CN113230226A

CN113230226A - Tinidazole tablet and preparation method thereof

Info

Publication number: CN113230226A
Application number: CN202110592329.1A
Authority: CN
Inventors: 范文峰; 覃开芳; 钟贞; 李玥颖; 曹珺; 王亚龙; 徐凯; 郑晓斌; 蓝美英
Original assignee: LIVZON GROUP LIVZON PHARMACEUTICAL FACTORY
Current assignee: LIVZON GROUP LIVZON PHARMACEUTICAL FACTORY
Priority date: 2021-05-28
Filing date: 2021-05-28
Publication date: 2021-08-10

Abstract

The invention discloses a tinidazole tablet and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. The tinidazole tablet is prepared by controlling the dosage and the particle size of raw materials and auxiliary materials and adopting a dry granulation process. The tinidazole tablet prepared by the preparation method can effectively improve the dissolution rate, disintegration time limit, hardness and friability of the tablet, effectively solves the problem of nitrite content increase caused by high temperature and high humidity in the existing wet granulation process, and has good production compliance and high production efficiency.

Description

Tinidazole tablet and preparation method thereof

Technical Field

The invention relates to the technical field of pharmaceutical preparations, in particular to a tinidazole tablet and a preparation method thereof.

Background

Tinidazole is a nitroimidazole derivative developed in the later 60 s, and is suitable for various anaerobic bacteria infections, such as septicemia, osteomyelitis, abdominal cavity infection, pelvic cavity infection, lung and bronchus infection, pneumonia, nasosinusitis, skin cellulitis, periodontal infection, postoperative wound infection, etc.; and pre-operative preventive medicine for colorectal surgery, gynecological surgery, oral surgery, and the like; in addition, it can be used for treating intestinal and parenteral amebiasis, trichomonas vaginalis, giardiasis, and gardnerella vaginitis.

Tinidazole has been prepared into various dosage forms widely used in clinic, such as injection, effervescent tablet, suppository, gargle, tablet and capsule. Wherein, the tablet has the advantages of accurate dosage, small difference of drug content, stable quality, and convenient administration, carrying and transportation. The common tinidazole tablet has good solubility under acidic conditions, can be absorbed quickly and completely after being dissolved in the stomach after being taken orally, has the bioavailability of about 100 percent, has the Tmax of 1.6 plus or minus 0.7h after being taken on an empty stomach, can delay the Tmax after a meal for about 2h, but does not influence the bioavailability.

The existing tinidazole tablets on the market still have the following defects:

the existing tinidazole tablets have low dissolution rate and poor disintegration time limit: the tinidazole raw material is loose in texture, low in hardness after granulation and large in friability, and if the hardness of the tablet is not enough in the tabletting and coating processes, the phenomena of edge breakage, corner chipping and even tablet cracking are easy to occur, so that the appearance of the tablet is seriously influenced. If the hardness of the tablet is simply increased to meet the requirements of tabletting and coating, the appearance of the tablet is improved, but the disintegration time is easily prolonged, so that the dissolution rate of the drug is unqualified. The tinidazole is extremely bitter in raw material, the tablet weight is reduced, the tinidazole is coated, and the taking compliance is increased.

Secondly, the tinidazole tablet tabletting process is poor in smoothness, so that the production efficiency is low: the main drug specification of the tinidazole tablet is 0.5g, the specification is large, the compressibility and the fluidity of the tinidazole raw material are poor, so that the smoothness of a tabletting process is poor, the hardness is low, the friability is large, the phenomena of face grinding and incomplete coating film are easy to occur in the coating process, and the production efficiency is seriously influenced. Meanwhile, the existing tinidazole tablets are generally prepared by a wet granulation process, and the high temperature of the wet granulation process can cause the increase of nitrous acid, so that the content of nitrite impurities in the tinidazole tablets is increased.

Therefore, the industrial production of tinidazole tablets urgently needs a preparation formula for effectively improving the dissolution rate, disintegration time limit, hardness and friability of the tablets and a preparation process for improving the powder properties of raw materials, improving the smoothness of a tabletting process, improving the integrity and appearance of a coating and further improving the production efficiency.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention aims to provide the tinidazole tablet and the preparation method thereof.

