Preparation process and application of stable roxithromycin tablet

Abstract

This invention discloses a preparation process and application of stable roxithromycin tablets. The tablet core is composed of roxithromycin, microcrystalline cellulose (1.0-1.5:1), hydroxypropyl methylcellulose (0.08-0.12:1), disintegrant, and lubricant. After dry granulation and tableting, a hydroxypropyl methylcellulose protective layer and a moisture-proof coating layer are sequentially coated, with a total coating weight gain of 4%-6%. The dry granulation roller pressure is 20-50 kN, preferably 30-40 kN. This invention, through synergistic optimization of formulation and process, constructs a "dense and stable inner layer + moisture-proof outer layer" structure. While ensuring good stability, flowability, hardness, and tableting performance, it effectively controls dissolution behavior and reduces the formation of related substances during preparation, enabling the formulation to maintain good quality stability during storage, making it suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of biopharmaceutical technology, and more specifically, to a preparation process and application of stable roxithromycin tablets. Background Technology

[0002] This invention first provides information on roxithromycin, a macrolide antibiotic widely used clinically to treat bacterial infections of the respiratory tract and skin soft tissues. However, its molecular structure contains functional groups sensitive to moisture and temperature, which may change during processing or under specific conditions, leading to increased concentrations of open-ring and oxidized substances. This can affect the stability of the formulation, resulting in decreased content and increased impurities, which not only affects efficacy but may also pose safety risks.

[0003] Currently, most commercially available roxithromycin tablets are produced using a wet granulation process, which involves granulation with water or alcohol solutions as binders, followed by drying and tableting. While this process facilitates tablet formation, it introduces a large amount of moisture and heat, accelerating roxithromycin degradation. Furthermore, ordinary tablets lack an effective moisture barrier, absorbing moisture significantly under high temperature and humidity storage conditions, thus accelerating drug decomposition. Although some existing technologies employ a single film coating, its effectiveness in blocking humid and hot conditions is limited, making it difficult to meet the requirements for long-term stability.

[0004] To improve stability, some studies have attempted to adjust the type or proportion of excipients, such as increasing the amount of filler to dilute the drug, or adding antioxidants or desiccants. However, these methods often sacrifice the flowability, hardness, or dissolution performance of the formulation, and may even be counterproductive due to the moisture absorption of the excipients themselves. Other approaches propose using dry granulation, but these have not systematically optimized key parameters such as rolling pressure and coating structure, nor have they formed an overall design of "core stability - outer moisture barrier," resulting in insignificant improvements in stability.

[0005] Therefore, how to significantly improve the chemical stability of roxithromycin tablets under humid and hot conditions while ensuring good formability, dissolution and content uniformity remains a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0006] This invention aims to provide a preparation process and application of stable roxithromycin tablets. By combining dry granulation with a specific formulation and a double-layer coating structure, the dissolution behavior can be effectively controlled without affecting the physical properties and release behavior of the formulation, thereby improving the consistency and controllability of the formulation quality.

[0007] This invention first provides a preparation process for stable roxithromycin tablets, comprising the following steps: (1) Tablet core preparation: Roxithromycin, microcrystalline cellulose and hydroxypropyl methylcellulose are mixed and granulated by dry method to obtain granules. Disintegrant and lubricant are added and then tableted. (2) Double coating: Hydroxypropyl methylcellulose protective layer and moisture-proof coating layer are sequentially coated on the surface of the tablet core.

[0008] In some embodiments, the components in the tablet core are, by weight, 1 part of roxithromycin, 1.0 to 1.5 parts of microcrystalline cellulose, 0.08 to 0.12 parts of hydroxypropyl methylcellulose, 0.5 to 3 parts of disintegrant, and 0.1 to 1 part of lubricant.

[0009] In some embodiments, the mass ratio of microcrystalline cellulose to roxithromycin is 1.2:1, and the mass ratio of hydroxypropyl methylcellulose to roxithromycin is 0.10:1.

[0010] In some embodiments, the dry granulation is performed using a roller press with a roller pressure of 20–50 kN, preferably 30–40 kN.

[0011] In some embodiments, the disintegrant is croscarmellose sodium and the lubricant is magnesium stearate.

[0012] In some embodiments, the total weight gain of the double coating is 4% to 6%, preferably 5%.

