CN102949370B

CN102949370B - A kind of Roflumilast tablet and preparation method thereof and detection method

Info

Publication number: CN102949370B
Application number: CN201210492939.5A
Authority: CN
Inventors: 张观福
Original assignee: Guizhou Xinbang Pharmaceutical Co Ltd
Current assignee: Guizhou Xinbang Pharmaceutical Co Ltd
Priority date: 2012-11-27
Filing date: 2012-11-27
Publication date: 2018-05-04
Anticipated expiration: 2032-11-27
Also published as: CN102949370A

Abstract

The present invention provides a kind of Roflumilast tablet and preparation method thereof and detection method, it is using 0.5mg roflumilasts as bulk pharmaceutical chemicals, add 100~150mg lactose, 80~120mg pregelatinized starch, 10~30mg PVP K30s and 0.5~2.6mg magnesium stearates, and using made of acetone, ethanol, purified water as solvent.The present invention is in view of the deficiencies of the prior art, prescription, preparation process to Roflumilast tablet are optimized, make the effect of it is to diseases such as treatment COPD more notable, and establish system, complete, effective component differentiates and content assaying method, the quality of the medicine can be effectively controlled, so that it is guaranteed that its clinical efficacy.

Description

A kind of Roflumilast tablet and preparation method thereof and detection method

Technical field

The present invention relates to a kind of Roflumilast tablet and preparation method thereof and detection method, belong to technical field of western medicines.

Background technology

Chronic obstructive pulmonary disease（Chronic obstructive pulmonary diseases abbreviations COPD）It is a kind of The disease that can be prevented and treated with flow limitation feature, flow limitation is not fully reversible, in sexual development is carried out, with lung Abnormal inflammatory reaction to the pernicious gases such as smoke from cigarette or deleterious particle is related.COPD mainly involves lungs, but can also cause Whole body（Or outside lung）Ill effect.Chronic obstructive pulmonary disease is also often closely related with heart failure and metabolic syndrome etc., These chronic presence suffered from the disease altogether may further aggravate the clinical manifestation of chronic obstructive pulmonary disease.As a kind of air flue and The chronic inflammation disease of lung, chronic obstructive pulmonary disease become global common disease and causing death Etiological it One.

Roflumilast is phosphodiesterase 4 inhibitors, for aiding in bronchodilator maintaining treatment adult and chronic branch Tracheitis is related and has the patients of severe COPD of frequent condition worse history, to reduce the risk of COPD deteriorations.The work of roflumilast It is by suppressing the PDE4 in lung cells, preventing CAMP from hydrolyzing with mechanism, so as to block inflammatory reaction signal transmission, reduces scorching The release of disease medium, and then the suppression such as breathing problems such as COPD and asthma are damaged caused by lung tissue, play anti-inflammatory effect.

It is by the exploitation of Nycomed companies, to for treating asthma and chronic obstructive pulmonary disease that roflumilast original, which grinds medicine, One new oral medicine, in July, 2010 are approved to be used to aid in bronchodilator maintaining treatment severe chronic to hinder in European Union Plug property tuberculosis（COPD）Patient, in European Union member countries, its trade name Daxas；On 2 28th, 2011, U.S. FDA was ratified it and is used for Reduce the symptom progression risk with chronic bronchitis and the serious COPD patient for having acute exacerbation history, the trade name in the U.S. Daliresp；The formulation that original grinds medicine listing is tablet, and specification is 500 μ g, and it is once a day, each one to recommend usage and dosage （500μg）.

The patent application of Application No. " 201210261940.7 " discloses a kind of roflumilast tablet preparation and its preparation side Method, it is made of roflumilast, lactose, starch, 30 POVIDONE K 30 BP/USP 90.Since PVP K90 viscosity is bigger than normal, prepare solution when conglomeration not It is easily scattered, it is necessary to certain time dissolves, be made tablet dissolution rate using PVP K90 partially slow, mobility and compressibility deviation； It is partially slow using starch dissolution rate in the case that povidone is as adhesive, it can also influence mobility and compressibility.

In addition, at present to roflumilast preparation also without a set of stringent reliable quality inspection standard.If without stringent Quality standard, obtained product cannot ensure its quality, as a result will influence the clinical efficacy of the medicine；So to improve sieve The therapeutic effect that special dose of fluorine department, it is ensured that medication safely, effectively and product quality stabilization, formulate a stringent reliable matter Amount standard becomes the basic demand ensured drug quality.With the development of Modern Instrument Analytical Technique, high performance liquid chromatography etc. Analysis method is more and more widely used in the quality control of medicine.

The content of the invention

It is an object of the present invention to provide a kind of Roflumilast tablet and preparation method thereof and detection method.The present invention is directed to The deficiencies in the prior art, prescription, preparation process to Roflumilast tablet are optimized, and make it to diseases such as treatment COPD Curative effect is more notable, and establish system, complete, effective component differentiates and content assaying method, can effectively control this The quality of medicine, so that it is guaranteed that its clinical efficacy.

Technical scheme：A kind of Roflumilast tablet, is using roflumilast 0.5mg as bulk pharmaceutical chemicals per tablet preparation, adds Enter appropriate filler, adhesive and lubricant, and using made of acetone, ethanol, purified water as solvent；The filler refers to Lactose, pregelatinized starch, lactose, pregelatinized starch account for the 50%~70% of filler weight, 30%~50% respectively；Described adhesive Refer to PVP K30, PVP K30 accounts for the 5%~10% of solution concentration；The lubricant refers to magnesium stearate, and magnesium stearate is 0.5~2.6mg.

Preferable Roflumilast tablet, be per tablet preparation using 0.5mg roflumilasts as bulk pharmaceutical chemicals, add 138.5mg lactose, 100mg pregelatinized starch, 20mg PVP K30s, 1mg magnesium stearates, and using made of acetone, ethanol, purified water as solvent.

The preparation method of foregoing Roflumilast tablet comprises the following steps：

S1, lactose, pregelatinized starch cross 60 mesh sieves, and add in Multifunctional coating comminutor；By roflumilast and acetone, Ethanol, purified water stir evenly, and add PVP K30, and roflumilast solution is made；

S2, pelletizes roflumilast solution, lactose, pregelatinized starch using fluidized bed spray granulation equipment, dry, Whole grain；

S3, the magnesium stearate added after 100 mesh sieves are uniformly mixed；

S4, after tabletting, coating to obtain the final product.

Specific preparation process comprises the following steps：

1st, preprocessing raw material and auxiliary material：Lactose, pregelatinized starch cross 60 mesh sieves, and above auxiliary material is weighed by 3 equal portions, standby 3 pots of throwings Material, 10000 every pot, and be transferred between granulation.

2nd, the preparation of adhesive：

2.1 take the 5000mL stainless steel barrels of cleaning, and install blender, are put with 250mL graduated cylinders measurement 200mL acetone stainless In steel drum.

2.2 precision weighing roflumilast 5.000g clarify solution with being added to while stirring in the acetone of 2.1.

2.3 add ethanol 2000mL under stirring in the solution of 2.2, continue to stir, it is pure to add 1300mL Change water, continue to stir evenly.

2.4 weigh 200g PVP K30s, are added under stirring in the solution of 2.3, continuing stirring makes solution clear Clearly, roflumilast solution is made.

3rd, lactose, pregelatinized starch are added in Multifunctional coating comminutor, starts air compressor, pressure reaches After 0.8MPa, opening Multifunctional coating comminutor makes material boiling mixing 3min；Compressor flow sets 35~120m³/ h, inlet air Temperature sets 75 ± 10 DEG C, and 45 ± 10 DEG C of control material temperature, monitors 30 ± 10 DEG C of leaving air temp.

4th, spraying granulation：0.2 ± 0.02MPa of atomizing pressure, 6.0 ± 2rpm of wriggling revolution speed, flow velocity about 8 ± 2mL/min, Compressor flow sets 35~120m³/ h, inlet air temperature set 75 ± 10 DEG C, and 45 ± 10 DEG C of control material temperature, detects wind-warm syndrome 30 ± 10 DEG C of degree；Recorded once per 5min；Before mist projection granulating terminates, roflumilast solution in pipeline is pressed into spray gun with purified water It is granulated, until purified water sprays.

5th, it is dry：Control 75 ± 10 DEG C of inlet air temperature, 45 ± 10 DEG C of temperature of charge, moisture control≤3.0%；Record measure As a result；Drying time about 20~25min；Stop heating, cooling waiting measurement result after 20min samplings；It is according to result decision No discharging；In the drying process if temperature of charge stops heating more than 55 DEG C, director should be reported immediately.

6th, whole grain：High speed pelletizing machine, sieve 1.0mm, rotary speed 700~1800rpm or 10~25Hz, first cross 20 mesh sieves, 20 mesh sieves are crossed after intransitable particle whole grain, the particle 30%~70% for all passing through 60 mesh sieves by 20 mesh, control.

7th, mix：

7.1 always mix additional material pretreatment：Magnesium stearate is crossed into 100 mesh sieves；

7.2 are added to roflumilast particle in SYH-50 mixers（Rotating speed 10rpm or 15Hz）Mix 10min；

7.3 add magnesium stearate mixing 10min；

7.4 granule contents are the 95.0~105.0% of labelled amount.

Wherein, the optimizing technology parameters of preparation method are：

（1）Granulating process parameter：35~120m of compressor flow³/ h, 6 ± 2rpm of wriggling revolution speed, atomizing pressure 0.2 ± 0.02MPa, 75 ± 10 DEG C of inlet air temperature, 45 ± 10 DEG C of temperature of charge；

（2）Drying Technology Parameter：35~120m of compressor flow³/ h, 75 ± 10 DEG C of inlet air temperature, temperature of charge 45 ± 10 DEG C, 20~25min of drying time；

（3）Whole grain technological parameter：Sieve 1.0mm, 700~1800rpm or（10~25Hz）, first cross 20 mesh sieves, it is impossible to logical 20 mesh sieves are crossed after the particle whole grain crossed, all by 20 mesh, control 60 mesh particles 30%~70% of ＜；

（4）Hybrid technique parameter：Rotating speed 10rpm or 15Hz, after particle mixing 10min, add mix lubricant 10min；

（5）Tablet forming technique parameter：Theoretical piece weight 260mg/ pieces, upper punching circle φ 9.0mm, middle mould circle 9.0mm, undershoot circle Shape φ 9.0mm, diameter range:9.0 ± 0.3mm, tableting pressure（Thickness is set）D1.8~2.0, piece 4.0 ± 0.5mm of thickness, tabletting Machine 20~30rpm of rotating speed, 40~110N of plain piece hardness；

（6）Coating process parameters：65~80 DEG C of inlet air temperature, 35~42 DEG C, flow velocity 1.5mL/min of piece bed tempertaure, coating Weightening 1.0%~2.0%.

The detection method of foregoing Roflumilast tablet includes character, discriminating, inspection and assay project；Wherein differentiate it is pair Roflumilast in preparation is differentiated；Inspection be this preparation is carried out respectively related material, organic residual solvent, dissolution rate, Uniformity of dosage units and microbial limit are checked；Assay is that roflumilast content is carried out using high performance liquid chromatography Measure.

Concrete content assay method is：

Equipment：HPLC UV detector；

Reagent：

Acetonitrile HPLC grade,

High purity water HPLC grade,

Potassium dihydrogen phosphate AR grade,

Phosphoric acid AR grade,

Potassium hydroxide AR grade；

Reference substance：Roflumilast working reference substance；

Chromatographic condition：It is filler with octadecylsilane chemically bonded silica, with phosphorus acid for adjusting pH value to 3.0 0.03mol/L potassium dihydrogen phosphates：Acetonitrile=40：60 be mobile phase, Detection wavelength 220nm, flow velocity 1mL/min, column temperature For 30 DEG C, sample size is 20 μ L；

The preparation of reference substance solution：Precision weighs roflumilast reference substance 20mg, puts in 100mL volumetric flasks, adds 50% acetonitrile Dissolve and be diluted to scale, shake up, precision measures 5mL and puts in 100mL volumetric flasks, adds 50% acetonitrile to dissolve and is diluted to scale, shakes It is even, it is parallel to prepare 2 parts, as reference substance solution and control solution.