In order to solve the problems, the technical scheme adopted by the invention is as follows:

a preparation method of tinidazole tablets comprises the following steps:

s1, weighing raw materials: raw materials and auxiliary materials are weighed according to the following compositions and mass ratios: 70-90% of tinidazole, 3-15% of adhesive, 0.5-3% of glidant, 3-10% of disintegrant, 1-20% of filler, 0.5-1.5% of lubricant and 2-4% of coating material; wherein the grain diameter of the tinidazole is d (0.9) less than or equal to 60 mu m.

S2, premixing: the tinidazole, the filling agent, part of the disintegrating agent, the glidant and part of the adhesive in the formula amount are put into a mixer to be mixed for 20-40 min and then are mixed uniformly.

S3, granulating: the dry granulation process is adopted for granulation, the speed of a conveyor is 80-200rpm, the interval between pressing wheels is 0.2mm, the rotating speed of the pressing wheels is 20-40rpm, and a whole grain screen is 18 meshes.

S4, total mixing: and (3) totally mixing the granules, the rest of disintegrant, the rest of adhesive and lubricant for 10-20 min.

S5, tabletting: the total mixed particles are fed into a tablet press, the hardness is controlled to be 8.0-17.0 kg, the weight difference of the tablets is +/-5%, and the friability check is in accordance with the specification.

S6, coating: coating with film coating premix.

As a preferred embodiment of the present invention, the binder is povidone K30 and/or povidone K90. The povidone is used as a binder, so that the hardness of the tablet can be increased, the disintegration time and the friability can be reduced, and the problem of knocking the tablet in the coating process is solved.

As a preferred embodiment of the present invention, the disintegrant is crospovidone. The dissolution rate can be improved by using the crospovidone as a disintegrant.

As a preferred embodiment of the invention, the glidant is colloidal silicon dioxide.

In a preferred embodiment of the present invention, the filler is silicified microcrystalline cellulose.

As a preferred embodiment of the invention, the lubricant is magnesium stearate.

As a preferred embodiment of the present invention, the tinidazole tablets comprise the following components by mass: 70-90% of tinidazole, 3-15% of povidone, 0.5-3% of colloidal silicon dioxide, 3-10% of crospovidone, 1-20% of silicified microcrystalline cellulose, 0.5-1.5% of magnesium stearate and 2-4% of coating material.

The invention also provides a tinidazole tablet which is prepared by adopting the preparation method.

Compared with the prior art, the invention has the beneficial effects that:

the preparation method adopts a dry granulation process, can improve the yield, reduce the production cost and energy consumption, avoid the problem of increase of genotoxic impurities caused by high temperature and high humidity in the wet granulation process, overcome the problem of poor flowability of a direct tabletting process, effectively improve the dissolution rate, disintegration time limit, hardness and friability of tablets, and improve the production compliance of process amplification, thereby improving the production efficiency. Meanwhile, the invention improves the release rate of the tinidazole tablet by controlling the particle size of the tinidazole raw material; the tablet weight can be effectively reduced by controlling the proportion of raw and auxiliary materials, reducing the consumption of the auxiliary materials and enabling the mass ratio of the tinidazole raw materials to be 70-90 percent in the prescription; the capsule type tablet is adopted, so that the administration compliance is effectively improved.

Detailed Description

The present invention will be described in further detail with reference to specific embodiments.

A tinidazole tablet comprises the following components in percentage by mass: 70-90% of tinidazole, 3-15% of adhesive, 0.5-3% of glidant, 3-10% of disintegrant, 1-20% of filler, 0.5-1.5% of lubricant and 2-4% of coating material.

In the above formula, the binder is preferably povidone K30 and/or povidone K90; the disintegrant is preferably crospovidone; the glidant is preferably colloidal silicon dioxide; the filler is preferably silicified microcrystalline cellulose; the lubricant is magnesium stearate; the coating material is: film coated premix.

The tinidazole tablet is prepared by adopting a dry granulation process, and the preparation method specifically comprises the following steps:

s1, weighing raw materials: the raw materials and the auxiliary materials are weighed according to the prescription.

S5, feeding the total mixed particles into a tablet press, controlling the hardness to be 8.0-17.0 kg and the weight difference to be +/-5%, and checking the friability to meet the requirements.

