Process optimization for the enhanced stability of diclofenac potassium granules and capsules    
Jiangyan Liu1#, Xiunan Li2#, Xiaoxue Zhang1, Haoyan Huang1, Liqing Chen1, Jinghao Cui1, Qingri Cao1* 
1. College of Pharmaceutical Sciences, Soochow University, Suzhou215123,China
2. Department of Pharmacy, Yanji City Hospital, Yanji 133000, China

 
Abstract: This study aimed to investigate the effects of different process parameters on the physical properties, in vitro dissolution rate, and short and long-term stability of diclofenac potassium (DFP) granules and capsules. DFP granules exhibited low total amounts of impurities when prepared through the wet granulation method using a granulating solvent with a low water/ethanol ratio. The impurities of the wet DFP mass dried at 70 °C were higher than those dried at 50 °C or 60 °C. DFP granules were stable under strong light exposure during preparation. DFP granules prepared using a granulating solvent with a 1:4 water/ethanol ratio had a relatively smaller particle size and higher angle of repose than those prepared using granulating solvents with other water/ethanol ratios. The dissolution rate of DFP capsules prepared using four different water/ethanol ratios was less than 2% after 10 min of dissolution and increased to 95% within 30 min of dissolution. The total amount of drug impurities of DFP capsules prepared using a granulating solvent with 1:4 water/ethanol ratio was considerably lower than those of DFP capsules prepared using a granulating solvent with a 1:0 water/ethanol solvent ratio. Regardless of the water/ethanol ratio, the capsules showed poor stabilitywhen exposed to high temperature (60 °C) and strong light (4500±500 Lux) for 10 days, but were relatively stable at high humidity (92.5% RH). The results of the long-term stability (25±2 °C and 60%±10% relative humidity) study showed that DFP granules were more stable than DFP capsules, and were stable for 12 months. The type of encapsulating material did not affect the 2-month stability of DFP. DFP granules are sensitive to granulating solvent and drying temperature and DFP capsules should be stored away from high temperature and strong light.                  
Keywords: Diclofenac potassium; Wet granulation; Physical properties; Stress test; Long-term stability   
CLC number: R943                Document code: A                 Article ID: 10031057(2018)28210
 
 
1. Introduction
Diclofenac, a derivative of phenylacetic acid, is a nonsteroidal anti-inflammatory drug. The mode of action of diclofenac involves the inhibition of prostaglandin synthesis through the inhibition of cyclooxygenase[1,2]. Diclofenac is commonly used to treat inflammatory disorders and mild to moderate postoperative or post-traumatic pain[3,4]; it is also effective against menstrual pain and endometriosis[3,4]. The physicochemical and pharmacological properties of diclofenac are listed in Table 1[5].  

Table 1. Physicochemical and pharmacological properties of diclofenac. 

   Diclofenac is poorly stable and readily degraded. Photodegradation in aqueous solution is one of the most important degradation processes of diclofenac
[6,7]. Commercially formulated diclofenac rapidly photodegrades with a residual content of 90% after only 4.38 min under a radiant exposure of 450 W/m2[8]. The photochemical decomposition products of diclofenac include 1-(2,6-dichlorophenyl) indolin-2-one and other quinone derivatives[9]. The bioavailability of hydrated diclofenac is affected by the formation of hydrated species given their different physico-chemical properties, such as stability, solubility, and dissolution rate. Anhydroussodium diclofenac exhibits a solid-solid transition to its hydrate form (tetrahydrate) through crystallization from water[1011]. Although the hydrated species of sodiumdiclofenac has good physical stability under room temperature[12], they tend to be unstable at high temperatures. Temperature also influences the stability of diclofenac[1316]. Heating sodium diclofenac to different temperatures (60 °C, 70 °C and 80 °C) revealed that the thermal sensitivity of diclofenac increased with increasing temperature[14].
To improve the stability of diclofenac potassium (DFP) (Fig. 1), sodium hydroxide has been incorporated into a DFP-loaded microcrystalline cellulose pellet prepared by extrusion-spheronization. However, the addition of sodium hydroxide to orally administered DFP causes the aggressive local release of alkali and electrolyte disturbances. Novel gel formulations have also been designed to increase the stability of diclofenac by incorporating chemical light-absorbers or by entrapping the drug in cyclodextrin[17]. This approach, however, would increase production costs and requires the development of a more reliable scale-up process.


Figure 1.
Chemical structure of diclofenac potassium (DFP). 