The preparation of sample solution：Take Roflumilast tablet finely ground in right amount, precision weighs the powder equivalent to roflumilast 0.5mg End, puts in the measuring bottle of 50mL, with 50% acetonitrile ultrasonic dissolution, then adds 50% dilution in acetonitrile, with membrane filtration, to take subsequent filtrate to scale For sample solution.

System suitability is tested：Advanced 5 pin of reference substance solution, then into control 1 pin of solution.Chromatogram is recorded, with pair of 5 pins Average value according to product solution is reference substance, and it is sample that 1 pin, which controls solution, calculates the reference substance rate of recovery；

Acceptable standard：Number of theoretical plate is not less than 2000 based on roflumilast peak；The rate of recovery of two parts of reference substances is 98.0% Between~102.0%；The relative deviation of 5 parts of roflumilast peak retention times is not more than 2.0%；Roflumilast peak and other impurities peak Separating degree should be greater than 1.5；

Experimentation：After system suitability qualification, each sample solution is parallel into 1 pin, records chromatogram, by external standard method with Calculated by peak area；Calculation formula is as follows：

In formula：A₁For the peak area of roflumilast in sample solution,

A₂For the peak area of roflumilast in reference substance solution,

C is the correction factor of reference substance,

S, Sr is respectively the extension rate of sample and reference substance,

W₁For the sample weighting amount of reference substance, unit mg；

W₂For the sample weighting amount of sample, unit mg,

M be sample average piece weight, unit mg,

T be sample labelled amount, unit mg.

Particular exam method is：

（1）Related material：

Instrument：HPLC UV detector；

Reagent：It is identical with assay item；

Chromatographic condition：Chromatographic column is AlltimaTM, C18,250 × 4.6mm, 5 μm, with the 0.02M KH of pH 3.5₂PO₄： CH₃CN=42：58 be mobile phase, and column temperature is 30 °C, Detection wavelength 254nm, flow velocity 1.0mL/min, and sampling volume is 20 μ L, run time 30min, data acquisition 30min；

The preparation of reference substance solution：Precision weighs roflumilast working reference substance, roflumilast impurity reference substance A, impurity Reference substance B, each 5mg of impurity reference substance D, impurity reference substance C 2mg are dissolved and diluted with acetonitrile in same 100mL volumetric flasks To scale, shake up, filter, obtain control stock solution（Stock solution is compareed containing roflumilast, impurity reference substance A, impurity reference substance B, miscellaneous 20 μ g/mL of matter reference substance D each 50 μ g/mL, impurity reference substance C）；Draw 5.0mL and compare stock solution in 100mL volumetric flasks, use Acetonitrile dissolves and is diluted to scale, shakes up, filtering；（The reference substance solution is containing roflumilast, impurity reference substance A, impurity reference substance B, each 2.5 μ g/mL of impurity reference substance D, impurity reference substance C are 1.0 μ g/mL）；

The same reference substance solution of system suitability solution；

The preparation of sample solution：30, this preparation is taken, claims gross weight, calculates average piece weight；Pulverize, weigh equivalent to sieve fluorine department The appropriate powder of special 5mg accurately adds acetonitrile 10.0mL with pipette in 25mL volumetric flasks, covers plug, ultrasonic 10min, Shaking frequently, take out and stand, take upper liquid, 0.45 micrometer Millipore membrane filtration, discards primary filtrate 1mL, collects subsequent filtrate to obtain the final product, Sample solution concentration is 0.5mg/mL；

Experimentation：After stablizing into sample solvent acetonitrile to system, sampling system applicability solution, makes gained peak area RSD must not exceed 5.0%, take 10 μ L of above contrast solution to inject liquid chromatograph, adjusts detection sensitivity, makes principal component chromatography Peak height is the 20% of full scale, then takes 10 μ L of test solution, injects liquid chromatograph；

Acceptable standard：Roflumilast peak tailing factor must not exceed 2.0；Roflumilast peak column effect is not less than 5000；Sieve Fluorine Si Te peaks are not less than 1.5 with impurity C separating degrees；

Calculate：Calculated by external standard method；

（a）Known impurities, calculated by peak area is compareed with known impurities：

In formula：A Spl are corresponding impurity peak area in sample solution,

A Std are corresponding impurity peak area in reference substance solution,

Mg Spl are sample sample weighting amount,

Mg Std are known impurities sample weighting amount,

F is the correction factor of known impurities,

AveT is average piece weight,

P is labelled amount；

（b）Unknown impuritie, is calculated with 0.50% roflumilast peak in reference substance solution：

In formula：A Spl are corresponding impurity peak area in sample solution,

AStd is roflumilast peak area in reference substance solution,

Mg Spl are sample sample weighting amount,

Mg Std are roflumilast reference substance sample weighting amount,

F is roflumilast reference substance correction factor,

AveT is average piece weight,

P is labelled amount；

（2）Organic residual solvent：

Instrument：GC hydrogen ion flame detectors；

Chromatographic condition：Agilent 6890N, HS-2 type head-space samplers, chromatographic column are Agilent DB-624 capillaries Chromatographic column, carrier gas are nitrogen, and flow velocity 5.0mL/min, constant current injector temperature is 200 DEG C, and detector temperature is 250 DEG C of FID, Column temperature keeps 7min, split ratio 3 for 40 DEG C：1, sample size 1mL, head space temperature are 80 DEG C, and clack box temperature is 120 DEG C, pipe Road temperature is 120 DEG C, equilibration time 30min；

The preparation of reference substance solution：Precision weighs ethanol 100mg, and acetone 100mg is put in 100mL measuring bottles, adds suitable quantity of water Make dissolving, and constant volume puts scale, precision measures 10mL and puts in 100mL measuring bottles, and constant volume is diluted with water, then the accurate 5mL that measures is put In 20mL ml headspace bottles, capping, as reference substance solution；

The preparation of sample solution：Precision weighing 500mg Roflumilast tablets powder sample adds 5mL into 20mL ml headspace bottles Water dissolves, and seals to obtain the final product；

System suitability solution prepares same reference substance solution；

Experimentation：It is accurate respectively to measure reference substance solution and for trying after stablizing into blank solution dimethyl sulfoxide to system Each 1.0 μ L of product solution, inject gas chromatograph, record chromatogram；

Acceptable standard：Number of theoretical plate must not calculate less than 5000, and the separating degree between each residual solvent peak should be not less than 1.5, main peak area RSD obtained by 5 pin working reference substance solution of continuous sample introduction must not exceed 5.0%；

Calculate：Calculate the content of each organic residual solvent in sample respectively with external standard method；Calculation formula is as follows：

In formula：Aspl is organic solvent peak area in sample solution,

Astd is organic solvent peak area in reference substance solution,

Mg spl are sample sample weighting amount,

Mg std are organic solvent sample weighting amount；

（3）Dissolution rate：Reference《Chinese Pharmacopoeia》2010 editions Ⅹ the second methods of C of annex, method number is HR001-F01-M03；

Instrument：HPLC UV detector, intelligent dissolution test system；

Reagent：

Acetonitrile HPLC grade,

High purity water HPLC grade,

Potassium dihydrogen phosphate AR grade,

Phosphoric acid ARgrade,

Hydrochloric acid ARgrade,

Lauryl sodium sulfate AR grade；

Reference substance：Roflumilast working reference substance；

Sample solvent：0.1M HCl（Containing 0.25% lauryl sodium sulfate）；

Chromatographic condition：It is filler with octadecylsilane chemically bonded silica；With with phosphorus acid for adjusting pH value to 3.0 0.03mol/L potassium dihydrogen phosphates-acetonitrile=40：60 be mobile phase；Detection wavelength is 220nm, flow velocity 1mL/min, column temperature For 30 DEG C, sample size is 50 μ L；

The preparation of reference substance solution：Precision weighs roflumilast reference substance 22mg, puts in 100mL volumetric flasks, and solubilization goes out to be situated between Matter dissolves and is diluted to scale, shakes up, and precision measures 5mL and puts in 100mL volumetric flasks, adds dissolution medium to dissolve and is diluted to quarter Degree, shakes up, then accurate measurement 5mL puts in 100mL measuring bottles and is settled to scale with dissolution medium dilution, shakes up, to obtain the final product, parallel preparation 2 parts, as reference substance solution and control solution；

The preparation of sample solution：Operated by big agar diffusion method；Before measure, necessary debugging is carried out to apparatus, makes blade bottom Portion measures the 0.1M HCl of the volume 900mL of degassed processing away from 25 ± 2mm of stripping rotor bottom respectively（Containing 0.25% dodecyl Sodium sulphate）Put in each stripping rotor, heat, treat that dissolution medium constant temperature at 37 DEG C ± 0.5 DEG C, after its is steady, takes sample 6 Piece, puts into 6 stripping rotors respectively, and rotating speed is 50 turns/min, timing immediately；After 30min, away from blade top and liquid level Put and away from stripping rotor inner wall not less than dissolution fluid 10mL is drawn at 10mm, immediately with membrane filtration, discard primary filtrate 3mL, ask for Sample to filtration should be completed in 30 seconds, and it is sample solution to take subsequent filtrate；

System suitability：Advanced 5 pin of reference substance solution, then into control 1 pin of solution, chromatogram is recorded, with pair of 5 pins Average value according to product solution is reference substance, and it is sample that 2 pins, which control solution, calculates the reference substance rate of recovery；

Acceptable standard：Roflumilast peak number of theoretical plate is not less than 2000 based on roflumilast peak；Time of two parts of reference substances Between yield is 98.0%~102.0%；The relative deviation of 5 parts of roflumilast peak retention times is not more than 2.0%；Roflumilast peak 1.5 are should be greater than with the separating degree at other impurities peak；

Experimentation：After system suitability qualification, each sample solution records chromatogram, by external standard method with peak face into 1 pin Product calculates, and calculation formula is as follows：

In formula：A is sample peak area；

S, Sr is respectively the extension rate of sample box reference substance；

W be sample labelled amount, unit mg；

Wr be reference substance the amount of taking, unit mg；

C is the content of reference substance；

Ar is the peak area of reference substance solution.

（4）Uniformity of dosage units：This preparation is taken, is put in 50mL volumetric flasks, with reference to the method under assay item, according to China Two Ⅹ E of annex requirements of pharmacopeia 2010 edition, measure uniformity of dosage units；

（5）Microbial limit：Take this preparation, reference《Chinese Pharmacopoeia》2010 editions Ⅺ J conventional methods of annex calculate.

Specific discrimination method to roflumilast is：In the chromatogram recorded under assay item, sample solution main peak Retention time it is consistent with the retention time of reference substance solution main peak.

