febuxostat-40-mg-tablets-mechanism-of-action
Febuxostat is a medication used to manage and treat hyperuricemia and gout. It is in a class of drugs known as xanthine oxidase inhibitors. Due to an increased risk of cardiovascular mortality with febuxostat versus allopurinol, the FDA recently recommended limiting the use of febuxostat to patients for whom allopurinol is not efficacious or who experience severe adverse effects with allopurinol.
Mechanism of Action
Febuxostat is a non-purine selective inhibitor of the enzyme xanthine oxidase, which is involved in purine catabolism. The xanthine oxidase enzyme catalyzes two reactions that ultimately generate uric acid from hypoxanthine. Febuxostat is a potent, selective inhibitor of xanthine oxidase, forming a stable complex with both the reduced and oxidized form of the enzyme, thereby inhibiting its function. Treatment with febuxostat leads to lower serum uric acid levels in animals and humans. The therapeutic effect of febuxostat has as its basis the ability to lower serum uric acid levels in patients with hyperuricemia, defined by the uric acid serum concentration that exceeds the solubility of uric acid (approximately 7 mg/dL).The chemical structure of febuxostat does not resemble either purines or pyrimidine structures, and it does not appear to inhibit other enzymes in the nucleotide catabolic pathways.
Pharmacokinetics
- Absorption: Febuxostat is rapidly absorbed with peak plasma concentrations (Cmax) attained after 1 to 1.5 hours of oral administration. Approximately 49% of the orally administered dose of febuxostat is absorbed orally.
- Distribution: The steady-state volume of distribution of febuxostat is approximately 50 litters. Febuxostat has high plasma protein binding (PPB) and binds primarily to albumin. The PPB of febuxostat is approximately 99%.
- Metabolism: Febuxostat is extensively metabolized by conjugation via UGT (uridine diphosphate glucuronosyltransferase) enzymes, including UGT1A1, UGT1A3, UGT1A9, and UGT2B7. Febuxostat is metabolized by CYPs1A2, CYP2C8, CYP2C9, and non-CYP enzymes. Febuxostat also inhibits breast cancer resistance protein (BCRP) activity.
- Elimination: The apparent mean elimination half-life (t1/2) of febuxostat is approximately 5 to 8 hours. Metabolites of febuxostat are eliminated by both hepatic and renal routes. The percentage of febuxostat excreted unchanged in the urine is less than 5%.
Administration
Oral Administration
Take without regard to food or antacid use
Storage
Protect from light
Store at 25°C excursions permitted to 15-30°C
Reference: National Library of Medicine (https://www.ncbi.nlm.nih.gov/books/NBK544239/)
TABLE OF CONTENTS
| S.NO. | TITLE | Page No. | |
| 1.0 | PRODUCT DETAILS | ||
| 2.0 | MANUFACTURING FORMULA | ||
| 3.0 | LIST OF EQUIPMENTS | ||
| 4.0 | GENERAL PRECAUTIONS | ||
| 5.0 | MANUFACTURING INSTRUCTIONS | ||
| 6.0
|
MANUFACTURING PROCESS DETAILS | ||
| 6.1 | GRANULATION | ||
| 6.2 | COMPRESSION | ||
| 6.3 | COATING | ||
| 6.4 | BRAND DETAILS | ||
1.0 PRODUCT DETAILS OF Febuxostat 40:
| Product Name | Febuxostat Tablets |
| Product Description | White, round shape, biconvex, film coated tablet having both side plain. |
| Strength | Febuxostat 40 mg |
| Label claim
|
Each film coated tablet contains:
Febuxostat – 40 mg |
| Batch Size | 1,00,000 Tablets |
| Average Weight | 110 mg (Uncoated tablet)
112.2 mg (Film coated tablet) |
| Shelf Life | 24 months |
| Storage | Store in a cool, dry and dark place below 250C. |
| Drug Category | Xanthine Oxidase Inhibitors |
2.0 MANUFACTURING FORMULA OF Febuxostat 40:
| Material Name | Grade | Category | Quantity per Unit (In mg) | Overages | Batch Qty.