   In view of the above described challenges, this study
aimed to investigate and evaluate the effects of different process parameters on the physical properties, in vitro dissolution rate, and short and long-term stabilities of DFP granules and capsules. The flow properties, such as the angle of repose and size distribution of DFP granules, and the dissolution rate of DFP capsules were investigated. Moreover, the stress response and long-termstability of DFP granules and capsules were also evaluated. The results of our study might provide important guidance for the manufacture of DFP capsules. 
 
 
2. Materials and methods
2.1. Materials
Diclofenac potassium (DFP), corn starch, hydroxypropyl methylcellulose (HPMC), magnesium stearate (Mg-stearate), and white-blue hard gelatin capsules (Capsule 1) were kindly provided by Suzhou Homesun Pharmaceutical Co., Ltd. (Taichang, China). Red hard gelatin capsules (Capsule 2) were supplied by Zhejiang Yuexi Capsule Co., Ltd. (Xinchang, China). The white hydroxypropyl-methylcellulose capsule (Capsule 3) wasprovided by Shaoxing Kangke Capsule Co., Ltd. (Shaoxing, China).
2.2. Methods
2.2.1. Preparation of DFP granules and gapsules
The composition of DFP granules is shown in Table 2. DFP granules were prepared by the wet granulation method. Corn starch was used as a diluent, hydroxypropyl methylcellulose (HPMC) as a binder, and magnesium stearate as a lubricant. The corn starch was sieved through a 180 μm mesh and mixed with DFP. HPMC was dissolved in granulating solvents to form a 2% (w/v) HPMC binding solution. The 2% HPMC solution was added to the dry powder mixture, and the wet mass was formed through mixing. The wet mass was passed through a mesh (850 μm), and the resulting granules were oven dried. The dried granules were passed through a mesh (1003 μm), mixed with magnesium stearate, and blended for 15 min.

Table 2. Formulation composition of DFP granules (160 mg). 


   The effects of the formulation and preparation
parameters, such as the water–ethanol ratio (1:0, 4:1, 1:1 and 1:4, v/v %) of granulating solvents, duration of photoexposure (2 and 4 h), and drying temperature (50 °C, 60 °C, and 70 °C), on the stability of DFP granules were fully investigated. The detailed preparation process of various DFP granules is shown in Table 3.

Table 3. Preparation process of various DFP granules. 


   To investigate the effects of the encapsulating
material on the stability of DFP granules, hard gelatin capsule shells fabricated by two different companies (Capsule 1 and Capsule 2) and a HPMC capsule shell (Capsule 3) were used in this study. The blank capsule shells were filled with 160 mg granules, which were equivalent to 25 mg DFP, and prepared with water–ethanol (4:1, v/v).   
 
