Preparation method of trazodone hydrochloride sustained-release tablets and new tablet type

Abstract

The application discloses a preparation method of a trazodone hydrochloride sustained-release tablet and a new tablet type. The sustained-release tablet is mainly composed of trazodone hydrochloride, a skeleton material, a pore forming agent, a binder and a lubricant and the like medicinal auxiliaries. In the application, a swing granulator is used to granulate and integrate the materials. The optimal aging condition of the trazodone hydrochloride sustained-release tablet is obtained through sample dissolution, the problems of high material loss and high equipment energy consumption in the prior art prepared by a fluidized bed are avoided, the tablet type is screened, the product stability is ensured, and the defect of high friability and easy breaking of the original research tablet type is avoided.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, specifically to a method for preparing trazodone hydrochloride sustained-release tablets and a novel tablet form. Background Technology

[0002] The chemical name of trazodone hydrochloride is 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo[4,3-a]pyridin-3(2H)one hydrochloride, and its structural formula is shown below.

[0003] Trazodone hydrochloride is an antidepressant synthesized by the Italian company Angelini in 1972. It works by blocking serotonin receptors and inhibiting serotonin reuptake, similar in effect to tricyclic antidepressants and monoamine oxidase inhibitors, but with less cardiovascular toxicity and no anticholinergic side effects. Trazodone hydrochloride is well absorbed orally and has been used in several countries to treat mild to moderate depression. Its solubility is affected by pH, influencing absorption in the lower intestine, which limits the development of long-acting formulations. While immediate-release tablets typically require two or three doses daily, extended-release tablets only require one dose daily, maintaining stable blood concentrations, improving patient adherence, and reducing side effects.

[0004] CN101252932A discloses the formulation and preparation process of trazodone hydrochloride extended-release tablets (oleptro). This technical solution uses the extended-release excipient hydroxypropyl distarch phosphate (trade name Contamid) and a small amount of binder such as methyl cellulose to control drug release. However, the tablets prepared by this method are not only difficult to swallow due to their excessive weight, but also suffer from low release in the intestinal environment with a pH higher than 6.8 and incomplete release over 24 hours, potentially leading to insufficient drug release in the intestinal environment and accumulation problems. Therefore, this product has been withdrawn from the US market due to safety concerns, and there is still considerable room for improvement.

[0005] CN102935074A discloses a preparation method for trazodone hydrochloride osmotic pump controlled-release tablets from Chengdu Kanghong Pharmaceutical Group Co., Ltd. This formulation consists of three parts: a drug-containing tablet core, a semi-permeable membrane coating layer, and a release orifice. Although osmotic pump tablets can effectively control the drug release rate, their complex structure and the high requirements for equipment and performance in their preparation process make industrialization difficult. Furthermore, due to the large dosage of trazodone hydrochloride, the structural feature of osmotic pump tablets lies in using a drug-free propellant layer to facilitate the release of the drug-containing material from the release orifice. CN105748421A discloses a method for preparing trazodone hydrochloride sustained-release tablets. This method uses a wet granulation process, which has high requirements for the binder. The use of high-concentration alcohol poses safety hazards during production. The coating process for the tablets is relatively complex, requiring high-performance equipment and making industrialization difficult. This method is prone to causing inconsistencies in drug quality and poor reproducibility, hindering the production and promotion of sustained-release drugs. Furthermore, the standard dosage of trazodone hydrochloride is 150mg; with an additional 2 to 3 times the amount of sustained-release material, the resulting tablet weight typically exceeds 500mg, leading to patient compliance issues such as difficulty swallowing.

[0006] CN119896649A provides a method for preparing trazodone hydrochloride sustained-release tablets, which uses hot melt extrusion technology. The heating time is short and the production reproducibility is good. However, the screw hot melt extrusion process requires a high level of knowledge and has limited production capacity. In addition, the tablet shape is not controlled, the produced granules have poor compressibility, and the tablets have low hardness, which poses a quality risk of tablet breakage. Summary of the Invention

[0007] This invention provides an optimal method for preparing trazodone hydrochloride sustained-release tablets, ensuring stable and reproducible process and enabling stable and continuous release of trazodone hydrochloride over a certain period. Furthermore, the tablet form was optimized to address the issue of tablet breakage.

