CN101081214A - Methodc for preparing sub-micron gemfibrozil medicament powder - Google Patents

Abstract

The invention discloses a method for preparing submicron gemfibrozil drug powder, which belongs to the field of micronization of insoluble drugs. In the present invention, the gemfibrozil drug is dissolved in an aqueous sodium hydroxide solution, and then an aqueous hydrochloric acid solution containing a surfactant is added to carry out neutralization and replacement reactions to obtain the gemfibrozil drug suspension. The obtained drug suspension of gemfibrozil is filtered, washed and dried, thereby obtaining spherical gemfibrozil drug powder with a submicron particle size, and realizing the micronization of the poorly soluble drug. The method is simple in operation, easy to scale up, low in production cost, regular in appearance, narrow in particle size distribution and good in dispersibility, and lays a foundation for the industrial production of micronized gemfibrozil and the development and utilization of new dosage forms.

Description

A kind of preparation method of submicron gemfibrozil drug powder

technical field

The invention relates to a method for preparing gemfibrozil drug powder, in particular to a method for preparing submicron ultrafine gemfibrozil drug powder by adopting a reaction crystallization method.

Background technique

Gemfibrozil (Gemfibrozil), the chemical name is 2,2-dimethyl-5-(2,5-xylyloxy)-pentanoic acid, and its structural formula is:

It is a non-halogenated clofibrate lipid-lowering drug that can effectively reduce blood total cholesterol, total triglycerides, very low-density lipoprotein cholesterol and triglycerides, low-density lipoprotein cholesterol and triglycerides content, increase the concentration of high-density lipoprotein cholesterol. Therefore, it is widely used clinically to treat Fredrickson type IIa, type IIb, type III, type IV, type V hyperlipidemia and various coronary heart diseases, dyslipidemia and metabolic syndrome caused by diabetes. Gemfibrozil is currently on the market in the form of tablets and capsules.

Gemfibrozil is highly hydrophobic and usually needs to be mixed with pharmaceutical excipients, but even so, its dissolution rate in water or acidic media (such as gastric juice) is very slow, resulting in the biological degradation of the drug after oral administration. The availability is very low, making the daily dosage of gemfibrozil very large, usually 1200mg/day. Simultaneously, also limit the development and utilization of this drug new dosage form.

In order to reduce the daily dose of gemfibrozil and adapt to the market's requirements for new drug dosage forms, the dissolution rate and bioavailability of the drug must be improved.

U.S. Pat. No. 5281421 describes an improved formulation of oral gemfibrozil. This formulation is prepared by mixing gemfibrozil and a surfactant such as Tween 85 with a hydrophilic-lipophilic balance (HLB value) in the range of 10-50, so as to increase the dissolution rate of the drug mixture. The disadvantage of this formulation is that the amount of surfactant used as a non-pharmaceutical active ingredient is relatively large, about 1% to 4% (wt/wt).

U.S. Pat. No. 4761033 discloses a drug adsorbent and its preparation method. This adsorbent consists of magnesium aluminum silicate in which gemfibrozil and surfactant are adsorbed.

U.S.Pat.No.4753800 has introduced a kind of drug adsorbent and its preparation method. This sorbent consists of magnesium aluminum silicate in which gemfibrozil and edible waxes are adsorbed.

Above-mentioned these methods all are to improve the dissolution rate of gemfibrozil medicine by means of the solubilization of pharmaceutical excipients. The difference of the present invention is that the gemfibrozil drug is micronized by a reaction crystallization method to increase its specific surface area, thereby significantly increasing the dissolution rate of the drug. There is no report on increasing the drug dissolution rate of gemfibrozil by micronization.

The principle of reaction crystallization is: the process of crystallization through the chemical reaction of two or more components to produce supersaturation. In this process, new substances can be produced by adding reactants or adjusting the acid-base ratio. When the concentration of the new substance in solution exceeds its solubility, it crystallizes out. Through the control of reaction parameters such as reaction temperature, surfactant type and dosage, acid-base volume ratio and other reaction parameters in the process, the purpose of forming fine particles can be achieved.

