Valsartan tablet capable of improving dissolution rate and resisting moisture absorption and preparation process of valsartan tablet

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and relates to a valsartan tablet with improved dissolution rate and moisture absorption resistance and a preparation process thereof. The valsartan tablet formula comprises a main drug valsartan and auxiliary materials such as a filler, a disintegrating agent, a stable dissolution promoter, a cosolvent, an adhesive, a surfactant, a lubricant and the like, and the stable dissolution promoter is formed by compounding specific components and needs to be subjected to special treatment of low-temperature crushing and composite grinding. The preparation process adopts wet granulation and comprises the steps of pretreatment of auxiliary materials, premixing, granulation, drying, size stabilization, total mixing, tabletting and the like. According to the invention, the synergistic effect of improving the dissolution rate and optimizing the moisture absorption resistance is realized through a specifically combined stable dissolution promoter and a matched process.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a valsartan tablet with improved dissolution and moisture resistance, and its preparation process. Background Technology

[0002] Valsartan is an angiotensin II receptor antagonist antihypertensive drug. With its highly selective blocking effect on the binding of angiotensin II to AT1 receptors, it can effectively lower blood pressure and protect cardiovascular and renal target organs. It is widely used in the clinical treatment of diseases such as essential hypertension, heart failure, and diabetic nephropathy.

[0003] However, the inherent physicochemical properties of valsartan raw material present two major technological bottlenecks for tablet formulation development, severely restricting the clinical efficacy and market application of the product: 1. Insufficient dissolution leads to low bioavailability. Valsartan belongs to the BCS II class of drugs (low water solubility, high permeability). Its water solubility is extremely poor, and its crystal structure is dense, resulting in a slow dissolution rate in the gastrointestinal tract after oral administration. Dissolution rate becomes a key factor limiting the absorption of the drug in vivo.

[0004] 2. The problem of significantly reduced formulation stability due to high hygroscopicity. Valsartan raw material is highly hygroscopic, readily absorbing moisture from the environment during formulation production, storage, and transportation. Moisture intrusion can trigger a series of chain reactions, severely compromising formulation quality.

[0005] Chinese Patent CN104042580A discloses a valsartan dispersible tablet and its preparation method. The method uses micronization technology to control the particle size distribution of the valsartan active pharmaceutical ingredient to a D90 of less than 75 μm, thereby improving the dispersibility and dissolution rate of the valsartan dispersible tablet. Chinese Patent CN114642644A discloses a valsartan tablet and its preparation method. This tablet comprises a solid dispersion of valsartan, a filler, a disintegrant, and a lubricant. The use of a solid dispersion effectively combines the excipients to increase the solubility and dissolution rate of the poorly soluble active pharmaceutical ingredient, valsartan.

[0006] In existing technologies, there is a technical contradiction between improving the dissolution rate of valsartan tablets and controlling hygroscopicity. Solutions to improve dissolution rate (such as micronization and solid dispersions) often exacerbate hygroscopicity, making it impossible to guarantee the stability of valsartan. Therefore, developing a method that can simultaneously solve the two core problems of insufficient dissolution rate and decreased stability caused by hygroscopicity has become a technical challenge that urgently needs to be overcome in this field. Summary of the Invention

[0007] The purpose of this invention is to overcome the technical contradiction between improving the dissolution rate and controlling the hygroscopicity of valsartan tablets in the prior art, and to provide a valsartan tablet and its preparation process that can simultaneously solve the problems of insufficient dissolution rate and high hygroscopicity leading to decreased stability, ultimately achieving dual optimization of tablet bioavailability and storage stability, and ensuring the consistency and reliability of clinical efficacy.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is as follows: (a) Composition of Valsartan Tablets (by weight) Main drug: valsartan 100 parts; Filler: 100-200 parts, selected from one or more of lactose, starch, microcrystalline cellulose, mannitol, sucrose, dextrin, dicalcium phosphate, and sorbitol; Disintegrant: 12-20 parts, selected from one or more of croscarmellose sodium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, and croscarmellose; Stabilizing solubilizer: 15-33 parts, composed of xylitol glucoside 8-15 parts, fumed silica 4-10 parts, and glycine 3 parts. -8 parts composition; Cosolvent: 3-10 parts, selected from one or more of polyethylene glycol 6000, polyethylene glycol 4000, poloxamer 188, and hydroxypropyl-β-cyclodextrin; Adhesive: appropriate amount, which is purified water or 10% starch paste; Surfactant: 1-3 parts, selected from one or more of sodium dodecyl sulfate, Tween 65, and sucrose fatty acid ester; Lubricant: 1-3 parts, selected from one or more of magnesium stearate, talc, sodium stearate fumarate, and glyceryl behenate.