(In kg) |
| Dry Mixing | |||||
| Febuxostat | NA | API | 40 .0mg | 1 % | 4.040 kg |
| Starch | IP | Diluent | 20.0 mg | —- | 2.000 kg |
| MCCP PH-102 | IP | Diluent | 34.5 mg | —- | 3.450 kg |
| Binder | |||||
| PVPK-30 | IP | Binder | 2.0 mg | —- | 0.200 kg |
| Isopropyl Alcohol | IP | Solvent | 0.09 ml | —- | 9.000 liter |
| Lubricant | |||||
| Talcum | IP | Anti-caking agent | 3.0 mg | —- | 0.300 kg |
| Sodium Starch Glycolate | IP | Disintegrants | 9.0 mg | —- | 0.900 kg |
| Magnesium Stearate | IP | Anti- adherent | 1.1 mg | —- | 0.110 kg |
3.0 LIST OF EQUIPMENTS FOR Febuxostat 40:
| Sr. No. | Machineries/Equipments | Capacity | Equipment ID. |
| 1. | Weighing Balance | 100 kg | |
| 2. | Vibro Sifter (with SS Sieves No’s 20, 30, 40,60 and 100) | 30 inch dia | |
| 3. | Portable Stirrer | — | |
| 4. | Tray Dryer | 48 Trays | |
| 5. | Double Cone Blender | 65 liter | |
| 6. | Halogen Moisture Balance | — | |
| 7. | Compression Machine | 35 Station | |
| 8. | SS Containers | 10 liter,20 liter | — |
| 9. | Poly-lined HDPE Containers with lid | 30 liter (03 No’s) | — |
| 10. | Polybag | 1.0 kg ,2.0 kg | |
| 11. | Filter Cloth 100# | 0.5 Meter |
4.0 GENERAL PRECAUTIONS:
- API Description: A white or almost white powder.
- All the Manufacturing Activities shall be performed under controlled conditions (temperature NMT 25 0C and relative humidity NMT 60%).
- When working with Active Ingredients and drug product or mixture of Active Ingredients and Excipients, wear gloves and mask to avoid exposure and contact with any body parts.
- MANUFACTURING INSTRUCTIONS:
- All activities shall be performed as per current SOPs.
- Take the line clearance of every machine from QA before starting the manufacturing operation during batch to batch and product to product change over.
- Do not overwrite the entry. In case of mistake, cancel the entry by single line with sign & date and make correct entry.
- MANUFACTURING PROCESS DETAILS FOR Febuxostat 40:
6.1 GRANULATION:
STEP – I (SIFTING) For Febuxostat 40:
- Check Sieve Integrity (before sifting and after sifting).
- Set the Vibro Sifter (capacity: 30 inch dia) and sieve the Dispensed Materials as per Sieve Sizes mentioned below:
| Material Name | Std. Qty. (kg) | Sieve No. | |
| Dry Mixing | |||
| Febuxostat | 4.040 kg | 30 # | |
| Starch IP | 2.000 kg | 100 # | |
| MCCP PH-102 IP | 3.450 kg | 40 # | |
| Binder | |||
| PVPK-30 IP | 0.200 kg | 20 # | |
| Isopropyl Alcohol IP (IPA) | 9.000 liter | — | |
| Lubricant | |||
| Talcum IP | 0.300 kg | 60 # | |
| Sodium Starch Glycolate IP | 0.900 kg | 60 # | |
| Magnesium Stearate IP | 0.110 kg | 30 # | |
- Collect sifted Febuxostat (4.040 kg), Starch IP (2.000 kg) and MCCP PH-102 IP (3.450 kg) in Polybag (capacity: 10 kg)
- Collect sifted Talcum IP (0.300 kg) and Sodium Starch Glycolate IP (0.900 kg) in Polybag (capacity: 2.0 kg)
- Collect sifted Magnesium Stearate IP (0.110 kg) in Polybag (capacity: 1.0 kg).
STEP – II – (BINDER PREPARATION) For Febuxostat 40:
Take Isopropyl Alcohol IP (9.000 liter) in SS Container (capacity: 10 liter) and add PVPK-30 IP (0.200 kg) in it. Mix together with Portable Stirrer continuously stirring till dissolved properly in IPA.
Mixing Time: 10 minutes (To be validated in next batch).
Filter the solution with filter cloth 100 # in SS Container (capacity: 10 liter).