[0013] In some embodiments, the moisture-proof coating layer is at least one of acrylic resin, polyvinyl alcohol, or enteric polymer.

[0014] The present invention also provides stable roxithromycin tablets prepared by the above process.

[0015] The present invention also provides the use of the above-mentioned stable roxithromycin tablets in the preparation of a drug for improving the dissolution behavior of roxithromycin tablets and reducing the content of related substances.

[0016] In some embodiments, the drug is stored at 40°C / 75%RH for 10 days, and the content of related substances in the roxithromycin tablets is ≤3.0%.

[0017] Compared with the prior art, the present invention has at least the following beneficial effects: (1) Dry granulation avoids contact between water and high temperature with the drug, reducing the risk of degradation from the source, and the moisture content of the particles can be reduced to below 0.6%.

[0018] (2) By optimizing the ratio of microcrystalline cellulose to hydroxypropyl methylcellulose, a dense and low-hygroscopic granular structure is formed, which takes into account both the flowability and hardness of the tablets, and the friability is less than 0.6%.

[0019] (3) The double-layer coating constructs an "inner protection and outer defense" barrier, reducing the moisture absorption weight gain from 4.8% to 1.5%, and the content of related substances under 40℃ / 75%RH conditions for 10 days from 10.5% to 2.2%.

[0020] (4) While maintaining a dissolution rate of ≥90% at 30 minutes, the long-term stability was significantly improved. After 60 days of storage at 25℃ / 60%RH, the total related substances content was only 2.7%, which was far better than the 9.6% of the control group.

[0021] (5) The process parameters are clear and can be scaled up, making it suitable for industrial production and with good application prospects. Detailed Implementation

[0022] To make the technical problems, technical solutions and advantages of the present invention clearer, a detailed description will be given below in conjunction with specific embodiments.

[0023] Roxithromycin's dissolution behavior and formulation quality consistency during storage are easily affected by the formulation composition and process conditions. This invention provides a preparation process for stable roxithromycin tablets. Through systematic screening and optimization of the formulation composition and key process parameters, the screening is based on a method of single-factor variable control and multi-index comprehensive evaluation. The optimal formulation and process conditions are gradually determined using the formulation's physical properties (flowability, hardness, friability), content uniformity, and dissolution behavior as evaluation indicators. This creates a multi-layer coating structure of "inner stability + outer protection". Through dissolution tests and performance evaluations of related substances such as open-ring compounds, oxidized compounds, and glycosyl groups, the study verified that this technical solution can effectively regulate the dissolution behavior of roxithromycin tablets from aspects such as particle structure and release behavior.

[0024] Example 1: Screening of the ratio of filler to binder in roxithromycin tablets In this example, microcrystalline cellulose was selected as the filler and hydroxypropyl methylcellulose as the binder, which were mixed with roxithromycin raw material in different proportions. Croscarmellose sodium and magnesium stearate were used as disintegrant and lubricant, respectively. The specific operation was as follows: A certain amount of roxithromycin raw material, microcrystalline cellulose, and hydroxypropyl methylcellulose were weighed and placed in a high-speed mixer and mixed at 300 rpm for 10 min to ensure uniform dispersion. Subsequently, dry granulation was performed using a roller pressing method (roller pressing pressure 30 kN). After granulation through a 20-mesh sieve, 2% croscarmellose sodium (accounting for 2% of the total granules) was added and mixed for 5 min, followed by 0.5% magnesium stearate and mixed for 2 min to obtain granules for tableting.

[0025] First, to investigate the effect of hydroxypropyl methylcellulose (HPMC) as a binder on the system performance, the mass ratio of roxithromycin to microcrystalline cellulose was fixed at 1:1, and the amount of HPMC was adjusted accordingly. The mass ratios of roxithromycin, microcrystalline cellulose, and HPMC were set to 1:1:0.05, 1:1:0.08, 1:1:0.10, 1:1:0.12, and 1:1:0.15, respectively, and numbered A1-1, A1-2, A1-3, A1-4, and A1-5. Based on the above screening results, the effect of the amount of microcrystalline cellulose on the system performance was further investigated. The mass ratio of roxithromycin to hydroxypropyl methylcellulose was fixed at 1:0.10. Based on this, the amount of microcrystalline cellulose was adjusted to set the mass ratios of roxithromycin, microcrystalline cellulose and hydroxypropyl methylcellulose as 1:0.5:0.10, 1:1.0:0.10, 1:1.2:0.10, 1:1.5:0.10 and 1:2.0:0.10, respectively, and were numbered A2-1, A2-2, A2-3, A2-4 and A2-5.