S6, coating: coating with film coating premix.

S7, packaging: and (5) boxing and boxing the aluminum-plastic composite material.

First, the influence of the particle size of tinidazole as raw material on the dissolution curve

The formulations of experimental examples 1 to 4 were as follows: 500g of tinidazole, 5g of povidone K3040 g, 5g of colloidal silicon dioxide (internal addition), 10g of crospovidone (internal addition), 15g of crospovidone (external addition), 10g of silicified microcrystalline cellulose (external addition), 5.5g of magnesium stearate and 16g of coating material; 1000 pieces were prepared.

The differences between the experimental examples 1 to 4 are: the particle sizes of tinidazole are different, and are shown in table 1:

table 1 particle size of tinidazole raw material of experimental examples 1 to 4

	Experimental example 1	Experimental example 2	Experimental example 3	Experimental example 4
					Particle size (D90))	31.2um	46.7um	61.2um	85.6um

The dissolution rates of the tinidazole tablets prepared in experimental examples 1 to 4 by the above preparation method were measured, and the results are shown in table 2.

TABLE 2 particle size of Tinidazole starting materials of Experimental examples 1-4

Examples of the experiments	5min	10min	15min	30min
					1	65	94	96	99
2	63	92	97	100
					3	58	92	95	100
4	51	83	90	91

As can be seen from Table 2, the dissolution at the end point of the experimental examples 1-2 with the particle size less than 61.2um can be completed, while the dissolution at the end point of the experimental examples 3-4 with the particle size more than 61.2um can only reach 91%, so the particle size of tinidazole is controlled to be d (0.9) less than or equal to 60 μm.

Examples 1 to 6:

the formulations of examples 1-6 are shown in Table 3:

TABLE 3 formulations of examples 1-6

The preparation method of the embodiment 1-6 comprises the following steps:

S2, premixing: the tinidazole, the filler, the povidone, the colloidal silicon dioxide and the crospovidone (internal addition) in the formula amount are put into a mixer to be mixed for 20-40 min and are uniformly mixed.

S3, granulating: adopting a dry granulation process for granulation, wherein the specific process parameters are as follows: the speed of the conveyer is 80-200rpm, the interval between the press wheels is 0.2mm, the rotating speed of the press wheels is 20-40rpm, and the whole grain screen is 18 meshes.

S4, total mixing: and (3) putting the granules after finishing the granules, the crospovidone (added), the silicified microcrystalline cellulose (added) and the magnesium stearate into a mixer for mixing, wherein the mixing speed is 10rpm, and the mixing time is 10min, so that the total mixed granules are obtained.

S5, tabletting: and (3) feeding the total mixed particles into a tablet press, controlling the hardness to be 8.0-17.0 kg, controlling the weight difference of the tablets to be +/-5%, and checking the friability to meet the requirements.

S6, coating: 50% ethanol is used as solvent, the concentration is 6-8%, and the temperature of a tablet bed is controlled at 38-45 ℃ during coating.

In vitro dissolution rate determination method of tinidazole tablets

The in vitro dissolution rate determination method is as follows: according to the determination method of dissolution rate and release rate (first method of 0931 in the four-part general rules of the Chinese pharmacopoeia 2015 edition), 900ml of water is used as dissolution medium, the rotation speed is 100 revolutions per minute, and the sampling detection is carried out according to the method for 5min, 10min, 15min and 30min respectively. The results are shown in Table 4.

TABLE 4 dissolution test results of tinidazole tablets prepared in examples 1 to 6

As can be seen from table 4, the tinidazole tablets prepared in examples 1 to 6 have substantially no difference in dissolution curve in purified water, the dissolution curves in 15min are all greater than 85%, and the tinidazole tablets can be completely released in 30 min.

Third, example 1-6 tinidazole tablet friability measurement

The friability of each of examples 1 to 6 was measured as follows: according to the friability test method of tablets (0923 in the four-part general rules of the pharmacopoeia 2015 edition). The results are shown in Table 5.

TABLE 5 brittle fracture contrast of examples 1-6

Examples	Degree of friability
		1	0.09％
2	0.13％
		3	0.10％
4	0.12％
		5	0.07％
6	0.08％

As can be seen from the friability results in Table 5, the friability of the dry granulation tableting processes of examples 1 to 6 were substantially the same and could meet the requirements of the coating process.