STEP – III (DRY MIXING) For Febuxostat 40:
Transfer the sifted Febuxostat, Starch IP and MCCP PH-102 IP in SS Container (capacity: 20 liter) and dry mix the materials manually till uniform mixing.
Mixing Time: 15 minutes (manually) (To be validated in next batch).
STEP –IV (BINDING OF DRY MIX MATERIAL) For Febuxostat 40:
Slowly add the binder of Step-II in dry mix material of Step-III for 10 minutes till uniform binding and after binding collect the wet mass in four Trays (capacity: 3.00 kg each).
Mixing Time: 15 minutes (manually) (To be validated in next batch).
STEP –V– (DRYING) For Febuxostat 40:
Dry the wet material of Step-IV as follows:
Load these four trays in Tray Dryer.
First air dry the granules for 30 minutes in Tray Dryer. Ensure that Heaters are in OFF mode during air drying. After 30 minutes of air drying, Switch ON the heaters and set the temperature at 35°C and dry the granules, until the LOD of granules is achieved between 1 % at 105°C checking by Halogen Moisture Balance.
Air Drying Time: 30 minutes (Heaters should be OFF).
Drying Time: 02 hours (To be validated in next batch).
Drying Temperature: 30°C to 35°C.
Raking Frequency: After every 15 minutes.
STEP-VI- (SIZING/MILLING) For Febuxostat 40:
Check Sieve Integrity (before sifting and after sifting).
Set the Vibro Sifter and fix the sieve 40 # and sieve the dried material of Step-V. Collect the sized material in one Poly-lined HDPE Container (capacity: 30 liter).
STEP – VII (PRE –LUBRICATION) For Febuxostat 40:
Load the sized granules of Step-VI in Double Cone Blender (capacity : 65 liter) and add sifted Talcum IP, Sodium Starch Glycolate and mix properly till uniform mixing of sized material with Pre-Lubricating Materials.
Mixing Time: 30 minutes (15 minutes clockwise direction and 15 minutes anti-clockwise direction).
Mixing Speed: 10 RPM.
STEP – VIII (LUBRICATION) For Febuxostat 40:
Add the sifted Magnesium Stearate IP in Pre-Lubricated Material of Step-VII in Double Cone Blender and mix properly till uniform mixing of materials with Magnesium Stearate IP.
Mixing Time: 05 minutes.
Mixing Speed: 10 RPM.
STEP- X (BLEND SAMPLE ANALYSIS) For Febuxostat 40:
- After completion of lubrication, collect the composite blend sample (Qty. 10 gm) and send to QC for analysis according to the table below:
| Test | Specification |
| Appearance of blend
Blend Uniformity Blend Assay LOD Uniformity of content Bulk Density Tapped Density Compressibility Index Hausner Ratio |
White free flowing granular powder
90 % to 110 % 98 % to 103 % 1 % 85 % to 115 % To be established in next batch To be established in next batch To be established in next batch To be established in next batch |
STEP – XI For Febuxostat 40:
- Take Tare Weight of one Poly-lined HDPE Containers (capacity: 30 liter each), record the Tare Weight in BMR and unload the above blended material from Double Cone Blender in Poly-lined HDPE Containers (capacity: 30 liter each) and weigh the material with containers and record the Gross Weight of the material and calculate the Net Weight of the material as per given formula:
Net Weight = Gross Weight – Tare weight
- Affix the status label with following details – Product Name, Batch No., Batch Size, Mfg. Date, Exp. Date, Tare Weight, Gross Weight and Net Weight on the Poly-lined HDPE Containers.
- Batch Yield of Lubricated granules:
Theoretical Batch Yield: 11.000 kg (100 %)
Actual Batch Yield Limit NLT 10.890 kg (NLT 99 %) (To be established in next batch).
STEP – XII For Febuxostat 40:
- Clean all equipments used in the granulation as per respective equipment cleaning SOP.
6.2 COMPRESSION For Febuxostat 40:
STEP – I For Febuxostat 40:
- After receiving of QC approval for the blend, verify the Net Weight of the received blend as per status label in Granules Day Store.