[0009] (II) Key processing techniques for stabilizing solvents 1. Glycine pretreatment: Glycine is pulverized at -10~-5℃ to control the particle size D90≤10μm, and then passed through a 200-mesh sieve for later use; 2. Composite grinding: The pulverized glycine is mixed with xylitol glucoside and fumed silica, and then put into a high-speed shear mixing mill. The mixture is continuously ground for 15-20 minutes at a temperature of 40-50℃ and a speed of 3000-3500r / min to obtain a composite stable solubilizer.

[0010] (III) Preparation process of valsartan tablets (wet granulation) 1. Excipient pretreatment: Pass fillers, disintegrants, solubilizers, surfactants, and lubricants through a 100-mesh sieve for later use; 2. Premixing: Add valsartan raw material, pretreated fillers, 70% of the amount of disintegrant, solubilizer, and surfactant to a three-dimensional motion mixer and mix at 30-40 rpm at room temperature for 20-25 min; 3. Wet granulation: Add 15-25% of the total weight of binder to the premixed material and granulate at a stirring speed of 1200-1600 rpm and a cutting speed of 2200-2800 rpm for 6-10 min; 4. 1. Drying: Transfer the wet granules to a fluidized bed dryer and dry for 25-35 minutes at an inlet air temperature of 60-70℃, an outlet air temperature of 40-50℃, and an air velocity of 1.2-1.6 m / s; 5. Granulation: Granulate the dried granules through a 16-mesh sieve vibrating granulator; 6. Mixing: Add the treated stabilizing solvent, the remaining 30% disintegrant, and lubricant to the granulated granules and mix at room temperature at 30-40 r / min for 15-20 minutes; 7. Tableting: Use a rotary tablet press, adjust the tableting pressure to 9-13 kN, and control the tablet hardness to 3-5 kgf and the friability to ≤1.0%.

[0011] Compared with the prior art, the technical advantages of the present invention are as follows: This invention achieves three core technological breakthroughs through a specific combination of stable solvents and processing techniques: 1. Significantly improved dissolution rate: The synergistic effect of the components in the stable solvent improves the water solubility of valsartan, achieving a dissolution rate of over 98.5% within 30 minutes, far exceeding the control group; 2. Excellent moisture absorption performance: After being placed at 25℃ and 75% relative humidity for 7 days, the moisture absorption rate of the valsartan tablets of this invention is only 1.7-2.2%, with no adhesion or clumping, while the moisture absorption rate of the control group reaches a maximum of 10.5%; 3. Significantly optimized stability: After 6 months of accelerated testing, the dissolution rate change rate of the valsartan tablets of this invention is ≤3%, and the valsartan content remains above 99.5%, effectively avoiding the problems of dissolution decay and drug degradation in existing technologies. Attached Figure Description

[0012] Figure 1 Hygroscopicity of valsartan tablets in Examples 1-4 and Control Groups 1-7.

[0013] Figure 2 Dissolution of valsartan tablets in Examples 1-4 and Control Groups 1-7. Detailed Implementation

[0014] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.

[0015] Example 1 Valsartan Tablets formula: Preparation method: (1) Stabilizing and promoting solvent treatment: Glycine was placed in a cryogenic grinder and ground at -8℃ to a particle size D90≤10μm, then passed through a 200-mesh sieve for later use; xylitol glucoside, fumed silica and the above-ground glycine were mixed and added to a high-speed shear mixing grinder, and the grinding temperature was set to 45℃ and the speed to 3200r / min, and the grinding was continued for 15-20 minutes for later use.

[0016] (2) Pretreatment of other auxiliary materials: Take fillers, disintegrants, solubilizers, surfactants and lubricants, and pass them through a 100-mesh sieve for later use.