Fourth, investigation of genotoxic impurity nitrite in Tinidazole tablets of examples 1 to 6

The tinidazole tablet contains nitro, the structure is easily degraded into nitrite under high temperature, and the nitrite belongs to genotoxic impurities, so that the content of the nitrite needs to be strictly controlled.

The nitrite detection method comprises the following steps:

precisely weighing a proper amount of fine powder (about equivalent to 0.25g of tinidazole), placing the fine powder into a 50ml measuring flask, and adding 40ml of ultrapure water; performing ultrasonic treatment for 15min, cooling, repeating the ultrasonic treatment for 5 times, diluting with ultrapure water to scale, shaking, centrifuging, collecting supernatant, filtering with 045 μm PES filter membrane, and collecting filtrate as sample solution; in addition, a proper amount of nitrite standard solution is precisely measured, and diluted with ultrapure water to prepare solutions containing 25ng, 50ng, 100ng, 250ng, 500ng and 1000ng of nitrite per 1ml, which are used as control solutions.

The concentration gradient elution of the analytical column was carried out by ion chromatography (general guidelines of the four parts of the Chinese pharmacopoeia) using an anion exchange chromatography column (Dionexonpacas 19, 4 mm. times.250 mm or a chromatography column having equivalent performance) as a conductivity detector in a manner of inhibiting conductivity detection at a column temperature of 30 ℃ and a potassium hydroxide solution as a eluent at a flow rate of 1.0ml per minute according to the procedure shown in Table 6. Precisely measuring 100 μ l of each of the sample solution and the reference solution, and injecting into an ion chromatograph.

The number of theoretical plates in the reference solution is not less than 3000 calculated according to nitrite peak. If a nitrite peak exists in a chromatogram of the test solution, the content of nitrite is not more than 55ppm according to the standard curve method. The results are shown in Table 7.

TABLE 6 concentration gradient elution procedure

Time (min)	Concentration (mmol/L)
		0	15
12.0	15
		18.0	35
20.0	35
		20.1	15
30.0	15

TABLE 7 examples 1-6 and nitrite content of the starting material

Examples	Nitrite content (ppm)
		1	6.8
2	7.0
		3	6.2
4	6.7
		5	6.8
6	6.4
		Tinidazole raw material	6.7

As can be seen from table 7, the tinidazole tablets in examples 1 to 6 have no difference in nitrite content, and basically have no change in nitrite content compared with the tinidazole raw material, which indicates that dry granulation can effectively avoid the increase of nitrite caused in the preparation process.

Fifth, example 1 stability study of samples and Tinidazole starting Material

The samples obtained in the respective steps in the preparation method of example 1, the tinidazole tablets obtained and the raw materials used therefor were subjected to stability test under three conditions of high temperature of 60 ℃. + -. 2 ℃, high humidity RH 90. + -. 5% and strong light of 4500 lx. + -. 500lx, and the nitrite content was measured, and the results are shown in table 8.

TABLE 8 nitrite content in samples and raw materials of each procedure of example 1

The results in table 8 show that the nitrite in the tinidazole raw material can be significantly increased under the three conditions of temperature, humidity and illumination, which indicates that the tinidazole raw material is unstable to temperature, humidity and illumination, and attention should be paid to avoid introducing high temperature and high humidity in the preparation process and to avoid light. The process adopted by the sample in the embodiment 1 is dry granulation, high temperature and high humidity are avoided, the nitrite of the sample is basically unchanged in the preparation process, the increase trend appears in stability investigation, but the increase amplitude is obviously lower than the increase amplitude of the raw materials, and the result shows that the process avoids the wet granulation process and can effectively reduce the generation of the nitrite.

Sixthly, clinical comparison study

The sample obtained in example 1 (test preparation) was mixed with tinidazole tablets from Pfizer Limited

(reference formulation) BE experiments were carried out and the results are shown in Table 9.