- After confirmation continue the compression with 35 stations (B-Tooling) Compression Machine. Compress the blend as per the following parameters and In Process checks under controlled environmental condition.
| S.No | Parameters | Standard | No. of Tablets | In-Process Frequency |
| 1. | Feed frame alignment and adjustment | Should be satisfactory | —– | —– |
| 2. | Lower Weight Assembly | Should be satisfactory | —– | —– |
| 3. | Hydraulic Pressure | 5-6 Tones | —– | —– |
| 4. | Machine Speed | 18 RPM to 20 RPM | —– | —– |
| 6. | Upper Punch Size | 6.5 mm | —– | —– |
| 7. | Lower Punch Size | 6.5 mm | —– | —– |
| 8. | Diameter of the tablet | 6.5 mm | 6/Individual | 2 hours |
| 9. | Thickness of Tablets | 6.5 mm | 6/Individual | 2 hours |
| 10. | Weight of 20 Tablets | 2.200 gm. ± 2% | 20/Composite | 30 minutes |
| 11. | Product Description | White, round shape, biconvex, uncoated tablet having both side plain. | 20/Composite | 30 minutes |
| 12. | Uniformity of Weight | NMT 02 tablets out of 20 deviate from the standard average weight by more than 3 % and no single tablet deviates from the standard average weight by more than 5 % | 20/Composite | 01 hour |
| 13. | Standard Average Weight of Tablets | 110 mg ± 2 % | 20/Individual | 30 minutes |
| 14. | Hardness | NLT 3 kg/cm2 | 6/Individual | 30 minutes |
| 15. | Disintegration Time | NMT 15 min | 6/Composite | 01 hour |
| 16. | Friability | NMT 1% | 20/Composite | 01 hour |
- Collect the compressed tablets in SS Container (capacity: 20 liter each on both sides), when SS containers are filled with tablets, transfer the tablets in one Poly-lined HDPE Containers as given below in Step-III.
STEP – II For Febuxostat 40:
- Send the composite sample of compressed tablets (Qty. 30 tablets) to QC department for analysis.
STEP – III For Febuxostat 40:
- Take Tare Weight of one Poly-lined HDPE Containers (capacity: 30 liter each), record the Tare Weight in BMR and transfer the compressed tablets in Poly-lined HDPE Containers (capacity: 30 liter each) and weigh the compressed tablets with containers and record the Gross Weight of the compressed tablets and calculate the Net Weight of the material as per given formula:
Net Weight = Gross Weight – Tare weight
- Affix the status label with following details – Product Name, Batch No., Batch Size, Avg. Weight, Mfg. Date, Exp. Date, Tare Weight, Gross Weight and Net Weight on the Poly-lined HDPE Container.
- Batch Yield of Compressed Tablets:
Theoretical Batch Yield: 11.000 kg (100 %)
Actual Batch Yield Limit NLT 10.890 kg (NLT 99 %) (To be established in next batch)
STEP – IV For Febuxostat 40:
- After completion of compression of the tablets clean the Compression Machine as per cleaning SOP.
6.3 COATING For Febuxostat 40:
- Verify the Net Weight of the received compressed tablets for coating as per status label and after confirmation continue for tablet coating.
STEP – I (COATING MATERIALS DETAILS) For Febuxostat 40:
| Sr. No. | Material Name | Batch Quantity |
| 1. | HPMC E-15 IP | 0.200 kg. |
| 2. | Ethyl Cellulose IP | 0.009 kg |
| 3. | Titanium Dioxide IP | 0.011 kg |
| 4. | Isopropyl Alcohol (IPA) IP | 1.170 liter |
| 5. | Dichloromethane ( MDC) USP | 3.190 liter |
STEP-II (LIST OF EQUIPMENTS FOR COATING) For Febuxostat 40:
| Sr. No. | Machineries/Equipments | Capacity | Equipment ID. |
| 1. | Coating Pan | 24″ | |
| 2. | Spray Gun | 01 | — |
| 3. | Filter Cloth 100 # | 0.5 Meter | — |
| 4. | Portable Stirrer | — | — |
| 5. | SS Container | 10 liter (02 No’s) | — |
| 6. | Poly-lined HDPE Container with lid | 30 liter (01 No.) | — |
STEP – III (PREPARATION OF COATING SOLUTION) For Febuxostat 40:
- Mix HPMC E-15 IP (0.220 kg) and Ethyl Cellulose IP (0.009 kg) in Polybag (capacity: 1.00 kg) and mix properly for 5 minutes till uniform mixing.