[0008] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides two preparation methods for trazodone hydrochloride sustained-release tablets, which consist of trazodone hydrochloride, a sustained-release matrix, and other pharmaceutical excipients, including pore-forming agents, binders, and lubricants. The sustained-release granules are obtained by wet granulation and dry granulation using a granulator and a swing granulator. Magnesium stearate is added, and the mixture is then pressed into tablets using a special mold and aged to obtain trazodone hydrochloride sustained-release tablets.

[0009] In the above-mentioned sustained-release tablet technical solution, the sustained-release matrix material is carnauba wax, the water-soluble pore-forming agent is one or more of lactose, sucrose, mannitol, and fructose; the binder is one or more of polyvinylpyrrolidone, copolyvinylpyridine, and hexadecylpyridine chloride; and the lubricant is one or more of magnesium stearate, sodium stearate fumarate, and stearic acid.

[0010] Furthermore, the weight ratio between the sustained-release skeleton carnauba wax and the water-soluble porogen is 1:2, and the weight ratio between trazodone hydrochloride and the sustained-release skeleton is 3.125:1.

[0011] Furthermore, the preparation steps of trazodone hydrochloride sustained-release tablets include: mixing trazodone hydrochloride, matrix material, and water-soluble pore-forming agent in the sustained-release tablets, wet granulating and drying the granules using a swing granulator, and then pressing and aging the tablets using a mold after total mixing.

[0012] Furthermore, the preset rotation speed of the oscillating pellet mill is 55 r / min, and the screen for wet pelleting and dry sizing is 20 to 30 mesh.

[0013] In a further preferred embodiment, the preset rotation speed of the oscillating pellet mill is 55 r / min, the wet granulation screen is 24 mesh, and the dry granulation screen is 30 mesh.

[0014] Furthermore, the molds include a 12*4 original double-score mold, a 10*5 novel double-score mold, and a 9*6 novel double-score mold. Score studies were conducted on trazodone hydrochloride sustained-release tablets after tableting and aging.

[0015] Furthermore, the preset temperature for aging in the oven is 40–70°C, and the preset time is 2 hours.

[0016] The beneficial effects of the above-mentioned scheme are as follows: This invention uses a swing-type granulator to form sustained-release granules from carnauba wax and water-soluble fillers, selects optimal aging conditions, and allows the tablets to cool gradually, ensuring a more stable and controllable release effect. The formulation process is simple, and the preparation method overcomes the problems of high energy consumption, significant material loss during granulation, and excessively high production costs associated with fluidized bed granulation in existing technologies. The new tablet shape avoids the risks of low hardness and easy breakage associated with the original tablet shape. Attached Figure Description

[0017] Figure 1 This is a comparison chart of dissolution curves.

[0018] Figure 2 This is a comparison chart of dissolution rates under accelerated conditions.

[0019] Figure 3 These are schematic diagrams of the 10*5 new tablet type, the 12*4 original tablet type, and the 9*6 new tablet type. Detailed Implementation

[0020] The present invention will be described in detail below with reference to specific embodiments. The embodiments provided by the present invention are only for the purpose of helping to understand the technical solutions provided by the present invention, and cannot limit the scope of protection of the present invention; the present invention can be implemented in many different ways as defined and covered by the claims.