Detection method of the present invention includes：

（One）Character：This preparation is Film coated tablets, and whitening color is to off-white color after removing coating；

（Two）Assay：

Equipment：HPLC UV detector；

In formula：A₁For the peak area of roflumilast in sample solution,

A₂For the peak area of roflumilast in reference substance solution,

C is the correction factor of reference substance,

S, Sr is respectively the extension rate of sample and reference substance,

W₁For the sample weighting amount of reference substance, unit mg；

W₂For the sample weighting amount of sample, unit mg,

M be sample average piece weight, unit mg,

T be sample labelled amount, unit mg；

（Three）Check：

（1）Related material：

Instrument：HPLC UV detector；

The preparation of reference substance solution：Precision weighs roflumilast working reference substance, roflumilast impurity reference substance A, impurity Reference substance B, each 5mg of impurity reference substance D, impurity reference substance C 2mg are dissolved and diluted with acetonitrile in same 100mL volumetric flasks To scale, shake up, filter, obtain control stock solution（Stock solution is compareed containing roflumilast, impurity reference substance A, impurity reference substance B, miscellaneous 20 μ g/mL of matter reference substance D each 50 μ g/mL, impurity reference substance C）；Draw 5.0mL and compare stock solution in 100mL volumetric flasks, use Acetonitrile dissolves and is diluted to scale, shakes up, filtering；（The reference substance solution is containing roflumilast, impurity reference substance A, impurity reference substance B, each 2.5 μ g/mL of impurity reference substance D, 1.0 μ g/mL of impurity reference substance C）；

The same reference substance solution of system suitability solution；

Experimentation：After stablizing into sample solvent acetonitrile to system, sampling system applicability solution, makes gained peak area RSD must not exceed 5.0%, take 10 μ L of above contrast solution to inject liquid chromatograph, adjusts detection sensitivity, makes principal component chromatography Peak height is the 20% of full scale, then takes 10 μ L of test solution, injects liquid chromatograph；；

Calculate：Calculated by external standard method；

In formula：A Spl are corresponding impurity peak area in sample solution,

A Std are corresponding impurity peak area in reference substance solution,

Mg Spl are sample sample weighting amount,

Mg Std are known impurities sample weighting amount,

F is the correction factor of known impurities,

AveT is average piece weight,

P is labelled amount；

In formula：A Spl are corresponding impurity peak area in sample solution,

A Std are roflumilast peak area in reference substance solution,

Mg Spl are sample sample weighting amount,

Mg Std are roflumilast reference substance sample weighting amount,

F is roflumilast reference substance correction factor,

AveT is average piece weight,

P is labelled amount；

（2）Organic residual solvent：

Instrument：GC hydrogen ion flame detectors；

System suitability solution prepares same reference substance solution；

In formula：Aspl is organic solvent peak area in sample solution,

Astd is organic solvent peak area in reference substance solution,

Mg spl are sample sample weighting amount,

Mg std are organic solvent sample weighting amount；

Instrument：HPLC UV detector, intelligent dissolution test system；

In formula：A is sample peak area；

S, Sr is respectively the extension rate of sample box reference substance；

W be sample labelled amount, unit mg；

Wr be reference substance the amount of taking, unit mg；

C is the content of reference substance；

Ar is the peak area of reference substance solution；

（5）Microbial limit：Take this preparation, reference《Chinese Pharmacopoeia》2010 editions Ⅺ J conventional methods of annex calculate；

（Four）Differentiate：

In the chromatogram recorded under assay item, retention time and the reference substance solution main peak of sample solution main peak Retention time is consistent.

It is prescription and preparation process science in order to ensure Roflumilast tablet of the present invention, reasonable, feasible, applicant into Series of experimental research and investigation are gone.

First, the screening of prescription：

1st, roflumilast solution prepares solvent screening

According to roflumilast physicochemical property, acetone is soluble in, is slightly soluble in ethanol, it is not soluble in water, design following dissolution experiment.

1.1 add roflumilast 0.6003g dissolvings, solution clarification, i.e. 0.12006g/mL roflumilasts in 5mL acetone Acetone soln.

1.2 take 1mL roflumilast acetone solns to be diluted with water, and a small amount of water separates out crystallization, then adds 2mL acetone, does not still have Change.

1.3 take 1mL roflumilast acetone solns to add 2mL ethanol to dilute, and show settled solution, then add 5mL ethanol, shake up, clear Do not separate out clearly, add 8mL ethanol and shake up, clarification does not separate out, adds 15mL ethanol altogether, obtains roflumilast acetone ethanol solution.

1.4 take 1.3 lower roflumilast acetone ethanol solution 2mL to add 0.1M hydrochloric acid 1mL, shake up, and place 2h and do not separate out, 3h is placed to separate out.

1.5 take 1.3 lower roflumilast acetone ethanol solution 2mL to add 0.1M hydrochloric acid 2mL, shake up and place 1h precipitation knots It is brilliant.

1.6, which take 1.3 lower roflumilast acetone ethanol solution 2mL to add 1mL water, shakes up, and closed placement 2h does not separate out knot Crystalline substance, closed placement 7h do not separate out crystallization, separate out crystallization overnight.

1.7 povidone do not dissolve in acetone, are dissolved in ethanol, isopropanol, water, with a small amount of acetone solution raw material, add water or second Dissolving PVP does adhesive wet granulation after alcohol dilution：

1. ethanol is added under stirring according to 1.6 as a result, taking 0.1012g roflumilasts to be dissolved in 2mL acetone 20mL dilutes, and confirms solution clarification, is slowly added to water dilution, edged observation solution in side has nodeless mesh precipitation, when adding 11mL water Solution is clarified.PVP K302.0013g continuation stir about 15min is added under stirring again to be completely dissolved, obtains clarifying molten Liquid.

2. taking 0.0997g roflumilasts to be dissolved in 2mL acetone, ethanol 20mL dilutions are added under stirring, are confirmed Solution is clarified, and is slowly added to water dilution, and edged observation solution in side has nodeless mesh precipitation, and solution is clarified when adding 11mL water.Exist again PVP K902.0011g are added under stirring and continue stirring to being completely dissolved.The easy groups of rising of PVP K90 in course of dissolution, no Easily scattered, dissolving is slow.Settled solution is obtained after stir about 1h.

Conclusion：Experiment shows that roflumilast dissolves in acetone, then is diluted with ethanol, then is diluted with water and can obtain one The solution for interior stabilization of fixing time；The homogeneous solution of clarification can be obtained by adding povidone in this solution；The solution room temperature is transferred Put 7 it is small when do not separate out crystallization；Lay the foundation for wet granulation or fluidized bed spray granulation, carrying out the mistake of this technical study The volume of solution, solvent burden ratio are optimized according to prilling process and the scale that feeds intake in journey.

2nd, pregelatinized starch and starch screen

（1）Prescription

Table 1

Title	20110712	20110715
			Roflumilast	0.5mg	0.5mg
PVPK30	35mg	35mg
			Lactose	103.5mg	103.5mg
Starch	---	120mg
			Pregelatinized starch	120mg	---
Magnesium stearate	1mg	1mg
			Total amount	260mg	260mg

（2）Granulation

WBF-2 Multifunctional coating comminutors, fluidized bed spray granulation prepare roflumilast particle.

Table 2

Lot number

Compressor flow

Inlet air temperature

Temperature of charge

Peristaltic pump

Atomisation pressure

Drying time

Rotating speed

20110712

35m³/h

65-85℃

37-45℃

2.5rpm

0.18MPa

60min

20110715

35m³/h

65-85℃

38-41℃

2.5rpm

0.18MPa

60min

（3）Particle situation

Table 3

Test	20110712	20110715
			The mesh of particle screening≤60	61.4%	44.3%
Bulk density	0.57g/mL	0.51g/mL
			Tap density	0.73g/mL	0.64g/mL
Angle of repose≤40 °	32°	35°

（4）Tabletting situation

Table 4

（5）Dissolution rate situation

Experimental result is shown in Table 5~8.

Table 5

Table 6

Table 7

Table 8

Conclusion：It is partially slow using starch dissolution rate in the case where povidone is as adhesive, use pregelatinized starch energy Obtain grinding the close stripping curve of medicine with former, obtained mobility of particle is good, and compressibility is good.Therefore pregelatinized starch is selected.

3rd, PVP K30 and K90 are screened

（1）Prescription

Table 9

Title	20110726	20110711
			Roflumilast	0.5mg	0.5mg
PVPK30	---	10mg
			PVPK90	10mg	---
Lactose	128.5mg	128.5mg
			Pregelatinized starch	120mg	120mg
Magnesium stearate	1mg	1mg
			Total amount	260mg	260mg

（2）Granulation

Multifunctional coating comminutor, fluidized bed spray granulation prepare roflumilast particle.

Table 10

Lot number

Compressor flow

Inlet air temperature

Temperature of charge

Wriggling revolution speed

Atomisation pressure

Drying time

20110726

35m³/h

65-85℃

38-42℃

3.0rpm

0.18MPa

60min

20110711

30m³/h

65-85℃

38-45℃

2.5rpm

0.18MPa

60min

（3）Particle situation

Table 11

Test	20110726	20110711
			60 mesh of particle ＜	29.7%	48.0%
Bulk density	0.52g/mL	0.53g/mL
			Tap density	0.65g/mL	0.65g/mL
Angle of repose≤40 °	35°	36°

（4）Tabletting situation

Table 12

（5）Dissolution rate situation

Experimental result is shown in Table 13~16.

Table 13

Table 14

Table 15

Table 16

Conclusion：Experiment shows, different model adhesive same amount, and it is partially slow to be made tablet dissolution rate using PVP K90, Because its ratio of viscosities of PVP K90 PVPK30 is much bigger, when preparing solution conglomeration be not easy scattered, it is necessary to which certain time dissolves.And PVP K30 prepares particle in roflumilast solution, has good fluidity and compressibility.Therefore selection PVP K30, it is excellent by dosage Change, the close stripping curve of medicine is ground with former to obtain.

4th, coating powder screens

4.1 coating experiments

It is coated using Ka Lekang coating powders, checks appearance, measures dissolution rate.（Lot number：20110731）Plain piece dissolution Degree the results are shown in Table 17.

Table 17

Note * Core plain pieces, FC coating tablets.

The 4.2 happy health OPADRY of card

4.2.1 coating conditions

65-80 DEG C of inlet air temperature, 35-45 DEG C of piece bed tempertaure, flow velocity 1.5mL/min.

4.2.2 coating tablet appearance：Baby pink Film coated tablets, any surface finish, uniform color.

4.2.3 dissolution rate（Coating tablet weightening 1.4%）The results are shown in Table 18.

Table 18

Conclusion：Test result indicates that select this preparation of Ka Lekang coating powder bags, smooth appearance, uniform color, stripping curve Without significant change compared with plain piece, and approached with the former stripping curve for grinding medicine.Therefore the happy health coating powder of selection card.

2nd, formulation optimization：

1st, roflumilast solution solvent ratio optimization

1.1 solvent burden ratio Optimal Experimentals and result（It is shown in Table 19,20）

Table 19

Table 20

1.2 proportioning analyses：

1.2.1 liquor capacity 330-1010mL/2000 pieces have a significant effect the content of particle after granulation, and liquor capacity is got over Greatly, granule content is closer to 100%.Also have a significant effect to uniformity of dosage units control, test result indicates that selection 700mL can Granule content 95.0-105.0% is controlled, can also control tablet content uniformity A+1.8S≤15.

1.2.2 preferable solution ratio should be aqueous very high to be seldom containing acetone.Criterion obtains in certain volume Obtain settled solution.

1.2.3 acetone can obtain settled solution in the range of 5.72%-8.6% in different solutions volume, select acetone 5.72%（v/v%）.

1.2.4 ethanol will not separate out sieve fluorine in the range of 45.71%-60.6% when purified water ratio is no more than 37.14% Department is special.Select ethanol 57.14%（v/v%）.

1.2.5 wet concentration selects dosage 37.14%（v/v%）.