- Take Isopropyl Alcohol IP (1.170 kg) in SS Container (capacity: 10 liter) and add the mixture of Step-III (a) in IPA, mix together by Portable Stirrer continuously stirring properly till uniform mixing achieved.
- After that slowly add Dichloromethane USP (3.190 liter) in Step- III (b) with continuously stirring for 10 minutes.
- After uniform mixing add color Titanium Dioxide IP (0.011kg) in Step-III(c) solution and mix for 05 minutes with stirrer till uniform mixing achieved.
Speed of Stirrer: Constant
Mixing Time: 30 minutes (To be validated in next batch).
- Filter the coating solution with Filter Cloth 100 # in SS Container (capacity: 10 liter)
- Keep the solution for 15 minutes to let it the foam settle down. Thereafter proceed with coating process.
STEP – IV (COATING PROCEDURE) For Febuxostat 40:
- Coating will be done in one lot, take total compressed tablets for coating (11.000 kg)
- Load the tablets in coating pan (Capacity: 24″), start the hot air blower, set the supply air temperature at 70°C to 75°C and start the exhaust fan & warm the tablets bed 40°C to 45°C.
- After warming up the tablets, take weight of 100 warmed tablets and record the weight in BMR for calculation of weight buildup of tablets after coating.
- Set the coating parameter as given in below table and start the coating process by starting coating spray through gun.
| Parameter | Specification |
| No. of Baffles in coating pan | 03 |
| No. of Guns | 01 |
| Inlet Temperature | 70°C to 75°C (To be validated in next batch) |
| Peristaltic Pump Speed | 2 – 4 RPM (To be validated in next batch) |
| Atomization | 2.5 to 3.0 kg/cm2 |
| Gun to Tablet Bed Distance | 10 inch |
| BED Temperature | 400C to 45 0C (To be validated in next batch) |
| Pan RPM | 13 to 15 RPM |
| % Weight Gain
(Upto 1.5 to 2.0 %) |
Weight of Film Coated Tablets – Weight of uncoated warmed Tablets x 100 / Weight of Film Coated Tablets |
| Coating Time | 02 Hour (To be validated in next batch) |
- After completion of Film Coating, take weight of 100 film coated tablets and record the weight in BMR and calculate the weight gain by using Weight Gain Formula given in above table of Step-IV.
STEP – V (COATING IN-PROCESS CHECK PARAMETERS) For Febuxostat 40:
| Sr. No. | Parameters | Standard | No. of Tablets | In-Process Frequency |
| 1 | Product Description | White, round shape, biconvex film coated tablet having both side plain | 20 No. |
After batch completion |
| 2 | Weight of 20 Tablets after coating | 2.244 gm. (Weight gain 1.5 to 2 % ) | 20 No. | |
| 3 | Average Weight after coating | 112.2 mg (Weight gain 1.5 to 2 % ) | 20 No. | |
| 4 | Individual Tablets Weight Variation | NMT 02 tablets out of 20 deviate from the standard average weight by more than 3 % and no single tablet deviates from the standard average weight by more than 5 % | 20 No. | |
| 5 | Thickness | 2.72 mm ± 0.2 mm | 6 No. | |
| 6 | Disintegration | NMT 30 min. | 6 No. |
STEP – VI For Febuxostat 40:
- Send the composite sample of coated tablets (Qty. 30 tablets) to QC department for analysis.
STEP – VII For Febuxostat 40:
- Take Tare Weight of one Poly-lined HDPE Containers (capacity: 30 liter each), record the Tare Weight in BMR and transfer the coated tablets in Poly-lined HDPE Containers (capacity: 30 liter each) and weigh the coated tablets with containers and record the Gross Weight of the coated tablets and calculate the Net Weight of the material as per given formula:
Net Weight = Gross Weight – Tare weight
- Affix the status label with following details – Product Name, Batch No., Batch Size, Avg. Weight, Mfg. Date, Exp. Date, Tare Weight, Gross Weight and Net Weight on the Poly-lined HDPE Containers.
- Batch Yield of Coated Tablets:
Theoretical Batch Yield: 11.220 kg (100 %)
Actual Batch Yield Limit NLT 11.107 kg (NLT 99 %) (To be established in next batch).
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