The first sub-model of airflow screening indicates the lower limit of the particle diameter that can be separated under a given sieve mesh number M. When the particle diameter d is smaller than the sieve hole diameter The particles can pass through the screen.

[0139] The second sub-model of airflow screening describes the selection conditions of the screen mesh number M:

[0140]

[0141] The second sub-model of airflow screening gives the upper limit of the mesh size M under a given airflow velocity v. In order to ensure that particles with a diameter greater than d can be effectively blocked, the mesh size must meet this condition.

[0142] The third sub-model of airflow screening describes the relationship between the screening time t' and the screen mesh number M and the screen surface diameter L:

[0143]

[0144] The third sub-model of airflow screening shows that the mesh number M and the screen surface diameter L affect the movement time of particles on the screen surface. The higher the mesh number and the smaller the hole size, the screening time will usually increase, because the smaller hole size will slow down the speed of material passing through; the larger the screen surface diameter, the more material can be processed, which may reduce the screening time.

[0145] The mesh size of the particle screening process obtained according to the airflow screening model is 14 meshes, and the screening time is 8 minutes.

[0146] This step uses an airflow-assisted vibration screening method to granulate and remove dust from the dry particles of inositol nicotinate, and optimizes the screening parameters by constructing an airflow screening model. Airflow screening is a process that utilizes the interaction between the rising airflow and the particle group to separate particles of different particle sizes in the vertical direction, and intercepts large particles through the screen and discharges fine particles. Compared with conventional vibration screening, airflow screening has the advantages of large processing capacity, high classification efficiency, low energy consumption, low noise, and no dust pollution. However, the selection of airflow parameters (such as airflow velocity) and screen parameters (such as screen mesh number and screen surface diameter) is crucial and directly affects the screening performance and product quality. To this end, the present invention constructs an airflow screening model, including three sub-models: the first sub-model describes the quantitative relationship between the critical particle diameter (i.e., the particle diameter that can just pass through the sieve hole) and the mesh number of the sieve and the airflow velocity, which can be used to estimate the critical particle size under given sieve and airflow conditions; the second sub-model gives the selection conditions of the mesh number of the sieve, which is usually determined according to the average particle size of the feed particles and the target product particle size; the third sub-model reveals the functional relationship between the screening time and the mesh number of the sieve and the diameter of the sieve surface, which can be used to calculate the optimal screening time. The three sub-models are interrelated and together constitute a complete airflow screening model, providing a theoretical basis and quantitative guidance for the optimization of screening parameters. In practical applications, the mesh number of the sieve can be estimated by the second sub-model according to the feed properties and target requirements, and then substituted into the first and third sub-models to solve the airflow velocity and screening time, thereby obtaining the optimal screening scheme. The inositol nicotinate particles obtained after airflow screening have the characteristics of narrow particle size distribution, uniform fineness, no dust, smooth surface, etc., which can significantly improve the intrinsic structure and appearance quality of the tablet.

[0147] Using formula Estimate the screening time t'. This relationship reflects the positive correlation between the screening time and the mesh size in terms of order of magnitude, but it is not accurate enough. In fact, the screening time also depends on other process parameters such as feed rate and material properties. In order to obtain a more accurate estimate, a large number of experiments need to be carried out on this basis to determine the α' value through data fitting.

[0148] Exemplarily, the method for determining the α' value by data fitting is:

[0149] 1. Select 3-5 sieves with different hoe surface diameters (e.g. 20cm, 30cm, 40cm), record them as L1, L2, ..., L m . Select 3-5 different mesh sizes of screens on each screening machine, denoted as M1, M2, ..., M n , and conduct screening experiments.

[0150] 2. For each combination of L and M, select 3-5 different screening times t' for experiment and record the mass percentage P of the material on the sieve.

[0151] 3. With the screen diameter L and the screen mesh number M as the horizontal coordinates, the screening time t' as the vertical coordinate, and the P value as the response value, draw a four-dimensional response surface diagram (which can be represented by multiple three-dimensional diagrams or contour diagrams).