TABLE 9 BE comparison of the results of the experiments

As can be seen from Table 9, the tinidazole tablets produced in example 1 and the tinidazole tablets produced by Pfizer Limited

The biological equivalence is tested by a biological equivalence test of oral administration after meal. The test result shows that the tinidazole tablet as the tested preparation and the tinidazole tablet as the reference preparation

The safety of the method is better.

Comparative examples 1 to 5:

the formulations of comparative examples 1 to 5 were as shown in table 10, with conventional water-soluble binders such as hypromellose and hyprolose used as binders, and without the addition of fillers.

TABLE 10 formulation tables for comparative examples 1 to 5

Raw and auxiliary materials	Comparative example 1	Comparative example 2	Comparative example 3	Comparative example 4	Comparative example 5
						Tinidazole	500g	500g	500g	500g	500g
Hydroxypropyl methylcellulose	7g	--	--	--	--
						Hydroxypropyl cellulose	--	7g	--	3.5g	--
Povidone K90	--	--	7g	--	3.5g
						Croscarmellose sodium	25g	25g	25g	25g	25g
Purified water	133g	133g	133g	136.5g	136.5g
						Magnesium stearate	3g	3g	3g	3g	3g
Is made into	1000 tablets	1000 tablets	1000 tablets	1000 tablets	1000 tablets

The comparative examples 1 to 5 are prepared by adopting a traditional wet granulation process, and the preparation method specifically comprises the following steps:

s1, weighing raw materials: weighing the raw materials and the auxiliary materials according to the prescription.

S2, premixing: the tinidazole and the croscarmellose sodium with the prescription amount are filtered by a 1mm screen, and then are put into a wet granulator to be mixed for 5min, the rotating speed of a stirring paddle is 500rpm, the rotating speed of a cutter is 2000rpm, and the mixture is uniformly mixed.

S3, granulating: the hydroxypropyl methylcellulose, the hydroxypropyl cellulose and the povidone K90 in the prescription are dissolved in purified water of the prescription amount to prepare an adhesive for later use. Adding the adhesive with the prescription amount into the premix, rotating the stirring paddle at 500rpm and the cutter at 2000rpm, and granulating for 1-5 min.

S4, drying: drying with fluidized bed at air inlet temperature of 50-60 deg.C and water content of 2% or less.

S5, total mixing of whole grains: the granules were granulated with a 1.27mm sieve, and the granulated granules and magnesium stearate were put into a mixer and mixed at a mixing speed of 10rpm for 10min to obtain total mixed granules.

S6, tabletting: and (3) feeding the total mixed particles into a tablet press, controlling the hardness to be 8.0-17.0 kg, controlling the weight difference of the tablets to be +/-5%, and checking the friability to meet the requirements.

S7, coating: 50% ethanol is used as solvent, the concentration is 6-8%, and the temperature of a tablet bed is controlled at 38-45 ℃ during coating.

S8, packaging: and (5) boxing and boxing the aluminum-plastic composite material.

The friability and dissolution of the tinidazole tablets prepared in comparative examples 1-5 were measured, and the results are shown in tables 11 and 12.

TABLE 11 friability of comparative examples 1 to 5

Comparative example	Degree of friability
		1	1.32％
2	0.11％
		3	0.12％
4	0.15％
		5	0.14％

TABLE 12 dissolution rates of comparative examples 1 to 5

Comparative example	5min	10min	15min	30min
					2	23	45	64	88
3	21	41	65	89
					4	25	53	76	93
5	28	55	73	94

As can be seen from tables 11 and 12, the friability of comparative example 1 does not meet the requirements, the friability of comparative examples 2 to 5 meets the requirements, the product is a BCS1 type drug, the 15min dissolution of the reference preparation is more than 85%, and the dissolution of the sample prepared by wet granulation is obviously slower than that of the reference preparation.

Comparative examples 6 to 7:

the formulations of comparative examples 6 to 7, in which a filler was added and starch slurry was used as a binder, are shown in table 13.