[0026] The performance of granules obtained from formulations with different proportions was evaluated. Regarding physical properties, the flowability of the granules or the mixture before compression was determined by the angle of repose. A smaller angle of repose indicates better flowability. Tablet hardness was measured using a tablet hardness tester; 10 tablets were randomly selected from each batch, and the average value was taken, expressed in Newtons (N), to evaluate the mechanical strength of the tablets. Friability was determined according to the method specified in the Chinese Pharmacopoeia. A certain number of tablets were placed in a friability tester and rotated at a specified speed (25 rpm) for 4 minutes (100 revolutions). The percentage of mass loss was calculated, reflecting the tablets' tolerance during transportation and handling. The test results are shown in Table 1.

[0027] Table 1. Evaluation of physical properties of formulations with different filler-to-binder ratios A1-1 38.5 42 1.8 A1-2 31.2 65 0.9 A1-3 29.5 72 0.6 A1-4 27.8 78 0.5 A1-5 33.6 95 0.4 A2-1 36.8 58 1.3 A2-2 30.5 68 0.8 A2-3 27.2 75 0.5 A2-4 28.9 80 0.5 A2-5 32.8 92 0.6 The quality change was evaluated using accelerated stability testing. Samples were placed in a constant temperature and humidity chamber and stored for 10 days at 40℃ and 75% relative humidity (40℃ / 75% RH). Other peaks besides the main peak (roxithromycin content) (open-ring compounds, oxidized compounds, and glycosyl substances, etc.) were considered as related degradation products. The content of these related substances was determined by high-performance liquid chromatography (HPLC). The test results are shown in Table 2.

[0028] Table 2. Evaluation of quality changes in formulations with different filler and binder ratios A1-1 5.8 A1-2 3.6 A1-3 2.7 A1-4 2.4 A1-5 3.9 A2-1 4.9 A2-2 3.2 A2-3 2.2 A2-4 2.5 A2-5 3.6 Test results showed that the angles of repose for formulations A1-1 to A1-5 were 38.5°, 31.2°, 29.5°, 27.8°, and 33.6°, respectively, corresponding to tablet hardnesses of 42 N, 65 N, 72 N, 78 N, and 95 N, and friability of 1.8%, 0.9%, 0.6%, 0.5%, and 0.4%, respectively. After being stored at 40°C and 75% relative humidity for 10 days, the contents of related substances were measured to be 5.8%, 3.6%, 2.7%, 2.4%, and 3.9%, respectively. The results indicate that with the increase of hydroxypropyl methylcellulose content, the granulation properties gradually improved, manifested as a decrease in the angle of repose, an increase in tablet hardness, and a decrease in friability. When the amount of hydroxypropyl methylcellulose is low (A1-1), the particle structure is relatively loose, resulting in poor flowability and a high total related substances (TLS) content. When its amount is increased to an appropriate range (A1-3 to A1-4), the particle structure tends to be dense and uniform, and the formulation exhibits better flowability and mechanical strength, while the TLS content is significantly reduced, with A1-4 showing the best overall performance. When the amount of hydroxypropyl methylcellulose is further increased to a higher level (A1-5), the hygroscopicity of the system increases, leading to a slight increase in the TLS content, indicating that excessive binder is detrimental to the stability of the formulation.