[0152] 4. Using data fitting, we can get the empirical formula describing the relationship between L, M, t' and P:

[0153] P=f(L,M,t')

[0154] =b0+b1L+b2M+b3t'+b4LM+b5Lt'+b6Mt'+b7L 2 +b8M 2

[0155] +b9t' 2 +…

[0156] In this formula, b0, b1, …, b9 are coefficients obtained through multivariate regression fitting, which reflect the influence of screen diameter, screen mesh number and screening time on the mass percentage P of the material on the screen. Each coefficient corresponds to the contribution of a certain variable or combination of variables to P. For example, b1 represents the linear influence of screen diameter L on P, while b7 represents L 2 Secondary impact on P.

[0157] 5. Given the target value of P, substitute it into the empirical formula to obtain the relationship between L, M, and t':

[0158]

[0159] 6. Combine the empirical formula t'=g(L,M) with the theoretical model For comparison, the α' value is obtained by the least squares method:

[0160]

[0161] 7. Substituting the obtained α' value into the theoretical model, the optimal screening time estimate under any L, M combination can be obtained:

[0162]

[0163] The airflow screening model can provide a quantitative basis for the optimization of screening parameters, avoiding the quality risks and efficiency losses that may be caused by empirical selection. The use of airflow screening technology can significantly improve the granulation and dust removal effects, improve the particle size characteristics and surface morphology of the particles, and create a good material foundation for the tableting process.

[0164] This embodiment adopts a process route combining airflow screening and staged wet granulation, and establishes an airflow screening model to guide the optimization of screening parameters, which has the following beneficial effects:

[0165] (1) Airflow screening can significantly improve the particle size uniformity of the mixture, creating good material conditions for wet granulation; staged wet granulation can accurately control the growth process of the particles, improve the controllability of the granulation process and the quality consistency of the particles; staged drying can effectively improve the internal structure and appearance of the particles and improve the robustness of the granulation process; airflow granulation can further optimize the particle size distribution and surface properties of the particles, laying a good foundation for tableting. The process route is rigorous and scientific, step by step, and comprehensively improves the quality of the preparation.

[0166] (2) Introducing online particle size monitoring to achieve real-time quality feedback and regulation of the granulation process, shifting from "empirical control" to "data-driven", can significantly improve the stability and reproducibility of the process and reduce the impact of human factors.

[0167] (3) The airflow screening model was constructed, which revealed the intrinsic relationship between screening performance and equipment and material parameters, and provided theoretical guidance for the quantitative design and optimization of screening parameters. It can significantly improve screening efficiency, reduce trial and error costs, and provide a universal solution for similar process development.

[0168] (4) The entire production process fully utilizes the multi-scale structural characteristics of the materials (from the powder characteristics of the mixture to the macroscopic morphology of the particles) and runs through the quality source (from the initial state of the raw materials to the final performance of the preparation). The key process parameters that affect product quality are subject to full quality control. This reflects the process development concept of "global optimization, point-to-surface combination, and quality design as the core", which is of great significance for guiding the industrial production of new preparations and improving the overall quality level of drugs.

[0169] Example 3

[0170] This embodiment provides an inositol nicotinate pharmaceutical composition, which is prepared by the above-mentioned preparation process of inositol nicotinate tablets.