The particle size of the drug particles has a great influence on the drug dissolution rate. Generally speaking, the smaller the particle size of the drug particles, the larger the specific surface area and the faster the corresponding dissolution rate. Therefore, we use the morphology and size of the drug particles as the main characterization means of the prepared powder, supplemented by a small amount of dissolution experiments.

The instrument used to characterize the morphology and size of drug particles is a scanning electron microscope (SEM) (JSM-6360LV, JEOL Corporation, Japan).

Gemfibrozil drug concentration test adopts high performance liquid chromatography (Waters 2695, Waters Company, U.S.), and the supporting ultraviolet spectrum detector is Waters 2996 (Waters Company, U.S.).

Contents of the invention

The invention provides a new method for preparing gemfibrozil medicine crystalline powder. The gemfibrozil drug powder prepared according to the method has regular spherical shape, narrow particle size distribution and submicron particle size.

The technical scheme of the present invention is as follows: at a reaction crystallization temperature of 2°C to 30°C, the aqueous sodium hydroxide solution containing the gemfibrozil bulk drug is stirred and mixed with the aqueous hydrochloric acid solution containing a surfactant, and the stirring speed is 500rpm to 10000rpm , the stirring time is 30min～5h, the drug crystallizes out, and the suspension containing gemfibrozil drug particles is obtained. After the suspension is filtered, washed and dried, the spherical gemfibrozil with regular shape and narrow particle size distribution can be obtained. Rozier drug crystalline product.

The concentration of the gemfibrozil raw material in the sodium hydroxide aqueous solution of the present invention is 1.0g/100ml-3.5g/100ml.

The concentration of the sodium hydroxide aqueous solution in the present invention is 0.1mol/L-0.25mol/L.

The hydrochloric acid aqueous solution concentration of the present invention is 0.05mol/L～1.0mol/L.

The surfactant of the present invention is non-ionic surfactant polyvinylpyrrolidone and methylcellulose.

The dosage of the surfactant in the present invention is 0.1%-15% of the total weight of the medicine.

The volume ratio of the hydrochloric acid aqueous solution and the sodium hydroxide aqueous solution in the present invention is 1/1˜5/1.

The gemfibrozil crystalline powder obtained in the present invention has a spherical shape, a narrow particle size distribution, and a particle size of 500 nm to 5 μm.

Description of drawings

Figure 1 is a scanning electron micrograph of gemfibrozil bulk drug.

2 is a scanning electron micrograph of the gemfibrozil drug powder obtained in Example 1.

3 is a scanning electron micrograph of the gemfibrozil drug powder obtained in Example 2.

4 is a scanning electron micrograph of the gemfibrozil drug powder obtained in Example 3.

5 is a scanning electron micrograph of the gemfibrozil drug powder obtained in Example 4.

6 is a scanning electron micrograph of the gemfibrozil drug powder obtained in Example 5.

7 is a scanning electron micrograph of the gemfibrozil drug powder obtained in Example 6.

Fig. 8 is the infrared spectrograms of gemfibrozil drug powder and gemfibrozil bulk drug obtained in Experimental Examples 2, 5, and 6.

Fig. 9 is a dissolution curve of gemfibrozil drug granules and gemfibrozil bulk drug obtained in Experimental Examples 5 and 6.

Detailed ways

Example 1

Weigh 0.16g of polyvinylpyrrolidone K30 and dissolve it in 100ml of aqueous hydrochloric acid solution with a concentration of 0.25mol/L. After it is completely dissolved, pour it into a reaction kettle and stir at a speed of 1000rpm. Then weigh 3.0 g of the gemfibrozil bulk drug and dissolve it in 100 ml of aqueous sodium hydroxide with a concentration of 0.15 mol/L to obtain a gemfibrozil bulk drug solution. The obtained bulk drug solution was quickly added into the reaction kettle, and the gemfibrozil drug was reacted and crystallized at 20° C. to obtain a suspension of gemfibrozil drug particles, and the stirring was continued for 30 minutes. Then filter and rinse the filter cake with deionized water. The obtained filter cake was put into a forced air drying oven at 40° C. to dry for more than 3 hours to obtain the dried gemfibrozil drug powder. Observation with electron scanning electron microscope, as shown in the scanning electron microscope photo in Figure 2, the drug particles of gemfibrozil are spherical in shape with a particle size of 1 μm to 5 μm.