[0029] Further investigation into the effect of microcrystalline cellulose dosage on the system performance revealed that the angles of repose for formulations A2-1 to A2-5 were 36.8°, 30.5°, 27.2°, 28.9°, and 32.8°, respectively, corresponding to tablet hardnesses of 58 N, 68 N, 75 N, 80 N, and 92 N, and friability of 1.3%, 0.8%, 0.5%, 0.5%, and 0.6%, respectively. After being stored at 40°C and 75% relative humidity for 10 days, the total related substances content was measured to be 4.9%, 3.2%, 2.2%, 2.5%, and 3.6%, respectively. The results indicate that with increasing microcrystalline cellulose dosage, particle formation gradually improves, manifested by a decrease in the angle of repose, an increase in tablet hardness, and a decrease in friability. When the amount of microcrystalline cellulose is low (A2-1), the particle structure is not well supported, the system is relatively loose, resulting in poor flowability and high total related substances content. When its amount is increased to an appropriate range (A2-2 to A2-4), the particle structure tends to be dense and uniform, the formulation exhibits better flowability and mechanical strength, and the total related substances content is significantly reduced. Among them, A2-3 has the best overall performance.

[0030] In summary, when the amount of microcrystalline cellulose is 1.0–1.5 times the mass of roxithromycin and the amount of hydroxypropyl methylcellulose is 0.08–0.12 times, the particle formation and tableting performance are superior, while the total related substances content is low. Further optimization yields the best overall formulation performance when the amount of microcrystalline cellulose is approximately 1.2 times and the amount of hydroxypropyl methylcellulose is approximately 0.12 times. These proportions form a dense and low-hygroscopic particle system, significantly reducing the degradation of roxithromycin under humid and hot conditions while ensuring tableting performance.

[0031] Example 2: Screening of roxithromycin tablet granulation process Based on the preferred formulation obtained in Example 1, this example compares three granulation methods: wet granulation (using water as the binder), wet granulation (using ethanol as the solvent), and dry granulation (avoiding water / heat contact), designated B1, B2, and B3, respectively. In the wet granulation process, the powder is first mixed evenly, then approximately 10% by mass of binder is added to form a soft mass, which is then granulated through a 16-mesh sieve and dried at 50°C for 4 hours before granulation. The dry granulation process uses a roller granulator with a roller pressure of 30 kN and a rotation speed of 5 rpm.

[0032] The moisture content, content uniformity, and related substance content properties of the granules obtained under different processes were evaluated. Moisture content was determined using the weight loss method. 1–2 g of granule sample was placed in a moisture analyzer or oven and dried to constant weight at 105°C. The mass difference before and after drying was recorded, and the percentage weight loss was calculated as the moisture content of the sample. Content uniformity was determined using high-performance liquid chromatography (HPLC). The average value and relative standard deviation (RSD) were calculated based on the roxithromycin content in each individual sample to evaluate the uniformity of drug distribution in the formulation. A smaller RSD value indicates better content uniformity. Stability evaluation was performed in the same manner as in Example 1. The test results are shown in Tables 3-5.

[0033] Table 3. Moisture content of roxithromycin tablets obtained by different granulation processes B1 3.2 B2 1.8 B3 0.6 Table 4. Content uniformity of roxithromycin tablets obtained by different granulation processes B1 3.5 B2 2.8 B3 1.6 Table 5. Evaluation of quality changes of roxithromycin tablets obtained by different granulation processes B1 8.7 B2 5.4 B3 2.8 The moisture contents of the samples were determined to be 3.2%, 1.8%, and 0.6%, respectively. The corresponding total related substances (TRS) contents after 10 days at 40℃ and 75% relative humidity were 8.7%, 5.4%, and 2.8%, respectively, with content uniformity (RSD) of 3.5%, 2.8%, and 1.6%. The results indicate that wet granulation, due to the introduction of water or organic solvents, easily leads to the degradation of roxithromycin, while dry granulation can significantly reduce the moisture content of the system, thereby effectively improving stability.

[0034] Based on this, the dry granulation process parameters were further optimized, with a focus on the influence of roller pressure on particle performance and stability. Roller pressures of 10 kN, 20 kN, 30 kN, 40 kN, and 60 kN were set as C1, C2, C3, C4, and C5, respectively, while keeping other conditions consistent. The results are shown in Table 6.