[0021] This embodiment provides a sustained-release tablet containing trazodone hydrochloride. This embodiment addresses the shortcomings of existing patented sustained-release and controlled-release tablets of the same product by providing a simple formulation and manufacturing process for a trazodone hydrochloride sustained-release tablet. The self-made tablet exhibits good stability and good hardness and brittleness. Tables 1-3 show the specific formulations for each embodiment: Example S1: Table 1: Specific prescription for Example S1 Preparation: Sucrose was pulverized. Trazodone hydrochloride, carnauba wax, and sucrose were added to a wet granulator and mixed for 3 minutes. A wetting agent was added, and the mixture was granulated for 2 minutes. The granules were discharged and wet-granulated using a 24-mesh sieve in a swing granulator. After drying, the granules were dry-granulated using a 30-mesh sieve in a swing granulator to obtain sustained-release granules. Magnesium stearate was added and mixed for 10 minutes. The granules were then compressed using a new 10*5 mold to obtain trazodone hydrochloride sustained-release tablets. After aging at 60°C for 1 hour and then at 40°C for 1 hour, the hardness ranged from 2 to 6 KN, the friability was 0.3%, and the moisture content was 0.6%.

[0022] Example S2: Table 2: Specific prescription for Example S2 Preparation: Sucrose was pulverized. Trazodone hydrochloride, carnauba wax, and sucrose were added to a wet granulator and mixed for 3 minutes. A wetting agent was added, and the mixture was granulated for 2 minutes. The granules were discharged and wet-granulated using a 24-mesh sieving machine. After drying, the granules were dry-granulated using a 30-mesh sieving machine to obtain sustained-release granules. Magnesium stearate was added and mixed for 10 minutes. The granules were then compressed using the original 12*4 mold to obtain trazodone hydrochloride sustained-release tablets. After aging at 60°C for 1 hour and then at 40°C for 1 hour, the hardness ranged from 2 to 5 N, the friability was 0.4%, and the moisture content was 0.6%.

[0023] Example S3: Table 3: Specific prescription for Example S3 Preparation: Sucrose is pulverized. Trazodone hydrochloride, carnauba wax, and sucrose are added to a wet granulator and mixed for 3 minutes. A wetting agent is added, and the mixture is granulated for 2 minutes. The granules are then discharged and wet-granulated using a 24-mesh sieving machine. After drying, the granules are dry-granulated using a 30-mesh sieving machine to obtain sustained-release granules. Magnesium stearate is added and mixed for 10 minutes. The mixture is then compressed using a new 9*6 mold to obtain sustained-release tablets of trazodone hydrochloride. The tablets are aged at 60°C for 1 hour and then at 40°C for 1 hour to obtain sustained-release tablets of trazodone hydrochloride. The tablets are then aged to a hardness range of 2 to 5 N, a friability of 0.4%, and a moisture content of 0.6%.

[0024] Comparative Example D1: Table 4: Specific prescriptions for Comparative Example D1 Preparation: Sucrose was pulverized. Trazodone hydrochloride, carnauba wax, and sucrose were added to a wet granulator and mixed for 3 minutes. A wetting agent was added, and the mixture was granulated for 2 minutes. The granules were discharged and wet granulated using a 4*4 sieve of a granulator. After drying, the granules were dry granulated using a Φ1.5 sieve of a granulator to obtain sustained-release granules. Magnesium stearate was added and mixed for 10 minutes. The mixture was then compressed into tablets using a new 10*5 mold to obtain trazodone hydrochloride sustained-release tablets. The tablets were aged at 60°C for 1 hour and then at 40°C for 1 hour. The hardness range was 2 to 5 KN, the friability was 0.4%, and the moisture content was 0.6%.

[0025] Comparative Example D2: Table 5: Specific prescriptions for Comparative Example D2 Preparation: Sucrose was pulverized. Trazodone hydrochloride, carnauba wax, and sucrose were added to a wet granulator and mixed for 3 minutes. A wetting agent was added, and the mixture was granulated for 2 minutes. The granules were discharged and wet-granulated using a 24-mesh sieving machine. After drying, the granules were dry-granulated using a 30-mesh sieving machine to obtain sustained-release granules. Magnesium stearate was added and mixed for 10 minutes. The granules were then compressed using a new 10*5 mold to obtain trazodone hydrochloride sustained-release tablets. After aging at 70°C for 2 hours, the hardness ranged from 2 to 5 KN, the friability was 0.4%, and the moisture content was 0.6%.