1.3 determine solvent burden ratio

Table 21

Title	Quantity mL/ pieces	Quantity mL/2000 pieces	Quantity mL/ ten thousand	Ratio %
					Roflumilast	0.5mg	1.0g	5.0g	---
Acetone	0.02mL	40mL	200mL	5.72%
					Ethanol	0.2mL	400mL	2000mL	57.14%
Purified water	0.13mL	260mL	1300mL	37.14%
					Total amount	0.35mL	700mL	3500mL	100%

2nd, lactose and pregelatinized starch dosage optimization

2.1 prescription

Table 22

2.2 granulation

Table 23

Lot number

Compressor flow

Inlet air temperature

Temperature of charge

Wriggling revolution speed

Atomisation pressure

Drying time

20110731

35m³/h

65-85℃

36-40℃

3.0rpm

0.18MPa

60min

20110801

35m³/h

55-85℃

26-33℃

3.0rpm

0.18MPa

60min

20110802

35m³/h

60-80℃

27-37℃

3.0rpm

0.18MPa

60min

2.3 particle situations

Table 24

Test	20110731	20110801	20110802
				The mesh of particle≤60	47.0%	38.2%	56.9%
Bulk density	0.54g/mL	0.53g/mL	0.52g/mL
				Tap density	0.64g/mL	0.67g/mL	0.71g/mL
Angle of repose≤40 °	36°	35°	34°

2.4 tabletting situations

Table 25

Lot number

Piece weight

Punch die

Pressure

Hardness

Content

Uniformity A+1.8S≤15

20110731

260mg

φ9.0mm

d2.1

10.4kg

94.8%

8.8

20110801

260mg

φ9.0mm

d2.0

10.02kg

97.8%

3.8

20110802

260mg

φ9.0mm

d2.0

7.4kg

98.6%

2.7

2.5 dissolution rate situations

Table 26

Table 27

2.6 stability

Table 28

Note：* it is 40 DEG C of 75%RH

Conclusion：Experiment shows that lactose is suitably matched with pregelatinized starch（Lot number 20110801）Mist projection granulating can be expired The mobility of particle and compressibility of meaning, and stripping curve as grinding medicine phases with original can be obtained.Therefore determine lactose dosage 138.5mg/ Piece, pregelatinized starch dosage 100mg/ pieces.

3rd, PVP K30 dosage optimization

3.1 prescription

Table 29

Title	20110712	20110711	20110801
				Roflumilast	0.5mg	0.5mg	0.5mg
PVP K30	35mg	10mg	20mg
				Lactose	103.5mg	128.5mg	138.5mg
Pregelatinized starch	120mg	120mg	100mg
				Magnesium stearate	1mg	1.0mg	1.0mg
Total amount	260mg	260mg	260mg

3.2 granulation

Table 30

Lot number

Compressor flow

Inlet air temperature

Temperature of charge

Wriggling revolution speed

Atomisation pressure

Drying time

20110801

35m³/h

55-85℃

26-33℃

3.0rpm

0.18MPa

60min

20110711

30m³/h

65-85℃

38-45℃

25rpm

0.18MPa

60min

20110712

35m³/h

65-85℃

37-45℃

25rpm

0.18MPa

60min

3.3 particle situations

Table 31

Test	20110801	20110711	20110712
				60 mesh of particle ＜	38.2%	48.0%	61.4%
Bulk density	0.53g/mL	0.53g/mL	0.57g/mL
				Tap density	0.67g/mL	0.65g/mL	0.73g/mL
Angle of repose≤40 °	35°	36°	32°

3.4 tabletting situations

Table 32

3.5 dissolution rate situations

Table 33

Table 34

Table 35

Table 36

Conclusion：Experiment shows that PVP K30 dosage is bigger, and grain graininess is relatively large after granulation, and mobility of particle is opposite Preferably, but on dissolution rate there is a degree of influence.For dosage in 20mg/ pieces, particle has good fluidity, while molten Go out curve and grind medicine phases seemingly with original.Therefore determine that PVP K30 dosage is 20mg/ pieces（Equivalent to binder concn in solution 5.7%）.

4th, magnesium stearate dosage optimization

4.1 prescription

Table 37

4.2 granulation

Table 38

Lot number

Compressor flow

Inlet air temperature

Temperature of charge

Wriggling revolution speed

Atomisation pressure

Drying time

20110806

35m³/h

55-85℃

28-34℃

3.0rpm

0.18MPa

12min

20110801

35m³/h

55-85℃

26-33℃

3.0rpm

0.18MPa

60min

20110807

30m³/h

55-85℃

28-34℃

3.0rpm

0.18MPa

12min

20110812

35m³/h

65-85℃

31-35℃

3.0rpm

0.18MPa

18min

4.3 particle situations

Table 39

Test	20110806	20110801	20110807	20110812
					60 mesh of particle ＜	29.1%	38.2%	29.1%	31.6%
Bulk density	0.53g/mL	0.53g/mL	0.53g/mL	0.49g/mL
					Tap density	0.63g/mL	0.67g/mL	0.63g/mL	0.64g/mL
Angle of repose≤40 °	33°	35°	33°	30°

4.4 tabletting situations

Table 40

4.5 dissolution rate situations (20110801 related collection of illustrative plates referring to annex 1 page 156~page 235)

Table 41

Table 42

Table 43

Table 44

4.6 stability

Table 45

Note：* it is 40 DEG C of 75%RH.

Conclusion：Experiment shows that the dosage increase of magnesium stearate, tablet hardness has reduction trend,（2.5mg/ piece）In water Dissolution rate is slack-off, but dosage is very little（0.5mg/ pieces）There is sticking phenomenon,（1.0~1.5mg/ pieces）Stripping curve compared with It is good, consider hardness factor, select magnesium stearate dosage 1.0mg/ pieces.

5th, coating weight gain amount optimizes

5.1 coating situations（Coating parameter is provided by coating powder supplier）

5.1.1BY-300A seed-coating machine, temperature controller, frequency control；

5.1.210% coating suspensions are prepared；

5.1.3 65~80 DEG C of inlet air temperature of coating process control；

5.1.4 35~45 DEG C of coating process control sheet bed tempertaure；

5.1.5 coating process coutroi velocity 1.5mL/min.

5.2 coating weight gain amounts

Table 46

Lot number	20110801FC	20110809FC	20110810FC	20110811FC	20110814FC
						Weightening	1.04%	1.97%	1.5%	0.9%	1.0%、1.5%、

Amount

1.9%

5.3 dissolution rate：

Conclusion：Under the conditions of coating parameter is provided with reference to supplier, coating weight gain is shallow in the range of 0.9~1.97% Pink circular membrane garment piece, complete appearance, bright and clean, uniform color.Stripping curve grinds medicine phases seemingly with original.Therefore coating process parameters It is determined as：10% coating suspensions, and a pot rotating speed 5-30rpm, 65~75 DEG C of inlet air temperature, piece are suitably adjusted according to plain piece weight 35~45 DEG C of bed tempertaure, coating flow velocity 1.5mL/min, coating weight gain amount scope are determined as 1.0~2.0%.

3rd, prescription determines：

Table 47

Title	Quantity mg/ pieces	Quantity g/10,000	Acted in prescription
				Roflumilast	0.5mg	5g	Main ingredient
Lactose	138.5mg	1385g	Filler
				Pregelatinized starch	100mg	1000g	Filler
PVP K30	20mg	200g	Adhesive
				Magnesium stearate	1mg	10g	Lubricant
Acetone *	0.02mL	200mL	Solvent
				Ethanol *	0.2mL	2000mL	Solvent
Purified water *	0.13mL	1300mL	Solvent
				Plain piece weight	260mg (is free of solvent)	2600g (is free of solvent)	---
Roflumilast plain piece	260mg	2600g	Label
				Coating powder * *	5.2mg	52g	Film-coating material
It is coated sheet weight	265.2mg	2652g	---

Note：* solvent finally removes, and * * are configured to 10% aqueous suspension.

4th, the screening and optimization of preparation method：

1 process choice

Direct tablet compressing technological experiment after the grinding of 1.1 roflumilasts is mixed with auxiliary material

1.1.1 prescription

Table 48

Title	Quantity 20110501
		Roflumilast	0.5mg
Lactose	117.3mg
		Silica	1.2mg
Magnesium stearate	1mg
		Total amount	120mg

1.1.2 prepare

Roflumilast and silica mixed grinding, then mix, direct tablet compressing with the sieving of other auxiliary materials.

1.1.3 tabletting situation

Table 49

Lot number

Piece weight

Punch die

Pressure

Hardness

Content

Uniformity A+1.8S≤15

20110501

120mg

φ7.0mm

d2.1

10.4kg

92.7%

23.8

1.1.4 dissolution rate

Table 50

Table 51

Table 52

Table 53

1.1.5 conclusion：

Dissolution rate does not meet tablet requirement, and direct tablet compressing technique is eliminated after being mixed again with auxiliary material after raw material grinding.

After the grinding of 1.2 roflumilasts, after being mixed with auxiliary material, then the experiment of wet granulation, tablet forming technique

1.2.1 prescription

Table 54

1.2.2 granulation

Povidone aqueous solution is prepared as adhesive, after ground 100 mesh sieve of roflumilast, then with the multiple mistake of remaining auxiliary material Sieve is uniformly mixed.Add 60 DEG C of adhesive wet granulation, sieving, baking oven dryings, after 20 mesh sieve whole grains with mix lubricant.

1.2.3 tabletting situation

Table 55

Lot number

Piece weight

Punch die

Pressure

Hardness

Content

Uniformity A+1.8S≤15

20110606

250mg

φ9.0mm

d2.0

8.3kg

88.7%

14

20110608

250mg

φ9.0mm

d2.0

10.2kg

101.9%

3.6

20110625

250mg

φ9.0mm

d2.0

7.1kg

81.4%

21.2

1.2.4 dissolution rate

Table 56

Table 57

1.2.5 conclusion：

Dissolution rate does not meet tablet quality requirement, and content and uniformity of dosage units are difficult to control, and auxiliary after roflumilast grinding After material mixing, then wet granulation, tablet forming technique are eliminated.

Wet granulation, tablet forming technique in auxiliary material are added after the dissolving of 1.3 roflumilasts

1.3.1 prescription

Table 58

1.3.2 granulation：

1 roflumilast solution is prepared：

Roflumilast 0.5g is weighed, adds acetone 20mL to dissolve, adds ethanol 20mL to dilute, adds water 3mL dilutions.

2 granulations：

Auxiliary material adds roflumilast solution wet granulation in high speed wet granulator under stirring, crosses 20 mesh sieves.

3 dryings：

The 50 DEG C of dryings of fluid bed of BWF-2 Multifunctional coating comminutors.Electrostatic is serious, and particle is all attached in pot wall, does not have Fluidized state is formed, can not be dried.

50 DEG C of dryings in baking oven are transferred to, electrostatic is serious, 20 mesh sieve whole grains.

4 mixing：Mix lubricant is added, still cannot eliminate electrostatic.

1.3.3 particle situation

Electrostatic is serious.Tabletting is difficult.

1.3.4 tabletting situation

Tabletting is difficult, and monolithic weighs tabletting

Table 59

Lot number

Piece weight

Punch die

Pressure

Hardness

Content

Uniformity A+1.8S≤15

20110701

261.6mg

φ9.0mm

d2.0

10.4kg

92.0%

10.1

20110702

260mg

φ9.0mm

d2.0

10.3kg

103.6%

5.2

20110703

260mg

φ9.0mm

d2.1

2.9kg

98.7%

5.5

1.3.5 dissolution rate

Table 60

Table 61

1.3.6 conclusion:

Wet granulation, tablet forming technique in auxiliary material are added after roflumilast dissolving, since particle electrification is serious, is moistened by increasing Lubrication prescription dosage, could not also improve electrostatic phenomenon, cause tabletting difficult, it is impossible to realize continuous tabletting, can not realize control sheet weight Difference, this technique are eliminated.

Mist projection granulating, tablet forming technique experiment after the dissolving of 1.4 roflumilasts

1.4.1 prescription

Table 62

1.4.2 granulation

1 roflumilast solution is prepared：

2 mist projection granulatings：

WBF-2 Multifunctional coating comminutors, west gate sub-operating system, peristaltic pump, fluidized bed spray granulation.