Example 2

Weigh 0.15 g of methylcellulose and dissolve it in 100 ml of aqueous hydrochloric acid solution with a concentration of 0.25 mol/L. After it is completely dissolved, pour it into a reaction kettle and stir at a speed of 10,000 rpm. Then weigh 3.0 g of the gemfibrozil bulk drug and dissolve it in 100 ml of aqueous sodium hydroxide with a concentration of 0.15 mol/L to obtain a gemfibrozil bulk drug solution. Quickly add the obtained raw material drug solution into the reaction kettle, so that the gemfibrozil drug is reacted and crystallized at 18° C. to obtain a suspension of gemfibrozil drug particles, continue to stir and age for 30 minutes, then filter, and use deionized water Rinse filter cake. Put the obtained filter cake into a beaker, add water with a weight equivalent to 5 times the weight of the wet filter cake, and redisperse the filter cake in water under the action of ultrasound to obtain a uniform suspension. The resulting suspension was poured into liquid nitrogen, and the ice cubes containing the gemfibrozil drug particles were dried with a freeze dryer to obtain dried gemfibrozil drug particles. Observed by scanning electron microscope, the drug particles of gemfibrozil are spherical, with a particle size of 500nm to 2 μm, a narrow particle size distribution, and links between particles to form a network structure, as shown in the scanning electron microscope photo in Figure 3.

Example 3

Weigh 0.39g of methylcellulose and dissolve it in 500ml of aqueous hydrochloric acid solution with a concentration of 0.05mol/L. After it is completely dissolved, pour it into a reaction kettle and stir at a speed of 2000rpm. Then weigh 2.6g of the gemfibrozil bulk drug and dissolve it in 100ml of sodium hydroxide solution with a concentration of 0.10mol/L to obtain the gemfibrozil bulk drug solution. Quickly add the obtained raw drug solution into the reaction kettle, make the gemfibrozil drug react and crystallize at 20° C. to obtain a suspension of gemfibrozil drug particles, continue to stir and age for 30 minutes, then filter, and use deionized water Rinse filter cake. The obtained filter cake is put into a quick drying apparatus for drying to obtain dry gemfibrozil drug powder. Observed by scanning electron microscope, gemfibrozil drug particles are spherical, with a particle size of 500nm-2μm and a narrow particle size distribution, as shown in the scanning electron microscope photo in Figure 4.

Example 4

Weigh 0.05g of methylcellulose and dissolve it in 100ml of aqueous hydrochloric acid solution with a concentration of 0.5mol/L. After it is completely dissolved, pour it into a reaction kettle and stir at a speed of 500rpm. Then weigh 0.5 g of the gemfibrozil bulk drug and dissolve it in 50 ml of aqueous sodium hydroxide solution with a concentration of 0.5 mol/L to obtain the gemfibrozil bulk drug solution. Quickly add the obtained raw material drug solution into the reaction kettle, so that the gemfibrozil drug is reacted and crystallized at 17° C. to obtain a suspension of gemfibrozil drug particles, continue to stir and age for 30 minutes, then filter, and use deionized water Rinse filter cake. The obtained filter cake is dried to obtain dry gemfibrozil drug powder. Observed by scanning electron microscope, the particle size of gemfibrozil drug particles is 1 μm to 3 μm, as shown in the scanning electron microscope photo in FIG. 5 .