[0017] (3) Premixing of active pharmaceutical ingredient and excipients: Valsartan raw material, pretreated filler, 70% of total disintegrant, solubilizer and surfactant are put into a three-dimensional motion mixer, set the speed to 30-40 r / min and mix at room temperature for 20-25 minutes.

[0018] (4) Wet granulation: Add binder to the above premixed materials, the amount of which is 15-25% of the total weight of the materials. Set the stirring speed to 1200-1600 r / min, the cutting speed to 2200-2800 r / min, and the granulation time to 6-10 minutes.

[0019] (5) Drying: Transfer the wet particles into a fluidized bed dryer, set the inlet air temperature to 60-70℃, the outlet air temperature to 40-50℃, and the air speed to 1.2-1.6m / s, and dry for 25-35 minutes.

[0020] (6) Granulation: The dried granules are fed into a gyratory granulator and granulated using a 16-mesh sieve for later use.

[0021] (7) Mixing: Add the stabilized solvent, the remaining 30% disintegrant and lubricant treated in step (1) to the granulated particles, set the rotation speed to 30-40 r / min, and mix at room temperature for 15-20 minutes.

[0022] (8) Tableting: A rotary tablet press is used. The tableting pressure is adjusted to 9-13 kN, and the tablet hardness is controlled to be 3-5 kgf and the friability is ≤1.0%.

[0023] Example 2 Valsartan Tablets formula: Preparation method: (1) Stabilizing and promoting solvent treatment: Glycine was placed in a cryogenic grinder and ground at -7℃ to a particle size D90≤10μm, then passed through a 200-mesh sieve for later use; xylitol glucoside, fumed silica and the above-ground glycine were mixed and added to a high-speed shear mixing grinder, and the grinding temperature was set to 45℃ and the speed to 3300r / min, and the grinding was continued for 15-20 minutes for later use.

[0024] (2) Pretreatment of other auxiliary materials: Take fillers, disintegrants, solubilizers, surfactants and lubricants, and pass them through a 100-mesh sieve for later use.

[0025] (3) Premixing of active pharmaceutical ingredient and excipients: Valsartan raw material, pretreated filler, 70% of total disintegrant, solubilizer and surfactant are put into a three-dimensional motion mixer, set the speed to 30-40 r / min and mix at room temperature for 20-25 minutes.

[0026] (4) Wet granulation: Add binder to the above premixed materials, the amount of which is 15-25% of the total weight of the materials. Set the stirring speed to 1200-1600 r / min, the cutting speed to 2200-2800 r / min, and the granulation time to 6-10 minutes.

[0027] (5) Drying: Transfer the wet particles into a fluidized bed dryer, set the inlet air temperature to 60-70℃, the outlet air temperature to 40-50℃, and the air speed to 1.2-1.6m / s, and dry for 25-35 minutes.

[0028] (6) Granulation: The dried granules are fed into a gyratory granulator and granulated using a 16-mesh sieve for later use.

[0029] (7) Mixing: Add the stabilized solvent, the remaining 30% disintegrant and lubricant treated in step (1) to the granulated particles, set the rotation speed to 30-40 r / min, and mix at room temperature for 15-20 minutes.

[0030] (8) Tableting: A rotary tablet press is used. The tableting pressure is adjusted to 9-13 kN, and the tablet hardness is controlled to be 3-5 kgf and the friability is ≤1.0%.

[0031] Example 3 Valsartan Tablets formula: Preparation method: (1) Stabilizing and promoting solvent treatment: Glycine was placed in a cryogenic grinder and ground at -10℃ to a particle size D90≤10μm, and passed through a 200-mesh sieve for later use; xylitol glucoside, fumed silica and the above-ground glycine were mixed and added to a high-speed shear mixing grinder, and the grinding temperature was set to 40℃ and the speed to 3000r / min, and the grinding was continued for 15-20 minutes for later use.

[0032] (2) Pretreatment of other auxiliary materials: Take fillers, disintegrants, solubilizers, surfactants and lubricants, and pass them through a 100-mesh sieve for later use.

[0033] (3) Premixing of active pharmaceutical ingredient and excipients: Valsartan raw material, pretreated filler, 70% of total disintegrant, solubilizer and surfactant are put into a three-dimensional motion mixer, set the speed to 30-40 r / min and mix at room temperature for 20-25 minutes.