Table 63

Lot number

Compressor flow

Inlet air temperature

Temperature of charge

Wriggling revolution speed

Atomisation pressure

Drying time

20110731

35m³/h

65-85℃

36-40℃

3.0rpm

0.18MPa

60min

20110801

35m³/h

45-65℃

26-28℃

3.0rpm

0.18MPa

Granulation process

20110801

35m³/h

75-85℃

31-33℃

3.0rpm

0.18MPa

It is granulated last

20110801

35m³/h

75-85℃

33-49℃

---

60min

1.4.3 particle situation

Table 64

Test	20110731	20110801
			60 mesh of particle ＜	47.0%	38.2%
Bulk density	0.54g/mL	0.53g/mL
			Tap density	0.64g/mL	0.67g/mL
Angle of repose≤40 °	36°	35°

1.4.4 tabletting situation

Table 65

Lot number

Piece weight

Punch die

Pressure

Hardness

Content

Uniformity A+1.8S≤15

20110731

260mg

φ9.0mm

d2.1

10.4kg

94.8%

8.8

20110801

260mg

φ9.0mm

d2.0

10.02kg

97.8%

3.8

1.4.5 dissolution rate

Table 66

Table 67

Table 68

Table 69

1.4.6 stability

Table 70

Note：*40℃75%RH.

1.4.7 conclusion：

By controlling fluid bed compressor flow, inlet air temperature, temperature of charge, leaving air temp, spray gun atomizing pressure, peristaltic pump The technological parameter such as rotating speed or fluid flow, drying time realizes granulating process.Roflumilast solution is uniformly divided by mist projection granulating It is scattered in auxiliary material, realizes the requirement of the granule content uniformity；By controlling roflumilast liquor capacity, spray time, is reduced Significant loss, realizes granule content control；By controlling drying temperature, drying time to realize control pellet moisture and solvent Residual；By optimizing adjunct ingredient, proportioning, the species and dosage of adhesive realize the mobility and compressibility of particle.

Accordingly, it is determined that select mist projection granulating, tablet forming technique after roflumilast dissolving.

In addition, in order to ensure detection method science, reasonable, feasible, applicant carried out series of experimental research And investigation.

The preparation of reference substance：

The preparation of roflumilast reference substance：14g roflumilasts are added in 50mL ethyl acetate, are heated to flow back, then at Continue at a temperature of this after stirring 15min, room temperature（20~30 DEG C）Lower standing 5h crystallizations, filtering, cold ethyl acetate washing, 60~65 DEG C dry 2h, obtains roflumilast purified product 11.2g.

The preparation of impurity A reference substance：By the way that by roflumilast dissolving, heating obtains impurity A crude product in an acidic solution, then It is purified to impurity A reference substance, purity：98.4%, it is as follows that it reacts circuit：

The preparation of impurity B reference substance：Roflumilast starting material 3-（The third methoxyl group of ring）- 4- difluoro-methoxy-benzoic acids （Purity：99.6%）As impurity B reference substance.

The preparation of impurity C reference substances：Roflumilast impurity C reference substances, purity are obtained by process above route：98.2%, It is as follows that it reacts circuit：

The preparation of impurity D reference substances：Roflumilast impurity D reference substances, purity are obtained by following process route：97.5%, It is as follows that it reacts circuit：

The scaling method of reference substance purity is to use chromatographic condition of the roflumilast in relation to material detection method（Method number： HR001S01M04）, each impurity reference substance solution for preparing 0.5mg/mL is measured (normalization method) and has the miscellaneous of UV absorption Matter, then with identical organic matched UV detector is measured without buffer salt mobile phase, using evaporative light dispersion dispersion not Impurity (no UV absorption impurity) is detected, reference substance purity is obtained after deducting these impurity；The scaling method of content is in purity On the basis of, deduct residue on ignition, residual solvent and moisture and obtain.It the results are shown in Table 71.

Table 71

1. character

According to self-control 3 batches of sample properties, draft for：This preparation is Film coated tablets, and whitening color is to off-white color after removing coating.

2. differentiate

Through examining, the guarantor of this preparations. Control product (WS20110502) and sample (20110815,20110816,20110817) Stay time consistency.

3. check

3.1 in relation to material

The related material of roflumilast is checked using HPLC methods, because auxiliary material has a very big absorption at 215nm, known to interference The measure of impurity A, B, we have used 240-260nm absorption bands instead, select 254nm effectively to remove auxiliary material interference, but the wavelength Lower absorptivity is less than 215nm, we add sample size, and the results show can effectively analyze related impurities.To selected color Spectral condition has made respective party jurisprudential study, the results showed that, using the testing conditions of this standard can effectively realize roflumilast with The separation of known impurities A, B, C, D, and can separate and check what is produced through the destruction of the conditions such as acid, alkali, oxidation, high temperature, strong light Impurity, the separating degree of each impurity peaks and roflumilast peak meet the requirements；The related material detection sensitivity of Roflumilast tablet is high, can be full The requirement of sufficient Roflumilast tablet Related substances separation.The inspection result of continuous sample is shown in Table 72.

72 Roflumilast tablet Related substances separation result of table

Note：ND is not detect.

3.2 organic residual solvent

Since this preparation has used three classes solvent in preparation process：Ethanol and acetone, therefore mainly for both the above Solvent establishes organic solvent inspection method, because, containing a large amount of insoluble auxiliary materials, we establish headspace injection method in preparation, and Methodological study is carried out, selected chromatographic condition can realize the separation of etoh solvent and acetone to be measured in sample well, respectively treat Solvent detection sensitivity height is surveyed, is the proper method for checking Roflumilast tablet organic solvent residual.It can be seen according to measurement result Go out, acetone residue amount is seldom in test agent in continuous 3 batches of this preparation, and ethanol is also far below 5000ppm, with reference to the correlation of ICHQ3C The residual of guideline, ethanol and acetone must not exceed 5000ppm, we by the verification result according to actual preparation process, For the limit of tightened up restriction two kinds of solution, it is specified that ethanol must not exceed 5000ppm, acetone must not exceed 1000ppm.Continuously The organic residual solvent inspection result of sample is shown in Table 73.

73 organic solvent residual test result of table

Lot number	Ethanol	Acetone
			20110815	2510ppm	53ppm
20110816	1521ppm	29ppm
			20110817	1114ppm	17ppm

3.3 dissolution rate：

Show that roflumilast belongs to Biopharmaceutics Classification II according to documents and materials, while measure raw material in condition of different pH Under solubility after, screening different volumes dissolution medium cannot reach complete dissolution；Consider to add surfactant to increase Dissolution rate, adds in surface active agent tween-chromatograms after 80s that baseline fluctuation is larger, causes to be unable to Accurate Determining its dissolution Degree.Surfactant SDS is added, not interference measurement, then determined after being screened to various concentrations, containing 0.25% The 900mL dissolution mediums of lauryl sodium sulfate can meet sink conditions, and grind medicine using original and dissolution medium is confirmed After prove it is feasible.Confirm that 50 turns/min is more suitable after being screened to different rotating speeds.Roflumilast is measured using HPLC methods The dissolution rate of piece, through methodological study, selected leaching condition it is reproducible, precision is high, is suitable method.This preparation connects The dissolution determination result of test agent see the table below in three batches continuous.Provide the dissolution rate of this preparation in 30min according to result of study The 80.0% of labelled amount must not be less than.Dissolution determination the results are shown in Table 74.

74 dissolution determination result of table

3.4 uniformity of dosage units：

Every labelled amount of this preparation is 0.5mg, according to《Chinese Pharmacopoeia》2010 editions two Ⅹ E of annex requirements, measure content The uniformity.3 batches of uniformity of dosage units of this preparation pilot scale meet the requirements.

3.5 limit test of microbe

According to《Chinese Pharmacopoeia》2010 editions two Ⅺ J microbial decolorization inspections, should meet regulation.The pilot scale of this preparation Three batches check in accordance with the law, meet regulation.

4 assays

This preparation is using the content of HPLC methods measure Roflumilast tablet, and through methodological study, selected chromatographic condition can be realized The good separation of roflumilast main peak and known impurities peak and catabolite, precision is high, reproducible, is roflumilast content Measure suitable method.The assay of test agent the results are shown in Table 75 in continuous three batches of this preparation.This is provided according to result of study The content of preparation in labelled amount 90.0%~110.0%.

Table 75

Lot number	20110815	20110816	20110817
				Content（%）	97.4	96.3	97.5

Compared with prior art, the present invention improves the preparation process of roflumilast tablet, makes it to treatment The effect of diseases such as COPD, is more notable；Moreover, the present invention established for improved roflumilast tablet it is system, complete , effective quality determining method, the specificity of the method is strong, precision is high, favorable reproducibility, the rate of recovery are high, measurement result Accurately, achieveed the purpose that effective control drug quality, ensure that the stabilization of product quality and the safety of clinical application, Effectively.

Embodiment

With reference to embodiment, the present invention is further illustrated.

Embodiment 1：It is using 0.5mg roflumilasts as bulk pharmaceutical chemicals per tablet preparation, adds 100mg lactose, 80mg pregelatinateds form sediment Powder, 10mg PVP K30s and 0.5mg magnesium stearates, and using made of acetone, ethanol, purified water as solvent.By lactose, in advance Gelling starch crosses 60 mesh sieves, and adds in Multifunctional coating comminutor；By roflumilast and acetone, ethanol, purified water stirring It is even, PVP K30 is added, roflumilast solution is made；Using fluidized bed spray granulation equipment to roflumilast solution, breast Sugar, pregelatinized starch are pelletized, dry, whole grain；The magnesium stearate added after 100 mesh sieves is uniformly mixed；Tabletting, be coated it Afterwards up to roflumilast tablet.

Embodiment 2：It is using 0.5mg roflumilasts as bulk pharmaceutical chemicals per tablet preparation, adds 150mg lactose, 120mg pregelatinateds form sediment Powder, 30mg PVP K30s and 2.6mg magnesium stearates, and using made of acetone, ethanol, purified water as solvent.By lactose, in advance Gelling starch crosses 60 mesh sieves, and adds in Multifunctional coating comminutor；By roflumilast and acetone, ethanol, purified water stirring It is even, PVP K30 is added, roflumilast solution is made；Using fluidized bed spray granulation equipment to roflumilast solution, breast Sugar, pregelatinized starch are pelletized, dry, whole grain；The magnesium stearate added after 100 mesh sieves is uniformly mixed；Tabletting, be coated it Afterwards up to roflumilast tablet.Wherein, preparation technology parameter is：

（3）Whole grain technological parameter：Sieve 1.0mm, 700~1800rpm or 10~25Hz, first cross 20 mesh sieves, it is impossible to pass through Particle whole grain after cross 20 mesh sieves, above-mentioned all by the particles of 20 mesh sieves after 60 mesh sieves, percent of pass is 30%~70%；

（5）Tablet forming technique parameter：Theoretical piece weight 260mg/ pieces, upper punching circle φ 9.0mm, middle mould circle 9.0mm, undershoot circle Shape φ 9.0mm, diameter range are 9.0 ± 0.3mm, tableting pressure d1.8~2.0, piece 4.0 ± 0.5mm of thickness, tablet press machine rotating speed 20 ~30rpm, 40~110N of plain piece hardness；

（6）Coating process parameters：Inlet air temperature is 65~80 DEG C, and piece bed tempertaure is 35~42 DEG C, flow velocity 1.5mL/ Min, coating weight gain are 1.0%~2.0%.