TABLE 13 formulation tables for comparative examples 6 to 7

Raw and auxiliary materials	Comparative example 6	Comparative example 7
			Tinidazole	500g	500g
Microcrystalline cellulose	50g	50g
			Croscarmellose sodium	25g	40g
4% starch slurry	Proper amount of	Proper amount of
			Magnesium stearate	3g	3g
Is made into	1000 tablets	1000 tablets

Comparative examples 6 to 7 were prepared using a conventional wet granulation process, and the preparation method was as follows:

S2, premixing: the tinidazole, the microcrystalline cellulose and the croscarmellose sodium with the prescription amount are screened by a 1mm screen, and then are put into a wet granulator to be mixed for 5min, the rotating speed of a stirring paddle is 500rpm, the rotating speed of a cutter is 2000rpm, and the mixture is uniformly mixed.

S3, granulating: preparing the starch in the formula into 4% starch slurry for later use. Adding the starch slurry of the prescription amount into the premix, rotating the stirring paddle at 500rpm and the cutter at 2000rpm, and granulating for 1-5 min.

The results of the friability and dissolution of the tinidazole tablets prepared in comparative examples 6 to 7 are shown in tables 14 and 15.

TABLE 14 friability of comparative examples 6 to 7

Comparative example	Degree of friability
		6	0.45％
7	0.43％

TABLE 15 dissolution rates of comparative examples 6 to 7

Comparative example	5min	10min	15min	30min
					6	34	53	70	91
7	45	63	82	94

As can be seen from tables 14 and 15, the friability of comparative examples 6 and 7 meets the requirements, but the friability is higher, the coating process affects the smoothness of the tablet surface, and knocking occurs around the tablet; the dissolution curve result shows that the dissolution result is not more than 85% in 15min, and the dissolution curve result is not satisfactory because the nitrite of the raw material of the product can be obviously increased under high temperature and high humidity, and the dissolution result of wet granulation is slow, and the wet granulation process is obviously inferior to the dry granulation process from the aspects of prescription and process.

In conclusion, the tinidazole tablet is prepared by adopting a dry granulation process, the dosage and the particle size of the raw and auxiliary materials are controlled, the dissolution rate, the disintegration time limit, the hardness and the friability of the tablet can be effectively improved, and meanwhile, the production compliance is good and the production efficiency is high.

The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.

Claims

1. A method for preparing tinidazole tablets is characterized by comprising the following steps: the method comprises the following steps:

s1, weighing raw materials: raw materials and auxiliary materials are weighed according to the following compositions and mass ratios: 70-90% of tinidazole, 3-15% of adhesive, 0.5-3% of glidant, 3-10% of disintegrant, 1-20% of filler, 0.5-1.5% of lubricant and 2-4% of coating material; wherein the particle size of the tinidazole is d (0.9) less than or equal to 60 mu m;

s2, premixing: putting the tinidazole, the filler, part of the disintegrant, the glidant and part of the adhesive in a formula amount into a mixer, mixing for 20-40 min, and uniformly mixing;

s3, granulating: granulating by adopting a dry granulation process, and sieving with a 18-mesh sieve;

s4, total mixing: mixing the granules, the rest of disintegrant, the rest of adhesive and lubricant for 10-20 min;

s5, tabletting: feeding the total mixed particles into a tablet press, controlling the hardness to be 8.0-17.0 kg and the weight difference of the tablets to be +/-5%, and checking the friability to meet the specification;

s6, coating: coating with film coating premix, and ethanol as solvent.

2. The method for preparing tinidazole tablets according to claim 1, characterized in that: the binder is povidone K30 and/or povidone K90.

3. The method for preparing tinidazole tablets according to claim 1, characterized in that: the disintegrant is crospovidone.

4. The method for preparing tinidazole tablets according to claim 1, characterized in that: the glidant is colloidal silicon dioxide.

5. The method for preparing tinidazole tablets according to claim 1, characterized in that: the filler is silicified microcrystalline cellulose.

6. The method for preparing tinidazole tablets according to claim 1, characterized in that: the lubricant is magnesium stearate.

7. The method for preparing tinidazole tablets according to claim 1, characterized in that: the tinidazole tablet comprises the following components in percentage by mass: 70-90% of tinidazole, 3-15% of povidone, 0.5-3% of colloidal silicon dioxide, 3-10% of crospovidone, 1-20% of silicified microcrystalline cellulose, 0.5-1.5% of magnesium stearate and 2-4% of coating material.

8. A tinidazole tablet is characterized in that: the preparation method is characterized by being prepared by the preparation method of any one of claims 1-7.