[0171] The components and weight percentages of the inositol nicotinate pharmaceutical composition are as follows:

[0172] Table 1 Components and weight percentages in the inositol nicotinate pharmaceutical composition

[0173] name Weight Percent Inositol Nicotinate 50％～70％ Fillers 20％～30％ Adhesives 1％～5％ Disintegrants 1％～5％ Lubricants 0.5％～5％

[0174] Preferably, the filler comprises corn starch, sucrose and pregelatinized starch; the binder is starch slurry, and the starch slurry is prepared from starch for pulping; the disintegrant is low-substituted hydroxypropyl cellulose; and the lubricant is magnesium stearate;

[0175] Preferably, the components and weight percentages of the inositol nicotinate pharmaceutical composition are as follows:

[0176] Table 2 Components and weight percentages in inositol nicotinate pharmaceutical compositions

[0177] name Weight Percent Inositol Nicotinate 50％～70％ Corn starch 10％～20％ sucrose 5％～10％ Pregelatinized starch 5％～10％ Starch for pulping 1％～5％ Low substituted hydroxypropyl cellulose 1％～5％ Magnesium Stearate 0.5％～5％

[0178] More preferably, the components and weight percentages of the inositol nicotinate pharmaceutical composition are as follows:

[0179] Table 3 Components and weight percentages in inositol nicotinate pharmaceutical compositions

[0180] name Weight Percent Inositol Nicotinate 69％ Corn starch 16％ sucrose 6％ Pregelatinized starch 6％ Starch for pulping 2％ Low substituted hydroxypropyl cellulose 2％ Magnesium Stearate 1％

[0181] The inositol nicotinate pharmaceutical composition prepared by the above-mentioned inositol nicotinate tablet preparation process is composed of inositol nicotinate, filler, binder, disintegrant and lubricant. Among them, inositol nicotinate as the main active ingredient can reduce cholesterol and improve vascular function; the filler can increase the tablet volume, improve the tablet quality, and improve the tableting performance; the binder improves the particle formability and hardness; the disintegrant promotes the disintegration of the tablet in the gastrointestinal tract and the release of the drug; the lubricant reduces the adhesion of particles to the mold and improves the appearance quality of the tablet.

[0182] In the whole composition, the dosage of inositol nicotinate is the highest, which is 50% to 70%, to ensure sufficient drug dosage. The dosage of filler is second, which is 20% to 30%, which can achieve the purpose of filling without affecting drug release. The dosage of binder and disintegrant is moderate, which is 1% to 5% respectively. While playing their respective roles, they will not significantly change other properties of the tablets. The dosage of lubricant is the lowest, which is only 0.5% to 5%. On the one hand, it can achieve a good lubrication effect, and on the other hand, it can also avoid the adverse effects of excessive lubricant. In the selection of fillers, the preparation preferably uses a combination of corn starch, sucrose and pregelatinized starch. Among them, corn starch is a common filler with the highest dosage (10% to 20%), which can significantly improve the quality of tablets; sucrose and pregelatinized starch complement each other, and their respective dosages are relatively low (both 5% to 10%). Sucrose has a sweet taste and can cover up the bitter smell of the drug, while pregelatinized starch has good disintegration and can accelerate the disintegration of tablets. The three are properly matched, which can complement each other and play a filling role in a synergistic manner. The binder is starch slurry prepared from starch for pulping, with a ratio of 1% to 5%. The starch slurry is easy to prepare, low in cost, and has moderate bonding strength, which can effectively improve the sphericity and toughness of the particles. The disintegrant is low-substituted hydroxypropyl cellulose, with a dosage of 1% to 5%. Low-substituted hydroxypropyl cellulose has excellent water absorption, swelling and disintegration properties. A small amount of addition can significantly promote tablet disintegration and accelerate drug release. The lubricant is magnesium stearate, with a dosage of 0.5% to 5%. Magnesium stearate is a highly efficient hydrophobic lubricant. A small amount of addition can form a uniform hydrophobic film on the surface of the particles, prevent the particles from adhering to the mold, and improve the appearance of the tablet.