Embodiment 3：It is using 0.5mg roflumilasts as bulk pharmaceutical chemicals per tablet preparation, adds 138.5mg lactose, 100mg pregelatinateds Starch, 20mg PVP K30s, 1mg magnesium stearates, and solvent is used as using 0.02mL acetone, 0.2mL ethanol, 0.13mL purified waters It is manufactured.Lactose, pregelatinized starch are crossed into 60 mesh sieves, and added in Multifunctional coating comminutor；By roflumilast and acetone, second Alcohol, purified water stir evenly, and add PVP K30, and roflumilast solution is made；Using fluidized bed spray granulation equipment to sieve Fluorine department spy's solution, lactose, pregelatinized starch are pelletized, dry, whole grain；It is equal to add the mixing of the magnesium stearate after 100 mesh sieves It is even；After tabletting, coating to obtain the final product.Wherein, specific preparation method is as follows：

2nd, the preparation of adhesive：

7th, mix：

7.3 add magnesium stearate mixing 10min；

7.4 granule contents are the 95.0~105.0% of labelled amount.

Embodiment 4：The complete detection method of Roflumilast tablet of the present invention is：

（Two）Assay：

Equipment：HPLC UV detector；

The preparation of reference substance solution：Precision weighs roflumilast reference substance 20mg, puts in 100mL volumetric flasks, adds 50% acetonitrile Dissolve and be diluted to scale, shake up, precision measures 5mL and puts in 100mL volumetric flasks, adds 50% acetonitrile to dissolve and is diluted to scale, shakes It is even, it is parallel to prepare 2 parts, as reference substance solution and control solution；

The preparation of sample solution：Take Roflumilast tablet finely ground in right amount, precision weighs the powder equivalent to roflumilast 0.5mg End, puts in the measuring bottle of 50mL, with 50% acetonitrile ultrasonic dissolution, then adds 50% dilution in acetonitrile, with membrane filtration, to take subsequent filtrate to scale For sample solution；

System suitability is tested：Advanced 5 pin of reference substance solution, then into control 1 pin of solution, chromatogram is recorded, with pair of 5 pins Average value according to product solution is reference substance, and it is sample that 1 pin, which controls solution, calculates the reference substance rate of recovery；

In formula：A₁For the peak area of roflumilast in sample solution,

A₂For the peak area of roflumilast in reference substance solution,

C is the correction factor of reference substance,

S, Sr is respectively the extension rate of sample and reference substance,

W₁For the sample weighting amount of reference substance, unit mg；

W₂For the sample weighting amount of sample, unit mg,

M be sample average piece weight, unit mg,

T be sample labelled amount, unit mg；

（Three）Check：

（1）Related material：

Instrument：HPLC UV detector；

The same reference substance solution of system suitability solution；

Calculate：Calculated by external standard method；

In formula：A Spl are corresponding impurity peak area in sample solution,

A Std are corresponding impurity peak area in reference substance solution,

Mg Spl are sample sample weighting amount,

Mg Std are known impurities sample weighting amount,

F is the correction factor of known impurities,

AveT is average piece weight,

P is labelled amount；

In formula：A Spl are corresponding impurity peak area in sample solution,

AStd is roflumilast peak area in reference substance solution,

Mg Spl are sample sample weighting amount,

Mg Std are roflumilast reference substance sample weighting amount,

F is roflumilast reference substance correction factor,

AveT is average piece weight,

P is labelled amount；

（2）Organic residual solvent：

Instrument：GC hydrogen ion flame detectors；

System suitability solution prepares same reference substance solution；

In formula：Aspl is organic solvent peak area in sample solution,

Astd is organic solvent peak area in reference substance solution,

Mg spl are sample sample weighting amount,

Mg std are organic solvent sample weighting amount；

（3）Dissolution rate：With reference to 2010 editions annex of Chinese Pharmacopoeia, Ⅹ the second methods of C, method number is HR001-F01-M03；

Instrument：HPLC UV detector, intelligent dissolution test system；

In formula：A is sample peak area；

S, Sr is respectively the extension rate of sample box reference substance；

W be sample labelled amount, unit mg；

Wr be reference substance the amount of taking, unit mg；

C is the content of reference substance；

Ar is the peak area of reference substance solution；

（Four）Differentiate：

Claims

A kind of 1. Roflumilast tablet, it is characterised in that：Be using 0.5mg roflumilasts as bulk pharmaceutical chemicals, add 100~150mg lactose, 80~120mg pregelatinized starch, 10~30mg PVP K30s and 0.5~1mg magnesium stearates, and with acetone, ethanol, purified water As made of solvent.
2. Roflumilast tablet according to claim 1, it is characterised in that：It is using 0.5mg roflumilasts as bulk pharmaceutical chemicals, adds 138.5mg lactose, 100mg pregelatinized starch, 20mg PVP K30s, 1mg magnesium stearates, and made with acetone, ethanol, purified water For made of solvent.
3. the preparation method of the Roflumilast tablet as any one of claim 1-2, it is characterised in that the preparation method Comprise the following steps：

S1, lactose, pregelatinized starch cross 60 mesh sieves, and add in Multifunctional coating comminutor；By roflumilast and acetone, second Alcohol, purified water stir evenly, and add PVP K30, and roflumilast solution is made；

S2, pelletizes roflumilast solution, lactose, pregelatinized starch using fluidized bed spray granulation equipment, dry, whole Grain；

S3, the magnesium stearate added after 100 mesh sieves are uniformly mixed；

S4, after tabletting, coating to obtain the final product；

Wherein, (1) granulating process parameter：35~120m of compressor flow³/ h, 6 ± 2rpm of wriggling revolution speed, atomizing pressure 0.2 ± 0.02MPa, 75 ± 10 DEG C of inlet air temperature, 45 ± 10 DEG C of temperature of charge；

(2) Drying Technology Parameter：35~120m of compressor flow³/ h, 75 ± 10 DEG C of inlet air temperature, 45 ± 10 DEG C of temperature of charge are dry 20~25min of time；

(3) whole grain technological parameter：Sieve 1.0mm, 700~1800rpm or 10~25Hz, first cross 20 mesh sieves, it is impossible to passed through 20 mesh sieves are crossed after grain whole grain, above-mentioned all by the particle of 20 mesh sieves after 60 mesh sieves, percent of pass is 30%~70%；

(4) hybrid technique parameter：Rotating speed 10rpm or 15Hz, after particle mixing 10min, add mix lubricant 10min；

(5) tablet forming technique parameter：Theoretical piece weight 260mg/ pieces, upper punching circle φ 9.0mm, middle mould circle 9.0mm, undershoot circle φ 9.0mm, diameter range are 9.0 ± 0.3mm, tableting pressure d1.8~2.0, piece 4.0 ± 0.5mm of thickness, tablet press machine rotating speed 20~ 30rpm, 40~110N of plain piece hardness；

(6) coating process parameters：Inlet air temperature is 65~80 DEG C, and piece bed tempertaure is 35~42 DEG C, flow velocity 1.5mL/min, bag Clothing weightening is 1.0%~2.0%.
4. the detection method of the Roflumilast tablet as any one of claim 1-2, it is characterised in that：The detection method Including character, discriminating, inspection and assay project；Wherein differentiate it is that the roflumilast in preparation is differentiated；Inspection is Related material, organic residual solvent, dissolution rate, uniformity of dosage units and microbial limit is carried out to this preparation respectively to check； Assay is that roflumilast content is measured using high performance liquid chromatography；Concrete content assay method is：

Equipment：HPLC UV detector；

Chromatographic condition：It is filler with octadecylsilane chemically bonded silica, with the 0.03mol/L of phosphorus acid for adjusting pH value to 3.0 Potassium dihydrogen phosphate：Acetonitrile=40：60 be mobile phase, and Detection wavelength 220nm, flow velocity 1mL/min, column temperature is 30 DEG C, Sample size is 20 μ L；

The preparation of reference substance solution：Precision weighs roflumilast reference substance 20mg, puts in 100mL volumetric flasks, adds 50% acetonitrile molten Solve and be diluted to scale, shake up, precision measures 5mL and puts in 100mL volumetric flasks, adds 50% acetonitrile to dissolve and is diluted to scale, shakes It is even, it is parallel to prepare 2 parts, as reference substance solution and control solution；

The preparation of sample solution：Take Roflumilast tablet finely ground in right amount, the powder that precision is weighed equivalent to roflumilast 0.5mg is put In the measuring bottle of 50mL, with 50% acetonitrile ultrasonic dissolution, then add 50% dilution in acetonitrile to scale, with membrane filtration, take the subsequent filtrate to be Sample solution；

System suitability is tested：Advanced 5 pin of reference substance solution, then into control 1 pin of solution, chromatogram is recorded, with the reference substance of 5 pins The average value of solution is reference substance, and it is sample that 1 pin, which controls solution, calculates the reference substance rate of recovery；

Acceptable standard：Number of theoretical plate is not less than 2000 based on roflumilast peak；The rate of recovery of two parts of reference substances 98.0%~ Between 102.0%；The relative deviation of 5 parts of roflumilast peak retention times is not more than 2.0%；Roflumilast peak and other impurities peak Separating degree should be greater than 1.5；

Experimentation：After system suitability qualification, each sample solution is parallel into 1 pin, chromatogram is recorded, by external standard method with peak face Product calculates；Calculation formula is as follows：

In formula：A₁For the peak area of roflumilast in sample solution,

A₂For the peak area of roflumilast in reference substance solution,

C is the correction factor of reference substance,

S, Sr is respectively the extension rate of sample and reference substance,

W₁For the sample weighting amount of reference substance, unit mg；

W₂For the sample weighting amount of sample, unit mg,

M be sample average piece weight, unit mg,

T be sample labelled amount, unit mg.
5. the detection method of Roflumilast tablet according to claim 4, it is characterised in that：Particular exam method is：

(1) related material：

Instrument：HPLC UV detector；

Chromatographic condition：Chromatographic column is AlltimaTM, C18,250 × 4.6mm, 5 μm, with the 0.02M KH of pH 3.5₂PO₄：CH₃CN =42：58 be mobile phase, and column temperature is 30 DEG C, Detection wavelength 254nm, flow velocity 1.0mL/min, and sampling volume is 20 μ L, fortune The row time is 30min, data acquisition 30min；

The preparation of reference substance solution：Precision weighs roflumilast working reference substance, roflumilast impurity reference substance A, impurity control Product B, each 5mg of impurity reference substance D, impurity reference substance C 2mg are dissolved with acetonitrile in same 100mL volumetric flasks and are diluted to quarter Degree, shakes up, and filters, obtains control stock solution；Draw 5.0mL and compare stock solution in 100mL volumetric flasks, dissolved and diluted with acetonitrile To scale, shake up, filter；

The same reference substance solution of system suitability solution；

The preparation of sample solution：30, this preparation is taken, claims gross weight, calculates average piece weight；Pulverize, weigh equivalent to roflumilast The appropriate powder of 5mg accurately adds acetonitrile 10.0mL with pipette in 25mL volumetric flasks, covers plug, ultrasonic 10min, no When shake, take out and stand, take upper liquid, 0.45 micrometer Millipore membrane filtration, discards primary filtrate 1mL, collects subsequent filtrate to obtain the final product, sample Product solution concentration is 0.5mg/mL；

Experimentation：After stablizing into sample solvent acetonitrile to system, sampling system applicability solution, makes gained peak area RSD not More than 5.0% 10 μ L of above contrast solution must be taken to inject liquid chromatograph, adjust detection sensitivity, make principal component chromatography peak height For the 20% of full scale, then 10 μ L of test solution are taken, inject liquid chromatograph；

Acceptable standard：Roflumilast peak tailing factor must not exceed 2.0；Roflumilast peak column effect is not less than 5000；Sieve fluorine department Special peak is not less than 1.5 with impurity C separating degrees；