[0034] (4) Wet granulation: Add binder to the above premixed materials, the amount of which is 15-25% of the total weight of the materials. Set the stirring speed to 1200-1600 r / min, the cutting speed to 2200-2800 r / min, and the granulation time to 6-10 minutes.

[0035] (5) Drying: Transfer the wet particles into a fluidized bed dryer, set the inlet air temperature to 60-70℃, the outlet air temperature to 40-50℃, and the air speed to 1.2-1.6m / s, and dry for 25-35 minutes.

[0036] (6) Granulation: The dried granules are fed into a gyratory granulator and granulated using a 16-mesh sieve for later use.

[0037] (7) Mixing: Add the stabilized solvent, the remaining 30% disintegrant and lubricant treated in step (1) to the granulated particles, set the rotation speed to 30-40 r / min, and mix at room temperature for 15-20 minutes.

[0038] (8) Tableting: A rotary tablet press is used. The tableting pressure is adjusted to 9-13 kN, and the tablet hardness is controlled to be 3-5 kgf and the friability is ≤1.0%.

[0039] Example 4 Valsartan Tablets formula: Preparation method: (1) Stabilizing and promoting solvent treatment: Glycine was placed in a cryogenic grinder and ground at -5℃ to a particle size D90≤10μm, then passed through a 200-mesh sieve for later use; xylitol glucoside, fumed silica and the above-ground glycine were mixed and added to a high-speed shear mixing grinder, and the grinding temperature was set to 50℃ and the speed to 3500r / min, and the grinding was continued for 15-20 minutes for later use.

[0040] (2) Pretreatment of other auxiliary materials: Take fillers, disintegrants, solubilizers, surfactants and lubricants, and pass them through a 100-mesh sieve for later use.

[0041] (3) Premixing of active pharmaceutical ingredient and excipients: Valsartan raw material, pretreated filler, 70% of total disintegrant, solubilizer and surfactant are put into a three-dimensional motion mixer, set the speed to 30-40 r / min and mix at room temperature for 20-25 minutes.

[0042] (4) Wet granulation: Add binder to the above premixed materials, the amount of which is 15-25% of the total weight of the materials. Set the stirring speed to 1200-1600 r / min, the cutting speed to 2200-2800 r / min, and the granulation time to 6-10 minutes.

[0043] (5) Drying: Transfer the wet particles into a fluidized bed dryer, set the inlet air temperature to 60-70℃, the outlet air temperature to 40-50℃, and the air speed to 1.2-1.6m / s, and dry for 25-35 minutes.

[0044] (6) Granulation: The dried granules are fed into a gyratory granulator and granulated using a 16-mesh sieve for later use.

[0045] (7) Mixing: Add the stabilized solvent, the remaining 30% disintegrant and lubricant treated in step (1) to the granulated particles, set the rotation speed to 30-40 r / min, and mix at room temperature for 15-20 minutes.

[0046] (8) Tableting: A rotary tablet press is used. The tableting pressure is adjusted to 9-13 kN, and the tablet hardness is controlled to be 3-5 kgf and the friability is ≤1.0%.

[0047] Verification of the technical effect of stable solvent promoter Using Example 1 of this invention as the baseline formulation, seven control samples were designed using a "single variable substitution + missing control" approach. Only the composition of the stabilizing solvent was changed, while keeping the other components, dosages, and preparation processes completely consistent. The synergistic effect of the three components was verified from three core dimensions: hygroscopicity, dissolution, and stability.

[0048] Table 1 Experimental Design Moisture resistance verification experiment Experimental conditions: Constant temperature and humidity chamber (temperature 25℃±1℃, relative humidity 75%±2%). Initial weighing: Record the initial weight (W0) of each group of samples. Periodic weighing: Accurately weigh (Wt) after 24h, 48h, 72h, and 168h (7 days). Moisture absorption rate (%) = (Wt-W0) / W0×100%. Appearance observation: Record the appearance of the samples (whether there is clumping, discoloration, surface adhesion, disintegration, etc.), and use a three-level evaluation of "no abnormality (√), slight adhesion (△), obvious clumping (×)".