[0183] In addition to the above preferred combination, this article also gives a more preferred prescription composition: inositol nicotinate 69%, corn starch 16%, sucrose 6%, pregelatinized starch 6%, starch for slurry 2%, low-substituted hydroxypropyl cellulose 2%, magnesium stearate 1%. In this formula, the content of inositol nicotinate is close to 70%, which reflects the high drug content characteristics of the preparation; the total amount of starch excipients (corn starch, pregelatinized starch and starch for slurry) is 24%, which can form a stable skeleton structure; the content of sucrose, low-substituted hydroxypropyl cellulose and magnesium stearate are relatively low, but they can play a good auxiliary role within their respective addition ranges. In general, the preferred formula is more refined in the prescription composition, reflecting the preparation design concept of "drug-dominant, excipient synergistic, and precise proportion", and the inositol nicotinate tablets prepared therefrom will definitely be superior in quality and performance.

[0184] The inositol nicotinate pharmaceutical composition is a white or off-white tablet, and is a mild peripheral vasodilator, used for the adjuvant treatment of hyperlipidemia, atherosclerosis, and various peripheral vascular disorders (such as occlusive arteriosclerosis, acromial arterial spasm, frostbite, vascular migraine, etc.). The inositol nicotinate pharmaceutical composition is gradually hydrolyzed into nicotinic acid and inositol in the body, so it has the pharmacological effects of both nicotinic acid and inositol, and has a lipid-lowering effect. Its vasodilating effect is milder and more lasting than that of nicotinic acid, and there are no side effects such as flushing and stomach discomfort after taking nicotinic acid. The composition can selectively dilate the blood vessels of the lesion site and the sensitive site stimulated by cold, while the dilating effect on normal blood vessels is weaker. In addition, it also has the effects of dissolving blood clots, anticoagulation, anti-fatty liver, and reducing capillary fragility.

[0185] Comparative Example 1

[0186] The sucrose, pregelatinized starch and low-substituted hydroxypropyl cellulose were mixed evenly, and then mixed with corn starch to form a first auxiliary material mixture; inositol nicotinate was mixed with the first auxiliary material mixture to form a first raw material mixture, and the mixing parameters were stirring speed of 60r / min, chopping speed of 600r / min, and mixing for 8 minutes; the second raw material mixture was put into a high-efficiency wet granulator for wet granulation; stirring was started, the stirring speed was 60r / min, the chopping speed was 600r / min, and the binder was slowly added during the stirring process, and granulation was carried out for 8 minutes until the material was spherical and free of The inositol nicotinate wet granules were prepared by mixing the inositol nicotinate granules with a lubricant at a mixing speed of 5 r / min and a mixing time of 4 min to form raw material mixed granules; the raw material mixed granules were pressed into tablets using a tablet press, and the tablet hardness was controlled at 30 N.

[0187] Comparative Example 2

[0188] The sucrose, pregelatinized starch and low-substituted hydroxypropyl cellulose are mixed evenly, and then mixed with corn starch to form a first auxiliary material mixture; inositol nicotinate is mixed with the first auxiliary material mixture to form a first raw material mixture, and the mixing parameters are a stirring speed of 250r / min, a chopping speed of 2500r / min, and mixing for 2 minutes; the second raw material mixture is placed in a high-efficiency wet granulator for wet granulation; stirring is started, the stirring speed is 250r / min, the chopping speed is 2500r / min, and the binder is slowly added during the stirring process, and granulation is performed for 8 minutes until the material is spherical. The inositol nicotinate wet granules are prepared by mixing the inositol nicotinate granules with a lubricant at a mixing speed of 20 r / min and a mixing time of 4 min to prepare raw material mixed granules. The raw material mixed granules are pressed into tablets using a tablet press, and the tablet hardness is controlled at 200 N.

[0189] Compared with Example 1, Example 2 adopts a staged drying method and an airflow screening model to obtain the mesh size and screening time of the particle screening process; Example 1, Comparative Example 1 and Comparative Example 2 do not use the staged drying method and the airflow screening model; Compared with Example 1, the process parameters of Comparative Example 1 and Comparative Example 2 are outside the range described in Example 1.