Calculate：Calculated by external standard method；

(a) known impurities, calculated by peak area is compareed with known impurities：

<mrow> <mi>%</mi> <mo>=</mo> <mfrac> <mrow> <mi>A</mi> <mi> </mi> <mi>S</mi> <mi>p</mi> <mi>l</mi> </mrow> <mrow> <mi>A</mi> <mi> </mi> <mi>S</mi> <mi>t</mi> <mi>d</mi> </mrow> </mfrac> <mo>&times;</mo> <mfrac> <mrow> <mi>m</mi> <mi>g</mi> <mi> </mi> <mi>S</mi> <mi>t</mi> <mi>d</mi> <mo>&times;</mo> <mi>f</mi> </mrow> <mn>100</mn> </mfrac> <mo>&times;</mo> <mfrac> <mn>5</mn> <mn>100</mn> </mfrac> <mo>&times;</mo> <mfrac> <mn>10</mn> <mrow> <mi>m</mi> <mi>g</mi> <mi> </mi> <mi>S</mi> <mi>p</mi> <mi>l</mi> </mrow> </mfrac> <mo>&times;</mo> <mfrac> <mrow> <mi>A</mi> <mi>v</mi> <mi>e</mi> <mi>T</mi> </mrow> <mi>P</mi> </mfrac> <mo>&times;</mo> <mn>100</mn> <mo>,</mo> </mrow>

In formula：A Spl are corresponding impurity peak area in sample solution,

A Std are corresponding impurity peak area in reference substance solution,

Mg Spl are sample sample weighting amount,

Mg Std are known impurities sample weighting amount,

F is the correction factor of known impurities,

AveT is average piece weight,

P is labelled amount；

(b) unknown impuritie, is calculated with 0.50% roflumilast peak in reference substance solution：

<mrow> <mi>%</mi> <mo>=</mo> <mfrac> <mrow> <mi>A</mi> <mi> </mi> <mi>S</mi> <mi>p</mi> <mi>l</mi> </mrow> <mrow> <mi>A</mi> <mi> </mi> <mi>S</mi> <mi>t</mi> <mi>d</mi> </mrow> </mfrac> <mo>&times;</mo> <mfrac> <mrow> <mi>m</mi> <mi>g</mi> <mi> </mi> <mi>S</mi> <mi>t</mi> <mi>d</mi> <mo>&times;</mo> <mi>f</mi> </mrow> <mn>100</mn> </mfrac> <mo>&times;</mo> <mfrac> <mn>5</mn> <mn>100</mn> </mfrac> <mo>&times;</mo> <mfrac> <mn>10</mn> <mrow> <mi>m</mi> <mi>g</mi> <mi> </mi> <mi>S</mi> <mi>p</mi> <mi>l</mi> </mrow> </mfrac> <mo>&times;</mo> <mfrac> <mrow> <mi>A</mi> <mi>v</mi> <mi>e</mi> <mi>T</mi> </mrow> <mi>P</mi> </mfrac> <mo>&times;</mo> <mn>100</mn> <mo>,</mo> </mrow>

In formula：A Spl are corresponding impurity peak area in sample solution,

A Std are roflumilast peak area in reference substance solution,

Mg Spl are sample sample weighting amount,

Mg Std are roflumilast reference substance sample weighting amount,

F is roflumilast reference substance correction factor,

AveT is average piece weight,

P is labelled amount；

(2) organic residual solvent：

Instrument：GC hydrogen ion flame detectors；

Chromatographic condition：Agilent 6890N, HS-2 type head-space samplers, chromatographic column are Agilent DB-624 capillary chromatographies Column, carrier gas are nitrogen, flow velocity 5.0mL/min, and constant current injector temperature is 200 DEG C, and detector temperature is 250 DEG C of FID, column temperature For 40 DEG C of holding 7min, split ratio 3：1, sample size 1mL, head space temperature are 80 DEG C, and clack box temperature is 120 DEG C, pipeline temperature Spend for 120 DEG C, equilibration time 30min；

The preparation of reference substance solution：Precision weighs ethanol 100mg, and acetone 100mg is put in 100mL measuring bottles, and addition suitable quantity of water makes molten Solution, and constant volume puts scale, precision measures 10mL and puts in 100mL measuring bottles, and constant volume is diluted with water, then the accurate 5mL that measures puts 20mL tops In empty bottle, capping, as reference substance solution；

The preparation of sample solution：It is water-soluble to add 5mL into 20mL ml headspace bottles for precision weighing 500mg Roflumilast tablets powder sample Solution, seals to obtain the final product；

System suitability solution prepares same reference substance solution；

Experimentation：After stablizing into blank solution dimethyl sulfoxide to system, accurate measurement reference substance solution and test sample are molten respectively Each 1.0 μ L of liquid, inject gas chromatograph, record chromatogram；

Acceptable standard：Number of theoretical plate must not calculate less than 5000, and the separating degree between each residual solvent peak should be not less than 1.5, Main peak area RSD obtained by 5 pin working reference substance solution of continuous sample introduction must not exceed 5.0%；

Calculate：Calculate the content of each organic residual solvent in sample respectively with external standard method；Calculation formula is as follows：

<mrow> <mi>%</mi> <mo>=</mo> <mfrac> <mrow> <mi>A</mi> <mi>s</mi> <mi>p</mi> <mi>l</mi> <mo>&times;</mo> <mi>m</mi> <mi>g</mi> <mi> </mi> <mi>s</mi> <mi>t</mi> <mi>d</mi> <mo>&times;</mo> <mn>100</mn> </mrow> <mrow> <mi>A</mi> <mi>s</mi> <mi>t</mi> <mi>d</mi> <mo>&times;</mo> <mi>m</mi> <mi>g</mi> <mi> </mi> <mi>s</mi> <mi>p</mi> <mi>l</mi> <mo>&times;</mo> <mn>100</mn> <mo>&times;</mo> <mn>100</mn> </mrow> </mfrac> </mrow>

In formula：Aspl is organic solvent peak area in sample solution,

Astd is organic solvent peak area in reference substance solution,

Mg spl are sample sample weighting amount,

Mg std are organic solvent sample weighting amount；

(3) dissolution rate：Reference《Chinese Pharmacopoeia》2010 editions Ⅹ the second methods of C of annex, method number is HR001-F01-M03；

Instrument：HPLC UV detector, intelligent dissolution test system；

Chromatographic condition：It is filler with octadecylsilane chemically bonded silica；With with the 0.03mol/L of phosphorus acid for adjusting pH value to 3.0 Potassium dihydrogen phosphate-acetonitrile=40：60 be mobile phase；Detection wavelength is 220nm, and flow velocity 1mL/min, column temperature is 30 DEG C, Sample size is 50 μ L；

The preparation of reference substance solution：Precision weighs roflumilast reference substance 22mg, puts in 100mL volumetric flasks, adds dissolution medium molten Solve and be diluted to scale, shake up, precision measures 5mL and puts in 100mL volumetric flasks, adds dissolution medium to dissolve and is diluted to scale, shakes It is even, then it is accurate measure 5mL and put in 100mL measuring bottles be settled to scale with dissolution medium dilution, shake up, it is to obtain the final product, parallel to prepare 2 parts, As reference substance solution and control solution；

The preparation of sample solution：Operated by big agar diffusion method；Before measure, necessary debugging is carried out to apparatus, make blade bottom away from 25 ± 2mm of stripping rotor bottom, measures the 0.1M containing 0.25% lauryl sodium sulfate of the volume 900mL of degassed processing respectively HCl is put in each stripping rotor, and heating, treats that dissolution medium constant temperature at 37 DEG C ± 0.5 DEG C, after its is steady, takes 6, sample, Put into respectively in 6 stripping rotors, rotating speed is 50 revs/min, timing immediately；After 30min, the midpoint away from blade top and liquid level , not less than dissolution fluid 10mL is drawn at 10mm, immediately with membrane filtration, primary filtrate 3mL is discarded with away from stripping rotor inner wall, from sampling It should be completed to filtration in 30 seconds, it is sample solution to take subsequent filtrate；

System suitability：Advanced 5 pin of reference substance solution, then into control 1 pin of solution, chromatogram is recorded, with the reference substance of 5 pins The average value of solution is reference substance, and it is sample that 2 pins, which control solution, calculates the reference substance rate of recovery；

Acceptable standard：Roflumilast peak number of theoretical plate is not less than 2000 based on roflumilast peak；The rate of recovery of two parts of reference substances Between 98.0%~102.0%；The relative deviation of 5 parts of roflumilast peak retention times is not more than 2.0%；Roflumilast peak with The separating degree at other impurities peak should be greater than 1.5；

Experimentation：After system suitability qualification, each sample solution records chromatogram, by external standard method in terms of peak area into 1 pin Calculate, calculation formula is as follows：

In formula：A is sample peak area；

S, Sr is respectively the extension rate of sample box reference substance；

W be sample labelled amount, unit mg；

Wr be reference substance the amount of taking, unit mg；

C is the content of reference substance；

Ar is the peak area of reference substance solution；

(4) uniformity of dosage units：This preparation is taken, is put in 50mL volumetric flasks, with reference to the method under assay item, according to Chinese Pharmacopoeia 2010 editions two Ⅹ E of annex requirements, measure uniformity of dosage units；

(5) microbial limit：Take this preparation, reference《Chinese Pharmacopoeia》2010 editions Ⅺ J conventional methods of annex calculate.
6. the detection method of Roflumilast tablet according to claim 4 or 5, it is characterised in that to the specific of roflumilast Discrimination method is：In the chromatogram recorded under assay item, retention time and the reference substance solution master of sample solution main peak The retention time at peak is consistent.
7. the detection method of Roflumilast tablet according to claim 6, it is characterised in that the detection method includes：

(1) character：This preparation is Film coated tablets, and whitening color is to off-white color after removing coating；

(2) assay：

Equipment：HPLC UV detector；

Chromatographic condition：It is filler with octadecylsilane chemically bonded silica, with the 0.03mol/L of phosphorus acid for adjusting pH value to 3.0 Potassium dihydrogen phosphate：Acetonitrile=40：60 be mobile phase, and Detection wavelength 220nm, flow velocity 1mL/min, column temperature is 30 DEG C, Sample size is 20 μ L；

The preparation of reference substance solution：Precision weighs roflumilast reference substance 20mg, puts in 100mL volumetric flasks, adds 50% acetonitrile molten Solve and be diluted to scale, shake up, precision measures 5mL and puts in 100mL volumetric flasks, adds 50% acetonitrile to dissolve and is diluted to scale, shakes It is even, it is parallel to prepare 2 parts, as reference substance solution and control solution；

The preparation of sample solution：Take Roflumilast tablet finely ground in right amount, precision weighs the powder equivalent to roflumilast 0.5mg, puts In the measuring bottle of 50mL, with 50% acetonitrile ultrasonic dissolution, then add 50% dilution in acetonitrile to scale, with membrane filtration, take the subsequent filtrate to be Sample solution；

System suitability is tested：Advanced 5 pin of reference substance solution, then into control 1 pin of solution, chromatogram is recorded, with the reference substance of 5 pins The average value of solution is reference substance, and it is sample that 1 pin, which controls solution, calculates the reference substance rate of recovery；

Acceptable standard：Number of theoretical plate is not less than 2000 based on roflumilast peak；The rate of recovery of two parts of reference substances 98.0%~ Between 102.0%；The relative deviation of 5 parts of roflumilast peak retention times is not more than 2.0%；Roflumilast peak and other impurities peak Separating degree should be greater than 1.5；

Experimentation：After system suitability qualification, each sample solution is parallel into 1 pin, chromatogram is recorded, by external standard method with peak face Product calculates；Calculation formula is as follows：