[0026] Comparative Example D3: Table 6: Specific prescriptions for Comparative Example D3 Preparation: Sucrose is pulverized. Trazodone hydrochloride, carnauba wax, and sucrose are added to a wet granulator and mixed for 3 minutes. A wetting agent is added, and the mixture is granulated for 2 minutes. The granules are then discharged and wet-granulated using a 24-mesh sieving machine. After drying, the granules are dry-granulated using a 30-mesh sieving machine to obtain sustained-release granules. Magnesium stearate is added and mixed for 10 minutes. The granules are then compressed using a new 10*5 mold to obtain trazodone hydrochloride sustained-release tablets. After aging at 40°C for 1 hour and then at 60°C for 1 hour, the hardness ranges from 2 to 5 KN, the friability is 0.4%, and the moisture content is 0.5%.

[0027] Analysis and Testing 1. Comparison of dissolution conditions (1) Take the trazodone hydrochloride sustained-release tablets prepared in Examples S1 to S3 and Comparative Examples D1 to D3 respectively, and conduct in vitro dissolution behavior studies according to the quality standards of trazodone hydrochloride sustained-release tablets marketed in China, and compare the release behavior with the original sample. Assay Method: Take this product and perform the dissolution and release determination method (Chinese Pharmacopoeia, Part IV, General Chapter 0931, Dissolution and Release Determination Method, Method 1), taking 10 ml samples at 0.5, 1, 2, 4, 6, 8, 10, and 12 hours respectively. Filter the sample through a 0.45 μm microporous membrane, discard the initial filtrate, and keep the subsequent filtrate for later use. Add the same volume of medium at the same temperature as needed. Measure the absorbance of the subsequent filtrate at 246 nm. Calculate the concentration of the sample solution at different times according to the standard curve. Investigate the relationship between the cumulative release over 12 hours and time. The dissolution standard is that, under the same medium and dissolution method conditions, the in vitro dissolution data in pH 6.0 medium at 2, 4, 8, and 12 hours should be 30%–55%, 50%–75%, 70%–95%, and above 85% of the labeled amount, respectively. Results are shown in Table 7 and 8. Figure 1 .

[0028] Table 7: Comparison of Dissolution Curves (2) Trazodone hydrochloride sustained-release tablets prepared in Examples S1-S3 and Comparative Examples D1-D3 were placed under accelerated conditions (40℃±2℃, RH75%±5%) for 1 month. The dissolution rates of the samples in pH 6.0 medium at 2, 4, 8, and 12 hours were determined according to the method in (1). The dissolution standards were 30%–55%, 50%–75%, 70%–95%, and above 85% of the labeled amount, respectively. The results are shown in Table 8 and... Figure 2 .

[0029] Table 8: Dissolution Comparison Data 2. Powder Science Comparison Table 9: Comparative Data on Powder Science 3. Scratch Study (1) Segmentation method The raw slices of Example S1 and Comparative Examples D2 to D3 were manually divided and cut with a knife, respectively. (2) For weight difference, randomly select 30 whole pieces, break them apart, and weigh one part of each piece after division. Discard the other parts and calculate the average weight. No more than one part of the divided piece can exceed 85% to 115% of the average weight. If more than one part of the divided piece exceeds 85% to 115% of the average weight, or if one part of the divided piece exceeds 75% to 125% of the average weight, it is deemed unqualified.

[0030] Table 10: Results of the Scratch Study (3) The weight loss after splitting is calculated as 15 whole tablets. The weight loss of the split portion should be controlled within 3.0% of the total weight of 15 whole tablets. The tablet fragments during the splitting process should not be included in the weight loss calculation.

[0031] Table 11: Results of the study on segmented weight loss (4) Friability: Take about 6.5g of the tablets, blow off the powder that falls off the tablets, weigh them accurately, place them in a cylinder, and rotate them 100 times. Take them out, blow off the powder in the same way, weigh them accurately, and the weight loss should not exceed 1.0%, and no broken, cracked or pulverized tablets should be detected.

[0032] Table 12: Results of Friability Study Discussion and analysis of results: The f2 values ​​of S1 and D2-D3 were compared respectively. The results showed that under the same tablet type and the same process but different aging conditions, aging at 60℃ and 40℃ for one hour each was the best aging condition. This allowed the tablets to cool down gradually, ensuring a more stable and controllable release effect.