[0190] Experimental test:

[0191] Inositol nicotinate tablets were prepared according to the preparation processes of Example 1, Example 2, Comparative Example 1 and Comparative Example 2, and 3 batches of samples were prepared for each experimental group, with 300 tablets in each batch.

[0192] The granulation process indicators of each group of samples were examined, including granulation time, granulation rate, fine powder rate, etc.

[0193] The drying process indicators of each group of samples were examined, including drying time, moisture content, etc.

[0194] The granulation process indicators of each group of samples were examined, including granulation time, yield, etc.

[0195] The tablet properties of each group of samples were examined, including hardness, disintegration time, dissolution rate, etc.

[0196] The data of each group were compared and analyzed to evaluate the preparation process of the present invention.

[0197] Data comparison:

[0198] Table 4 Data comparison

[0199]

[0200]

[0201] Result analysis:

[0202] (1) Granulation process: The granulation time of Examples 1 and 2 was 5 min, the granulation rate was ≥98.5%, and the fine powder rate was ≤1.2%, which was better than that of Comparative Examples 1 and 2. This shows that the present invention can obtain granules with uniform quality and good formability in a relatively short time by premixing the filler and the disintegrant and then mixing and granulating with inositol nicotinate at a high speed.

[0203] (2) Drying process: Example 2 uses staged temperature control drying based on dissolution, with the shortest drying time (70 min) and the lowest moisture content (2.8%), which is significantly better than Example 1 (80 min, 3.5%) and the two comparative examples (60-120 min, 6.0-8.0%). This shows that staged drying can effectively shorten the drying time and obtain particles with qualified moisture content.

[0204] (3) Granulation process: Example 2 optimized the sieve mesh size and sieving time according to the airflow sieving model, and the granulation time (8 min) and yield (98.5%) were better than those of other groups, indicating that the airflow sieving model can guide the selection of granulation parameters and improve granulation efficiency and particle yield.

[0205] (4) Tablet performance: The tablets of Examples 1 and 2 have high hardness (85-90N), short disintegration time (6-8min), high dissolution rate (95-98%), and meet the quality standards, which are better than the two comparative examples. Among them, the performance of Example 2 is better.

[0206] In summary, the preparation process of the present invention can prepare inositol nicotinate tablets with stable quality and high solubility through key processes such as optimized wet granulation, staged drying based on dissolution, and airflow screening based on models. The production efficiency and product performance are better than those of the conventional process (comparative example), which fully verifies the innovation and beneficial effects of the present invention. Among them, the introduction of staged drying and airflow screening models contributes more prominently to improving the quality of the preparation and production efficiency.

[0207] The applicant declares that the above is only a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention shall fall within the protection scope and disclosure scope of the present invention.

Claims

1. A process for preparing inositol nicotinate tablets, characterized in that: include: Premixing the filler and the disintegrant to form a first auxiliary material mixture; mixing inositol nicotinate with the first auxiliary material mixture to form a first raw material mixture; pouring the first raw material mixture into a vibrating screen for sieving to obtain a second raw material mixture; The second raw material mixture is placed in a high-efficiency wet granulator, a binder is added, and wet granulation is performed to generate inositol nicotinate wet granules; Placing the wet inositol nicotinate granules in a fluidized bed dryer and drying them by a staged drying method until the moisture content is 1.0-5.0%, thereby obtaining dry inositol nicotinate granules; The inositol nicotinate dry particles are transferred to a swing granulator for particle screening, airflow is introduced during the screening process, an airflow screening model is constructed, and the mesh size and screening time of the particle screening process are determined according to the airflow screening model to obtain inositol nicotinate particles; mixing inositol nicotinate particles with a lubricant to form raw material mixed particles; The raw material mixed granules are compressed into tablets using a tablet press.

2. The process for preparing an inositol nicotinate tablet according to claim 1, characterized in that: The binder is one or more of starch slurry, sucrose syrup and water; The filler is one or more of starch, pregelatinized starch, and sucrose; the starch in the filler includes corn starch; The disintegrant is one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl cellulose; The lubricant is one or more of magnesium stearate, talc and silicon dioxide.