[0035] Table 6. Effect of different roller pressures on formulation performance C1 Loose particles, mostly fine powder 55 2.9 4.2 C2 Good forming 68 2.1 3.5 C3 Dense and uniform 72 1.7 2.8 C4 Dense and uniform 78 1.5 2.6 C5 Excessive density 88 1.9 3.3 The results showed that when the rolling pressure was 10 kN, the particle density was insufficient, fine powder was easily generated, the tablet hardness after compression was low (about 55 N), and the content uniformity was poor (RSD about 2.9%). When the pressure was increased to 20 kN, the particle formability was significantly improved, the tablet hardness increased to about 68 N, and the total related substances content was about 3.5%. When the pressure was 30-40 kN, the particle structure was uniform and dense, the flowability was good, the tablet hardness was stable in the range of 70-80 N, the content uniformity was the best (RSD about 1.5%-1.7%), and the total related substances content was the lowest (about 2.6%-2.8%). When the pressure was further increased to 60 kN, the particles were excessively dense, the tablet disintegration after compression was delayed, and the total related substances content slightly increased (about 3.3%) due to the possible changes in microstructure caused by local stress.

[0036] In summary, the rolling pressure has a significant impact on the particle structure and stability. A relatively stable particle system can be obtained within the range of 20–50 kN, with 30–40 kN being the optimal range, achieving the lowest total related substances content while ensuring good tableting performance. Therefore, this invention preferably employs a dry granulation process, with a rolling pressure preferably of 20–50 kN, more preferably 30–40 kN.

[0037] Example 3: Screening of Roxithromycin Tablet Coating System Based on the roxithromycin tablet cores obtained in Examples 1 and 2, different coating structures were compared. The coating operation was carried out in a coating pan, with the inlet air temperature controlled at 50°C, the outlet air temperature at 40°C, the spray rate at 3 mL / min, and the pan speed at 8 rpm. The coating structures were uncoated, single-layer hydroxypropyl methylcellulose coating, and double-layer coating (inner layer being a hydroxypropyl methylcellulose protective layer, outer layer being a moisture-proof coating layer), labeled D1, D2, and D3 respectively.

[0038] The stability and moisture gain of different coating systems were evaluated. The stability test was conducted using the same method as in Example 1. The moisture gain was obtained by accurately weighing the mass before and after being placed in a constant temperature and humidity chamber at 25°C and 75% relative humidity for 48 hours. The percentage of the mass difference before and after moisture absorption relative to the initial mass was calculated as the moisture gain value, which was used to evaluate the moisture barrier ability of the coating system.

[0039] Table 7. Effects of different coating structures on stability and hygroscopicity D1 10.5 4.8 D2 6.3 3.2 D3 2.2 1.5 The results showed that, under conditions of 40℃ and 75% relative humidity for 10 days, the total related substances content of the uncoated sample was approximately 10.5%, that of the single-layer coated sample was approximately 6.3%, while that of the double-layer coated sample was reduced to approximately 2.2%; the corresponding 48-hour moisture gain was 4.8%, 3.2%, and 1.5%, respectively. Double-layer coating can significantly reduce moisture gain and the total related substances content.

[0040] Based on the established double-layer coating structure, the effect of coating weight gain on formulation stability and dissolution performance was further investigated. The tablet cores obtained in Example 2 were used for double-layer coating according to the double-layer coating process. The coating weight gain was adjusted by controlling the spray volume, ensuring simultaneous and uniform weight gain for both the inner hydroxypropyl methylcellulose coating and the outer moisture-proof coating. Samples with coating weight gains of 2%, 4%, 6%, and 8% were prepared, designated E1, E2, E3, and E4, respectively. All other process conditions remained consistent: the inlet air temperature was controlled at 50°C, the outlet air temperature at 40°C, the spray rate at 3 mL / min, and the pot speed at 8 rpm. The stability and dissolution performance of the obtained samples were evaluated, with the stability being the same as in Example 1. Dissolution was determined using the paddle method, with the dissolution medium being 900 mL of pH 6.8 phosphate buffer, the temperature being 37±0.5℃, and the paddle rotation being 50 rpm. Samples were taken after 30 min to determine the percentage of dissolution. The experimental results are shown in Table 8: Table 8. Effects of different coating weight gain on stability and dissolution performance E1 4.5 98 E2 2.8 95 E3 2.1 92 E4 2.0 85 Experimental results show that as the coating weight gain increases, the total related substances content of the formulation gradually decreases, indicating that the coating layer has a good barrier effect against moisture. However, when the coating weight gain exceeds 6%, the dissolution rate decreases significantly, indicating that an excessively thick coating layer has an adverse effect on drug release. Therefore, a coating weight gain below 4% is insufficient for moisture protection, while a gain above 6% affects dissolution performance. Considering both stability and release behavior, a coating weight gain of 4%–6% is preferred, and approximately 5% is more preferable. In summary, by constructing a two-layer coating system with an inner layer for stability and an outer layer for moisture protection, the degradation of roxithromycin can be significantly reduced while ensuring dissolution performance.