[0033] The self-made tablets and the original drug tablets were placed under accelerated conditions for one month. By comparing the dissolution, it was found that only S1 and S3 were within the standard limits, and S1 was more similar to the original drug tablets and had better stability.

[0034] Comparing the f2 values ​​of S1 and D1, S1 was found to be the highest, indicating that under the same flake type and aging conditions but different processes, the dissolution results of the swaying granulation machine are more similar to the reference, and the sustained-release effect is better. The powder science results in the table show that the material obtained by the swaying granulation machine has better flowability and compressibility than that obtained by the granulation machine, and that the granulation machine produces fine powder.

[0035] The score analysis data (S1, D2, and D3) revealed that the new 10*5 and 9*6 tablet formats showed higher weight difference and weight loss during segmentation compared to the original formulation, but lower friability. Comparing the f2 values ​​of S1, D2, and D3, it was found that under the same process and aging conditions, the 10*5 tablet format exhibited the best dissolution similarity. In conclusion, the new 10*5 tablet format makes tablet dissolution easier to control and effectively addresses the issues of easy breakage and high friability of the original tablet format.

[0036] In summary, the optimal granulation method based on the formulation, using a swing-type granulator and 10*5 new tablet form, with aging conditions of 60℃ and 40℃ for 1 hour each, is the best approach. This method can achieve better compressibility and flowability of the material, reduce breakage, achieve a dissolution rate more similar to the original drug, and ensure more stable and controllable release under both room temperature and accelerated conditions.

[0037] The above description is merely a preferred embodiment of the present invention and is not intended to limit the scope of the invention. Any modifications, equivalent substitutions, and improvements made based on the spirit and principles of the present invention should be considered as included within the protection scope of the present invention.

Claims

1. A method for preparing sustained-release tablets of trazodone hydrochloride, characterized in that, The sustained-release tablets are composed of trazodone hydrochloride, a sustained-release matrix, and other pharmaceutical excipients, including pore-forming agents, binders, and lubricants. After wet granulation using a granulator and a swing granulator, the tablets are dried in an oven, granulated, and then sustained-release granules are obtained. Magnesium stearate is added, and the mixture is compressed and aged to obtain trazodone hydrochloride sustained-release tablets.

2. The preparation method according to claim 1, characterized in that, The weight ratio of the sustained-release matrix to the porogen is 1:2, and the weight ratio of trazodone hydrochloride to the sustained-release matrix is ​​3.125:

1.

3. The preparation method according to any one of claims 1-2, characterized in that, The sustained-release matrix material is one or two of carnauba wax, insect wax, and beeswax; the water-soluble pore-forming agent is one or more of lactose, sucrose, mannitol, and saccharin; the binder is one or more of polyvinylpyrrolidone, copovidone, and hydroxypropyl methylcellulose; and the lubricant is one or more of magnesium stearate, sodium stearate fumarate, and stearic acid.

4. The preparation method according to claim 1, characterized in that, The specific operating steps include: mixing trazodone hydrochloride, matrix material, and water-soluble pore-forming agent in the sustained-release tablets, wet granulating and drying the granules using a swing-type granulator, and then pressing and aging the tablets using a mold after total mixing.

5. The preparation method according to claim 4, characterized in that, The preset rotation speed of the oscillating pellet mill is 55 r / min, and the wet granulation screen and the dry granulation screen are 20-30 mesh.

6. The preparation method according to claim 4, characterized in that, The molds include a 12*4 original double-score mold, a 10*5 novel double-score mold, and a 9*6 novel double-score mold. The scoring of trazodone hydrochloride sustained-release tablets was studied after tableting and aging.

7. The preparation method according to claim 4, characterized in that, The preset temperature for aging in the oven is 40-70℃, and the preset time is 2 hours.

8. A novel tablet form of trazodone hydrochloride sustained-release tablets, characterized in that, The sheet type is a 10×5 double-score sheet type.

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