In formula：A₁For the peak area of roflumilast in sample solution,

A₂For the peak area of roflumilast in reference substance solution,

C is the correction factor of reference substance,

S, Sr is respectively the extension rate of sample and reference substance,

W₁For the sample weighting amount of reference substance, unit mg,

W₂For the sample weighting amount of sample, unit mg,

M be sample average piece weight, unit mg,

T be sample labelled amount, unit mg；

(3) check：

(1) related material：

Instrument：HPLC UV detector；

Chromatographic condition：Chromatographic column is AlltimaTM, C18,250 × 4.6mm, 5 μm, with the 0.02M KH of pH 3.5₂PO₄：CH₃CN =42：58 be mobile phase, and column temperature is 30 DEG C, Detection wavelength 254nm, flow velocity 1.0mL/min, and sampling volume is 20 μ L, fortune The row time is 30min, data acquisition 30min；

The preparation of reference substance solution：Precision weighs roflumilast working reference substance, roflumilast impurity reference substance A, impurity control Product B, each 5mg of impurity reference substance D, impurity reference substance C 2mg are dissolved with acetonitrile in same 100mL volumetric flasks and are diluted to quarter Degree, shakes up, and filters, obtains control stock solution；Draw 5.0mL and compare stock solution in 100mL volumetric flasks, dissolved and diluted with acetonitrile To scale, shake up, filter；

The same reference substance solution of system suitability solution；

The preparation of sample solution：30, this preparation is taken, claims gross weight, calculates average piece weight；Pulverize, weigh equivalent to roflumilast The appropriate powder of 5mg accurately adds acetonitrile 10.0mL with pipette in 25mL volumetric flasks, covers plug, ultrasonic 10min, no When shake, take out and stand, take upper liquid, 0.45 micrometer Millipore membrane filtration, discards primary filtrate 1mL, collects subsequent filtrate to obtain the final product, sample Product solution concentration is 0.5mg/mL；

Experimentation：Into sample solvent acetonitrile, into system suitability solution, into 6 pin reference substance solutions, into sample solution, into right According to product solution；

Acceptable standard：Roflumilast peak tailing factor must not exceed 2.0；Roflumilast peak column effect is not less than 5000；Sieve fluorine department Special peak is not less than 1.5 with impurity C separating degrees；

Calculate：Calculated by external standard method；

(a) known impurities, calculated by peak area is compareed with known impurities：

<mrow> <mi>%</mi> <mo>=</mo> <mfrac> <mrow> <mi>A</mi> <mi> </mi> <mi>S</mi> <mi>p</mi> <mi>l</mi> </mrow> <mrow> <mi>A</mi> <mi> </mi> <mi>S</mi> <mi>t</mi> <mi>d</mi> </mrow> </mfrac> <mo>&times;</mo> <mfrac> <mrow> <mi>m</mi> <mi>g</mi> <mi> </mi> <mi>S</mi> <mi>t</mi> <mi>d</mi> <mo>&times;</mo> <mi>f</mi> </mrow> <mn>100</mn> </mfrac> <mo>&times;</mo> <mfrac> <mn>5</mn> <mn>100</mn> </mfrac> <mo>&times;</mo> <mfrac> <mn>10</mn> <mrow> <mi>m</mi> <mi>g</mi> <mi> </mi> <mi>S</mi> <mi>p</mi> <mi>l</mi> </mrow> </mfrac> <mo>&times;</mo> <mfrac> <mrow> <mi>A</mi> <mi>v</mi> <mi>e</mi> <mi>T</mi> </mrow> <mi>P</mi> </mfrac> <mo>&times;</mo> <mn>100</mn> <mo>,</mo> </mrow>

In formula：A Spl are corresponding impurity peak area in sample solution,

A Std are corresponding impurity peak area in reference substance solution,

Mg Spl are sample sample weighting amount,

Mg Std are known impurities sample weighting amount,

F is the correction factor of known impurities,

AveT is average piece weight,

P is labelled amount；

(b) unknown impuritie, is calculated with 0.50% roflumilast peak in reference substance solution：

<mrow> <mi>%</mi> <mo>=</mo> <mfrac> <mrow> <mi>A</mi> <mi> </mi> <mi>S</mi> <mi>p</mi> <mi>l</mi> </mrow> <mrow> <mi>A</mi> <mi> </mi> <mi>S</mi> <mi>t</mi> <mi>d</mi> </mrow> </mfrac> <mo>&times;</mo> <mfrac> <mrow> <mi>m</mi> <mi>g</mi> <mi> </mi> <mi>S</mi> <mi>t</mi> <mi>d</mi> <mo>&times;</mo> <mi>f</mi> </mrow> <mn>100</mn> </mfrac> <mo>&times;</mo> <mfrac> <mn>5</mn> <mn>100</mn> </mfrac> <mo>&times;</mo> <mfrac> <mn>10</mn> <mrow> <mi>m</mi> <mi>g</mi> <mi> </mi> <mi>S</mi> <mi>p</mi> <mi>l</mi> </mrow> </mfrac> <mo>&times;</mo> <mfrac> <mrow> <mi>A</mi> <mi>v</mi> <mi>e</mi> <mi>T</mi> </mrow> <mi>P</mi> </mfrac> <mo>&times;</mo> <mn>100</mn> <mo>,</mo> </mrow>

In formula：A Spl are corresponding impurity peak area in sample solution,

A Std are roflumilast peak area in reference substance solution,

Mg Spl are sample sample weighting amount,

Mg Std are roflumilast reference substance sample weighting amount,

F is roflumilast reference substance correction factor,

AveT is average piece weight,

P is labelled amount；

(2) organic residual solvent：

Instrument：GC hydrogen ion flame detectors；

Chromatographic condition：Agilent 6890N, HS-2 type head-space samplers, chromatographic column are Agilent DB-624 capillary chromatographies Column, carrier gas are nitrogen, flow velocity 5.0mL/min, and constant current injector temperature is 200 DEG C, and detector temperature is 250 DEG C of FID, column temperature For 40 DEG C of holding 7min, split ratio 3：1, sample size 1mL, head space temperature are 80 DEG C, and clack box temperature is 120 DEG C, pipeline temperature Spend for 120 DEG C, equilibration time 30min；

The preparation of reference substance solution：Precision weighs ethanol 100mg, and acetone 100mg is put in 100mL measuring bottles, and addition suitable quantity of water makes molten Solution, and constant volume puts scale, precision measures 10mL and puts in 100mL measuring bottles, and constant volume is diluted with water, then the accurate 5mL that measures puts 20mL tops In empty bottle, capping, as reference substance solution；

The preparation of sample solution：It is water-soluble to add 5mL into 20mL ml headspace bottles for precision weighing 500mg Roflumilast tablets powder sample Solution, seals to obtain the final product；

System suitability solution prepares same reference substance solution；

Experimentation：After stablizing into blank solution dimethyl sulfoxide to system, accurate measurement reference substance solution and test sample are molten respectively Each 1.0 μ L of liquid, inject gas chromatograph, record chromatogram；

Acceptable standard：Number of theoretical plate must not calculate less than 5000, and the separating degree between each residual solvent peak should be not less than 1.5, Main peak area RSD obtained by 5 pin working reference substance solution of continuous sample introduction must not exceed 5.0%；

Calculate：Calculate the content of each organic residual solvent in sample respectively with external standard method；Calculation formula is as follows：

<mrow> <mi>%</mi> <mo>=</mo> <mfrac> <mrow> <mi>A</mi> <mi>s</mi> <mi>p</mi> <mi>l</mi> <mo>&times;</mo> <mi>m</mi> <mi>g</mi> <mi> </mi> <mi>s</mi> <mi>t</mi> <mi>d</mi> <mo>&times;</mo> <mn>100</mn> </mrow> <mrow> <mi>A</mi> <mi>s</mi> <mi>t</mi> <mi>d</mi> <mo>&times;</mo> <mi>m</mi> <mi>g</mi> <mi> </mi> <mi>s</mi> <mi>p</mi> <mi>l</mi> <mo>&times;</mo> <mn>100</mn> <mo>&times;</mo> <mn>100</mn> </mrow> </mfrac> </mrow>

In formula：Aspl is organic solvent peak area in sample solution,

Astd is organic solvent peak area in reference substance solution,

Mg spl are sample sample weighting amount,

Mg std are organic solvent sample weighting amount；

(3) dissolution rate：Reference《Chinese Pharmacopoeia》2010 editions Ⅹ the second methods of C of annex, method number is HR001-F01-M03；

Instrument：HPLC UV detector, intelligent dissolution test system；

Chromatographic condition：It is filler with octadecylsilane chemically bonded silica；With with the 0.03mol/L of phosphorus acid for adjusting pH value to 3.0 Potassium dihydrogen phosphate-acetonitrile=40：60 be mobile phase；Detection wavelength is 220nm, and flow velocity 1mL/min, column temperature is 30 DEG C, Sample size is 50 μ L；

The preparation of reference substance solution：Precision weighs roflumilast reference substance 22mg, puts in 100mL volumetric flasks, adds dissolution medium molten Solve and be diluted to scale, shake up, precision measures 5mL and puts in 100mL volumetric flasks, adds dissolution medium to dissolve and is diluted to scale, shakes It is even, then it is accurate measure 5mL and put in 100mL measuring bottles be settled to scale with dissolution medium dilution, shake up, it is to obtain the final product, parallel to prepare 2 parts, As reference substance solution and control solution；

The preparation of sample solution：Operated by big agar diffusion method；Before measure, necessary debugging is carried out to apparatus, make blade bottom away from 25 ± 2mm of stripping rotor bottom, measures the 0.1M containing 0.25% lauryl sodium sulfate of the volume 900mL of degassed processing respectively HCl is put in each stripping rotor, and heating, treats that dissolution medium constant temperature at 37 DEG C ± 0.5 DEG C, after its is steady, takes 6, sample, Put into respectively in 6 stripping rotors, rotating speed is 50 turns/min, timing immediately；After 30min, the midpoint away from blade top and liquid level , not less than dissolution fluid 10mL is drawn at 10mm, immediately with membrane filtration, primary filtrate 3mL is discarded with away from stripping rotor inner wall, from sampling It should be completed to filtration in 30 seconds, it is sample solution to take subsequent filtrate；

System suitability：After stablizing into sample solvent acetonitrile to system, sampling system applicability solution, makes gained peak area RSD must not exceed 5.0%, take 10 μ L of above contrast solution to inject liquid chromatograph, adjusts detection sensitivity, makes principal component chromatography Peak height is the 20% of full scale, then takes 10 μ L of test solution, injects liquid chromatograph；

Acceptable standard：Roflumilast peak number of theoretical plate is not less than 2000 based on roflumilast peak；The rate of recovery of two parts of reference substances Between 98.0%~102.0%；The relative deviation of 5 parts of roflumilast peak retention times is not more than 2.0%；Roflumilast peak with The separating degree at other impurities peak should be greater than 1.5；

Experimentation：After system suitability qualification, each sample solution records chromatogram, by external standard method in terms of peak area into 1 pin Calculate, calculation formula is as follows：

In formula：A is sample peak area；

S, Sr is respectively the extension rate of sample box reference substance；

W be sample labelled amount, unit mg；

Wr be reference substance the amount of taking, unit mg；

C is the content of reference substance；

Ar is the peak area of reference substance solution；

(4) uniformity of dosage units：This preparation is taken, is put in 50mL volumetric flasks, with reference to the method under assay item, according to Chinese Pharmacopoeia 2010 editions two Ⅹ E of annex requirements, measure uniformity of dosage units；

(5) microbial limit：Take this preparation, reference《Chinese Pharmacopoeia》2010 editions Ⅺ J conventional methods of annex calculate；

(4) differentiate：

In the chromatogram recorded under assay item, the retention time of sample solution main peak and the reservation of reference substance solution main peak Time consistency.