2.2.2. HPLC analysis of DFP impurity
Accurately weighed granules, equivalent to 25 mg of DFP, were placed in 100 mL volumetric flasks. First, 30 mL of 70% methanol was added to dissolve the drug. The mixture was then vortexed. The resulting suspensionwas then brought to the target volume with 70% methanol.The sample was centrifuged at 6950 ×g, and the drug content in the supernatant was analyzed using a high-performance liquid chromatograph (HPLC) (LC-15C, Shimadzu, Japan) as described below.
DFP impurities were analyzed using a C18-WR (4.6 mm× 250 mm, 5 mm) column. The column temperature was maintained at 30 °C. The mobile phase consisted of 70% methanol and 30% water with 4% acetic acid (v/v). The flow rate was set at 1.0 mL/min, and the injected sample volume was 20 μL. The detection wavelength was set at 276 nm.
2.2.3. Surface morphology
A digital camera was used to visualize the surface morphology of DFP granules prepared using granulating solvents with different water/ethanol ratios.
2.2.4. Angle of repose of DFP granules
The flowability of DFP granules prepared with various granulating solvents was characterized by the angle of repose. To determine the angle of repose (θ), the granules were allowed to flow through a funnel fixed to a stand at a definite height (h). The tan1 θ of the height/radius of the heap of granules formed provided the angle of repose. 
2.2.5. Size distribution of DFP granules
The particle size distribution of DFP granules was evaluated using a sieve based method. The method involved stacking sieves with different meshe sizes (830, 380, 180, and 75 μm) on top of one another in ascending degrees of coarseness. Then, a known mass of DFP granules was placed on the top sieve. The sieves were agitated for 5 min, and the size distribution was obtained from the relative amounts of granules through gravimetric quantification.
2.2.6. Dissolution test
The dissolution test was performed using DFP capsulesfilled with granules prepared using granulating solventswith different water/ethanol ratios. The test was performedusing a basket method in 900 ml of water for 1 h at 75 r/min at 37 °C (n = 3). At predetermined time points (5, 10, 15, 30, 45, and 60 min), 1 mL of sample was collected from the dissolution medium. An equivalent volume of fresh medium was added back after sample collection to maintain the dissolution media at a constantvolume. The drug concentration in the sample was determined by HPLC as described above, and the cumulative release percentage of the drug was calculated.
2.2.7. Stress test
A stress test was performed using capsules containing two types of DFP granules prepared using granulating solvents with 1:0 or 1:4 water–ethanol ratio. The samples were stored at high temperature (60 °C), high relative humidity (92.5% RH), and strong light exposure (4500 1×). Samples were taken at 5 and 10 d after exposure to study the effect of the stress conditions. Changes in the total impurities in DFP capsules were analyzed using a HPLC system as described above.
2.2.8. Long-term stability
The long-term stability of DFP granules prepared with 1:0 water/ethanol or capsules filled with the above formulation was tested at 25±2 °C and 60%±5% RH[21].Samples were taken after 2, 4, and 12 months of exposure to the above conditions and then analyzed.
The effects of encapsulating material on drug stabilitywere also evaluated. Two different gelatin capsules and one HPMC capsules were used in this study, and changes in drug impurities were checked over a period of two months.
2.3. Results and discussion
2.3.1. Results
2.3.1.1. Effect of water/ethanol ratio on drug stability
Wet granulation is a technique that promotes the coalescence of primary particles using a binder liquid. This technique improves the flowability of the powder and improves the uniformity of drug content in the final product. The effects of granulating solvents with different water/ethanol ratios on the stability of DFP granules are shown in Figure 2. Granules prepared with 1:0, 4:1, 1:1, or 1:4 water–ethanol ratios were designated as F1, F2, F3, and F4 granules, respectively. The total amount of impurities in F1 granules was 0.099%, whichwas the highest of all the granules. The amount of impurities decreased from 0.099% to 0.037% when the water/ethanol ratio of granulating solvents was reduced to 50% (F3). A similar result was observed when the water/ethanol ratio was reduced further to 25% (F4).  
 
  
Figure 2. Effect of granulating solvents with various water/ethanol ratio on the total amount of impurities in DFP granules (F1, F2, F3 and F4) (n = 3). 


2.3.1.2. Effect of photoexposure duration on drug stability
Figure 3 shows the effect of photoexposure duration on the stability of the wet granule mass. The amount of impurities in the wet granules after 0, 2, and 4 h (F1, F5, and F6) of light exposure before drying was 0.099%, 0.103%, and 0.111%, respectively. The total amount of impurities was not remarkably different between the different granules.


Figure 3.
Effect of light exposure duration on the total amount of impurities in DFP granules prepared using distilled water as a granulating solvent (F1, F5 and F6) (n = 3). 

2.3.1
.3. Effect of drying temperature on drug stability
To evaluate the effect of drying temperature on the amount of impurities in the granules, the wet mass was dried at 50 °C, 60 °C, or 70 °C (F7, F1, or F8). As shown in Figure 4, the total amount of impurities in the DFP granules was 0.099%, which did not change significantly when the drying temperature was changed to 50 °C or 60 °C. However, the total amount of impurities significantly increased from 0.099% to 0.193% when the drying temperature was increased to 70 °C.


Figure 4.
Effect of drying temperature on the total amount of impurities in DFP granules prepared using distilled water as a granulating solvent (F1, F7 and F8) (n = 3). 

2.3.1.4. Surface morphology
The surface morphologies of DFP granules prepared using granulating solvents with different water/ethanol ratios are presented in Figure 5. F1 or F2 granules presented a uniform granular shape, whereas F3 and F4 granules exhibited relatively high powder proportions.
 

 
Figure 5. Surface morphologies of DFP granules prepared using granulating solvents with different water/ethanol ratios. (a) water/ethanol (v/v) =1:0 (F1);(b) water/ethanol (v/v) =4:1 (F2); (c) water/ethanol (v/v) =1:1 (F3); (d) water/ethanol (v/v) =1:4 (F4).
 
 
2.3.1.5. Angle of repose
The angle of repose is an important index of the flow properties of the granules. The angle of repose of DFP granules prepared using granulating solvents with different water/ethanol ratios are shown in Figure 6. The angle of repose of four different types of granules ranged from 28.1° to 35.3°. The angle of repose of F4 granules was higher than those of F1, F2, and F3 granules. The angle of repose of F1, F2, and F3 granules were not significantly different.


Figure 6.
Angle of reposes of DFP granules prepared using granulatingsolvents with different water/ethanol ratios (F1, F2, F3 and F4) (n = 3). 