[0049] Table 2 Results of moisture absorption test Table 2 shows that specific combinations of stabilizing solubilizers can significantly inhibit the hygroscopic behavior of valsartan tablets, allowing the tablets to maintain a good appearance even after long-term storage in high humidity environments, avoiding problems such as sticking and clumping. This antihygroscopic effect relies on the synergistic effect of xylitol glucoside, fumed silica, and glycine. The absence of any one of these components, their substitution with other substances, or the complete absence of such stabilizers will significantly reduce the tablets' hygroscopic inhibition ability.

[0050] Dissolution verification experiment Referencing the "Determination of Dissolution and Release Rate" in General Chapter 0931 of Part IV of the 2020 edition of the Chinese Pharmacopoeia, the dissolution rate of the drug was evaluated using the paddle method to simulate the gastrointestinal environment. Dissolution medium: 900 mL purified water; rotation speed: 50 r / min ± 1 r / min; temperature: 37℃ ± 0.5℃; detection method: high performance liquid chromatography (HPLC).

[0051] Table 3 Dissolution effect Table 3 shows that valsartan tablets containing a complex stable prosolvent can dissolve rapidly in a simulated gastrointestinal environment, with a significantly improved dissolution efficiency, which can effectively solve the problems of poor water solubility and slow dissolution of the active ingredient.

[0052] Stability verification of valsartan tablets Accelerated testing: Following the requirements of the Chinese Pharmacopoeia, the temperature was 40℃±2℃, the relative humidity was 75%±5%, and the product was sealed in packaging for 6 months. Performance testing: Repeated dissolution verification experiments were conducted, and the dissolution rate change over 30 minutes was calculated (change rate = (initial dissolution rate - dissolution rate at time point) / initial dissolution rate × 100%). The valsartan content was determined using HPLC according to the requirements of the Chinese Pharmacopoeia.

[0053] Table 4. Dissolution stability and content stability after 6 months of accelerated testing Table 4 shows that, as verified by accelerated testing, the valsartan tablets formulated in this invention maintain stable dissolution performance and drug content even after long-term storage, and their efficacy is not easily diminished. A proper combination of stabilizing solubilizers is crucial for ensuring stability. In contrast, formulations lacking key components, using substitute components, or without such stabilizers exhibit a significant decrease in dissolution rate and drug content under accelerated conditions.

Claims

1. A valsartan tablet, characterized in that, The formulation of the valsartan tablets, by weight, is as follows: 100 parts valsartan, 100-200 parts filler, 12-20 parts disintegrant, 15-33 parts stabilizing solubilizer, 3-10 parts cosolvent, appropriate amount of binder, 1-3 parts surfactant, and 1-3 parts lubricant; the stabilizing solubilizer is xylitol glucoside, fumed silica, and glycine.

2. The valsartan tablet according to claim 1, characterized in that, The stabilizing co-solvent consists of 8-15 parts xylitol glucoside, 4-10 parts fumed silica, and 3-8 parts glycine.

3. The valsartan tablet according to claim 1, characterized in that, The filler is selected from one or more of lactose, starch, microcrystalline cellulose, mannitol, sucrose, dextrin, dicalcium phosphate, and sorbitol.

4. The valsartan tablet according to claim 1, characterized in that, The disintegrant is selected from one or more of croscarmellose sodium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, and croscarmellose.

5. The valsartan tablet according to claim 1, characterized in that, The co-solvent is selected from one or more of polyethylene glycol 6000, polyethylene glycol 4000, poloxamer 188, and hydroxypropyl-β-cyclodextrin.

6. The valsartan tablet according to claim 1, characterized in that, The surfactant is selected from one or more of sodium dodecyl sulfate, Tween 65, and sucrose fatty acid esters.

7. The valsartan tablet according to claim 1, characterized in that, The lubricant is selected from one or more of magnesium stearate, talc, sodium stearate fumarate, and glyceryl behenate.

8. The valsartan tablet according to claim 1, characterized in that, The adhesive is purified water or 10% starch paste.

9. The valsartan tablet according to claim 1, characterized in that, The stable solvent is prepared by pulverizing glycine at -10 to -5°C, mixing it with xylitol glucoside and fumed silica, and grinding it at 40-50°C for 15-20 minutes.

10. The valsartan tablet according to claim 1, characterized in that, The valsartan tablets are prepared by wet granulation.

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