Example 5

Weigh 0.15g of methylcellulose and dissolve it in 100ml of aqueous hydrochloric acid solution with a concentration of 0.25mol/L. After it is completely dissolved, pour it into a reaction kettle and stir at a speed of 1500rpm. At the same time, a low-temperature alcohol-water mixture was introduced into the jacket of the reaction kettle to lower the temperature of the aqueous hydrochloric acid solution in the reaction kettle to 2°C. Then weigh 3.0 g of the gemfibrozil bulk drug and dissolve it in 100 ml of aqueous sodium hydroxide with a concentration of 0.15 mol/L to obtain a gemfibrozil bulk drug solution. Quickly add the obtained raw material drug solution into the reaction kettle, make the gemfibrozil drug react and crystallize at 2° C. to 5° C. to obtain a suspension of gemfibrozil drug particles, continue to stir and age for 5 hours, then filter, and use Rinse the filter cake with deionized water. Put the obtained filter cake into a beaker, add water with a weight equivalent to 5 times the weight of the wet filter cake, and redisperse the filter cake in water under the action of ultrasound to obtain a uniform suspension. The resulting suspension is sprayed into liquid nitrogen, and the ice powder containing gemfibrozil drug particles is dried with a freeze dryer to obtain dry gemfibrozil drug powder. Observed by scanning electron microscope, the drug particles of gemfibrozil are spherical, with a particle size of 500nm to 2 μm, a narrow particle size distribution, and links between particles to form a network structure, as shown in the scanning electron microscope photo in Figure 6.

Example 6

Weigh 0.30 g of methylcellulose and dissolve it in 200 ml of aqueous hydrochloric acid solution with a concentration of 0.25 mol/L. After it is completely dissolved, pour it into a reaction kettle and stir at a speed of 2500 rpm. Then weigh 6.0 g of the gemfibrozil bulk drug and dissolve it in 200 ml of aqueous sodium hydroxide solution with a concentration of 0.15 mol/L to obtain the gemfibrozil bulk drug solution. The obtained bulk drug solution is added into the reaction kettle at one time, and the gemfibrozil drug is reacted and crystallized at 28-30° C. to obtain a suspension of gemfibrozil drug particles, which is continued to be stirred and aged for 4 hours, then filtered, and used Rinse the filter cake with deionized water. Put the obtained filter cake into a beaker, add water with a weight equivalent to 5 times the weight of the wet filter cake, and redisperse the filter cake in water under the action of ultrasound to obtain a uniform suspension. The resulting suspension is sprayed into liquid nitrogen, and the ice powder containing gemfibrozil drug particles is dried with a freeze dryer to obtain dried gemfibrozil drug particles. Observed by scanning electron microscope, gemfibrozil drug particles are spherical, with a particle size of 500nm-2μm, narrow particle size distribution, and links between particles to form a network structure, as shown in the scanning electron microscope photo in Figure 7.

Claims (5)

1. A method for preparing submicron gemfibrozil drug powder, comprising the following steps: 1) Dissolving gemfibrozil in aqueous sodium hydroxide solution with a concentration of 0.10mol/L-0.25mol/L to prepare a gemfibrozil raw drug solution, wherein the concentration of gemfibrozil is 1.0g/100ml～ 3.5g/100ml; 2) When the reaction crystallization temperature is 2°C to 30°C, add the gemfibrozil raw drug solution mentioned above to the aqueous hydrochloric acid solution containing surfactant under stirring, wherein the concentration of the aqueous hydrochloric acid solution is 0.05mol/L- 0.50mol/L, obtain gemfibrozil drug particle suspension; 3) Continue to stir the obtained suspension to age for 30min to 5h; 4) Filtrating, washing and drying the obtained suspension of gemfibrozil drug particles to obtain spherical gemfibrozil drug powder with a particle size of 500 nm to 5 μm. 2. The preparation method according to claim 1, characterized in that: the surfactant described in step 2) is a nonionic surfactant polyvinylpyrrolidone or methylcellulose. 3. The preparation method according to claim 1, characterized in that the weight of the surfactant is 0.1% to 15% of the weight of the gemfibrozil drug. 4. The preparation method according to claim 1, characterized in that: the volume ratio of hydrochloric acid aqueous solution and sodium hydroxide aqueous solution is 1/1～5/1. 5. The preparation method according to claim 1, characterized in that: the stirring state described in step 2), characterized in that: the stirring speed is 500rpm-10000rpm.

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