2.3.1.6. Size
distribution
The size distributions of F1, F2, F3, and F4 granules are presented in Figure 7. Less than 5% (w/w) of the granules showed a particle size of less than 75 μm or more than 830 μm. F1, F2, and F3 granules exhibited a similar size distribution, indicating that equal portions of granules passed through each sieve. However, the size distribution of the F4 granules was considerably different. Over 60% of the F4 granules passed through 180 μm mesh, indicating that a higher proportion of ethanol in the granulating solvent resulted in smaller DFP granule particle size.


Figure 7.
Size distribution of DFP granules (F1, F2, F3 and F4) (n = 3). 

2.3.1.7.
In vitro dissolution study
The in vitro dissolution study of F1, F2, F3, and F4 granules was carried out in 900 ml of distilled water for 1 h by the basket method. As shown in Figure 8, drug release from the four types of DFP capsuleswas less than 2% at the initial stage or within 10 min of dissolution. Drug release increased to 95% in the following 20 min of dissolution.


Figure 8.
Dissolution profiles of DFP capsules filled with granules prepared using granulating solvents with different water/ethanol ratios (F1, F2, F3 and F4) (n = 3). 

2.3.1.8. Stress test
The stress test was conducted with capsules containing F1 and F4 granules. The test was performed under 60 °C, 92.5% RH, and 4500 1×light exposure. As shown in Figure 9, the total amount of impurities in the two types of DFP capsules did not significantly change after 10 d of exposure to high humidity. However, after 10 d of storage under high temperature, the amount of  impurities in the F1 capsules increased from 0.037% to 0.128% (Fig. 9A). In contrast, although the amount of impurities in the F4 capsules was lower (Fig. 9B), it demonstrated a similar trend as the F1 granules. After 10 days of exposure to strong light, the total amount of impurities in the two types of DFP capsules were also relatively increased compared with that at 0 days.


Figure 9. Stress test of DFP capsules under high temperature, high humidity, and strong light. (A) Capsules filled with granules prepared using granulating solvent with 1:0 water/ethanol ratios (F1); (B) Capsules filled with granules prepared using granulating solvent with 1:4 water/ethanol ratio (F4).
 
2.3.1.9. Long-term stability
The long-term stability of F1 granules and capsules filled F1 granules is shown in Figure 10. The amount of impurities in the F1 granules was lower than that in F1 capsules over the same storage period. After 12 monthsof storage, the impurities of the F1 granules and capsules increased from 0.084% to 0.117% and from 0.090% to 0.171%, respectively. 


Figure 10.
Long-term stability of DFP granules and capsules stored under 25±2 °C and 60%±10% RH. DFP granules were prepared using a granulating solvent with 1:0 water/ethanol ratio; DFP capsules (Capsule 1) were filled with DFP granules. 

2.3.1.10. Effect of the type of capsule shell on the stability of DFP capsules
Capsules 1, 2, and 3 were filled with DFP granules and stored at 25±2 °C and 60%±10% RH for 2 months. The total amount of impurities in these three capsules are presented in Figure 11. The total amount of impuritiesin Capsules 1 and 2 were slightly higher than those of Capsule 3 (i.e. Capsule 1>Capsule 2>Capsule 3;0.151%>0.146%>0.132%). The total amount of impuritiesin the three capsules, however, were not significantlydifferent. 


Figure 11.
Effect of encapsulating material on the total amount of impurities in DFP granules prepared using granulating solvent with 1:0 water/ethanol ratio (F1) (n = 3). Capsule 1 and Capsule 2 were gelatin capsules from different companies. Capsule 3 was an HPMC capsule. 