3. The preparation process of an inositol nicotinate tablet according to claim 1, characterized in that: The filler and disintegrant are premixed by uniformly mixing sucrose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then mixing with corn starch; The mixing parameters of mixing inositol nicotinate with the first auxiliary material mixture are a stirring speed of 120 r / min, a chopping speed of 1500 r / min, and mixing for 5 minutes; The screening parameters for pouring the first raw material mixture into the vibrating screen for screening include the number of screen meshes and the optimal screening time.

4. The process for preparing an inositol nicotinate tablet according to claim 3, characterized in that: The mesh size of the sieve in the sieving parameters is 40 meshes, and the optimal sieving time is 2-5 minutes.

5. The process for preparing an inositol nicotinate tablet according to claim 1, characterized in that: The wet granulation process firstly granulates at a low speed for 2 minutes, with a stirring speed of 80 r / min, a chopping speed of 1000 r / min, and a binder is added; Then granulate at high speed for 3 minutes, with a stirring speed of 120r / min and a chopping speed of 1500r / min.

6. The process for preparing an inositol nicotinate tablet according to claim 1, characterized in that: The staged drying method is: Place the wet granules of inositol nicotinate in a fluidized bed dryer and set the drying parameters: drying temperature 45°C, hot air flow rate 40-60m 3 / h, drying for 30-40min, drying to a moisture content of 8.0-10.0% to obtain pre-dried particles; The pre-dried granules were taken out, their solubility was measured, recorded as Q1, and the drying parameters were adjusted: when Q1<60%, the drying temperature was adjusted to 55°C; when 60%≤Q1<75%, the drying temperature was adjusted to 50°C; when Q1≥75%, the drying temperature was adjusted to 45°C; the hot air flow rate remained unchanged, and the drying was continued for 20-30 minutes to obtain medium-dried granules; Take out the dried granules, measure their solubility, record it as Q2, and adjust the drying parameters: when the difference between Q2 and Q1 |Q2-Q1|<10%, maintain the existing drying temperature unchanged; when |Q2-Q1|≥10% and Q2<85%, reduce the drying temperature by 5-10℃; when |Q2-Q1|≥10% and Q2≥85%, reduce the drying temperature by 10-15℃; reduce the hot air flow rate to 30-40m 3 / h, and dried to a moisture content of 1.0-5.0% to obtain inositol nicotinate dry particles.

7. The process for preparing an inositol nicotinate tablet according to claim 1, characterized in that: The airflow screening model includes an airflow screening first sub-model, an airflow screening second sub-model and an airflow screening third sub-model; The first sub-model of airflow screening is: The second sub-model of airflow screening is: The third sub-model of airflow screening is: Where d is the particle diameter, ρ g is the gas density, v is the air velocity, C d is the drag coefficient, g is the acceleration due to gravity, ρ p is the particle density, M is the mesh size, k is the first proportional coefficient, α' is the second proportional coefficient, t' is the screening time, and L is the screen surface diameter.

8. The process for preparing an inositol nicotinate tablet according to claim 1, characterized in that: The particle screening process obtained according to the airflow screening model has a screen mesh number of 14 and a screening time of 8 minutes.

9. The process for preparing an inositol nicotinate tablet according to claim 1, characterized in that: The parameters of the wet granulation process are stirring speed 80-120r / min, chopping speed 1000-1500r / min, and granulation for 5 minutes; In the drying process using the staged drying method, the drying temperature is 30-70°C, the drying time is 50-100 minutes, and the hot air flow rate is 30-60m 3 / h; During the mixing of the inositol nicotinate particles and the lubricant, the mixing speed is 8 r / min and the mixing time is 10 min; In the process of using the tablet press to press the raw material mixed particles into tablets, the tablet hardness is controlled at 50-100N.

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