[0041] Example 4: Long-term stability and validation of comparative formulation This example is used to examine the stability of the formulation of the present invention under long-term storage conditions and to compare it with a comparative formulation that does not adopt the technical solution of the present invention. The optimal formulation and process obtained from Examples 1-3 were selected to prepare samples, specifically roxithromycin tablets prepared using a formulation with microcrystalline cellulose and hydroxypropyl methylcellulose contents of 1.2 times and 0.10 times the roxithromycin raw material content, respectively, and using dry granulation and double-layer coating with a coating weight gain of approximately 5%. These were used as the experimental group. Simultaneously, a comparative sample was prepared using a wet granulation process without coating, while maintaining the same composition for all other components.

[0042] The two types of samples were placed in constant temperature and humidity chambers and stored at 25℃ / 60% relative humidity (long-term conditions) and 40℃ / 75% relative humidity (accelerated conditions), respectively. Samples were taken at 0, 10, 30, and 60 days to determine the roxithromycin content and total related substances content. The content was determined using high-performance liquid chromatography (HPLC), and the changes relative to the initial content were calculated. The experimental results are shown in Table 9.

[0043] Table 9. Evaluation of quality changes between the formulation of the present invention and the comparative formulation 0 d — 0 0 10 d 40℃ / 75%RH 2.1 9.8 30 d 40℃ / 75%RH 4.3 18.5 60 d 40℃ / 75%RH 6.8 28.2 30 d 25℃ / 60%RH 1.5 5.2 60 d 25℃ / 60%RH 2.7 9.6 Experimental results show that, under accelerated and long-term storage conditions, the rate of increase in total related substances content of the formulation of this invention is significantly lower than that of the comparative formulation, especially under high temperature and high humidity conditions. The use of dry granulation combined with a double-layer coating structure effectively inhibits moisture-induced quality changes, thereby significantly improving the quality stability of roxithromycin formulations.

[0044] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A preparation process for stable roxithromycin tablets, characterized in that, Includes the following steps: (1) Tablet core preparation: Roxithromycin, microcrystalline cellulose and hydroxypropyl methylcellulose are mixed and granulated by dry method to obtain granules. Disintegrant and lubricant are added and then tableted. (2) Double coating: Hydroxypropyl methylcellulose protective layer and moisture-proof coating layer are sequentially coated on the surface of the tablet core.

2. The preparation process according to claim 1, characterized in that, The components in the tablet core, by weight, are: 1 part roxithromycin, 1.0-1.5 parts microcrystalline cellulose, 0.08-0.12 parts hydroxypropyl methylcellulose, 0.5-3 parts disintegrant, and 0.1-1 parts lubricant.

3. The preparation process according to claim 2, characterized in that, The mass ratio of microcrystalline cellulose to roxithromycin is 1.2:1, and the mass ratio of hydroxypropyl methylcellulose to roxithromycin is 0.10:

1.

4. The preparation process according to claim 1, characterized in that, The dry granulation process uses a roller press with a roller pressure of 20–50 kN, preferably 30–40 kN.

5. The preparation process according to claim 1, characterized in that, The disintegrant is croscarmellose sodium and the lubricant is magnesium stearate.

6. The preparation process according to claim 1, characterized in that, The total weight gain of the double-layer coating is 4% to 6%, preferably 5%.

7. The preparation process according to claim 1, characterized in that, The moisture-proof coating layer is at least one of acrylic resin, polyvinyl alcohol, or enteric polymer.

8. A stable roxithromycin tablet prepared by the process described in any one of claims 1 to 7.

9. The use of the stable roxithromycin tablet of claim 8 in the preparation of a medicament for improving the dissolution behavior of roxithromycin tablets and reducing the content of related substances.

10. The application according to claim 9, characterized in that, The drug was stored at 40°C / 75%RH for 10 days, maintaining good dissolution consistency and low levels of related substances during storage.