2.3.2. Discussion
Diclofenac is a non-steroidal drug with anti-inflammatoryproperties and is usually available as a sodium or potassium salt, which has improved solubility and absorption[18]. According to drug standards published by China Food and Drug Administration (CFDA), the total amount of impurities in the DFP capsules should not exceed 1.0%. At present, many dosage forms of diclofenac suffer from high levels of contaminants introduced during preparation and storage. Some attempts have been made to solve this problem. For example, DFP pellets have been incorporated with sodium hydroxide or entrapped in cyclodextrin in commercial gel formulations[20]. However, these methods may result in unexpected side effects.
The formation of a hydrate would affect the physico-chemical properties and stability of the drug. In this study, we investigated the influence of the granulating solvent on the stability of the resultant DFP granules. Four types of DFP granules were prepared using granulating solvents with different water/ethanol ratios.The results showed that DFP granules were more stable when prepared using a granulating solvent with a low water/ethanol ratio and dried at low temperaturse. High water content could affect the stability of DFP granules. According to previous studies, DFP is degraded upon light exposure. Therefore, we investigated the effects of the duration of exposure to strong light (1 h or 2 h) on the stability of DFP during preparation. The results showed that the amount of DFP impurities with or without light exposure were relatively low, indicating that DFP granules were stable when exposed to light for short periods of time. The effects of various drying temperatures (50 °C, 60 °C, and 70 °C) were also investigated. The results indicated that high drying temperatures (70 °C) would increase the impurity content of DFP granules.
The angle of repose and size distribution of different granules were studied to determine the physical propertiesof DFP granules. DFP granules prepared using a granulating solvent with a 1:4 water/ethanol ratio had an angle of repose of 35.3°, indicating that it contained a high proportion of fine particles. The in vitro dissolution studies of capsules containing DFP granules prepared using granulating solvents with different water/ethanol ratios revealed that drug release from the capsules were less than 2% initially (within 10 min of dissolution) because of the slow disintegrationof the capsule shell. Afterwards, drug released reached up to 80% within 30 min of dissolution.
Stress response and long-term stability are two important storage. The stress test was performed in accordance with the relevant guidelines for DFP. Based on the results of the stress test, temperature and light exposure affect the storage stability of DFP capsules. Storing DFP granules and capsules at 25±2 °C and 60% ±10% RH for 12 months revealed that the DFP granules or capsules prepared using a granulating solvent with a 1:0 water–ethanol ratio was stable. In addition, the type of encapsulating material had no effect on the stability of DFP granules.
We examined the effects of different process parameters on the stability and purity of DFP granules. Our results might provide important guidance for the manufacture of DFP capsules by pharmaceutical companies. To improve the quality control of DFP preparations, further studies are needed to analyze the specific structure of each impurity by referencing to reference standard compounds.
4. Conclusion
The water–ethanol ratio of the granulating solvent and drying temperature are key process parameters that control the stability of DFP granules prepared through the wet granulation process. DFP granules prepared using a granulating solvent with a high water/ethanol ratio presented good flowability and size distribution. DFPcapsules should be stored away from high temperature and strong light exposure, and can demonstrate high stability even after 12 months of storage under 25±2 °C and 60% ±10% RH. 
Acknowledgements
This work was partially supported by the National Natural Science Foundation of China (Grant No. 81373333, 81311140267), and a Project Funded by the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions. 
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改善双氯芬酸钾颗粒及胶囊剂稳定性的工艺优化研究
刘疆燕1#,李秀男2#,张晓雪1, 黄豪雁1, 陈利清1, 崔京浩1, 曹青日1*
1. 苏州大学 药学院, 江苏 苏州 215123
2. 延吉市医院 药剂科, 吉林 延吉 133000 
摘要: 本研究考察了不同工艺因素对双氯芬酸钾(DFP)颗粒及胶囊的物理特性、体外溶出度、短期和长期稳定性的影响。采用湿法制粒方法,制备DFP颗粒,制粒溶剂中水/乙醇比例越低,所生成总有关物质越少。与50 °C60 °C干燥相比,湿物料在70 °C干燥时,有关物质生成更多。DFP颗粒制备过程中,药物对强光比较稳定。水/乙醇溶剂比例为1:4, DFP颗粒的粒度较小,休止角较大。4种不同水/乙醇溶剂比例制备的DFP颗粒,10分钟溶出度均低于2%,30分钟溶出度可达95%DFP胶囊(/乙醇, 1:4)的有关物质显著低于DFP胶囊(/乙醇, 1:0)。在高温(60 °C)或强光(4500±500 Lux)下保存10, DFP胶囊稳定性差,但在高湿条件(92.5% RH)比较稳定。在长期稳定性试验条件(25±2 °C , 60%±10%相对湿度)下保存12, DFP颗粒的稳定性优于DFP胶囊。2个月长期稳定性数据表明,胶囊材料种类对DFP的稳定性无影响。总之, DFP颗粒对溶剂种类和干燥温度敏感,DFP胶囊须在低温、避光条件下保管。 
关键词: 双氯芬酸钾; 湿法制粒; 物理特性; 影响因素试验; 长期稳定性
 
  
Received: 2017-12-15, Revised: 2018-01-28, Accepted: 2018-02-07.
Foundation items: National Natural Science Foundation of China(Grant No. 81373333, 81311140267).
#These authors contributed equally to this work.
*Corresponding author. Tel.: +86-512-69564123, E-mail: qrcao@suda.edu.cn    
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