Levocetirizine 5 mg Tablets IP
Levocetirizine Tablet belongs to a group of medicines called antihistamines. It is used to treat various allergic conditions such as hay fever, conjunctivitis, some skin reactions such as eczema, hives, and reactions to bites and stings. It also relieves watery eyes, runny nose, sneezing, and itching.
Levocetirizine tablets can be taken with or without food. The dose required by you may vary depending on what you are taking it for. Levocetirizine is usually taken in the evening, but follow the advice of your doctor on how to take it. You may need Levocetirizine tablet only on days you have symptoms, but if you are taking it to prevent the symptoms then you should take it regularly. If you miss doses or stop taking them earlier than advised, your symptoms may come back.
Levocetirizine is generally very safe. The most common side effects include feeling sleepy or dizzy, dry mouth, fatigue, and headache. These are usually mild and go away after a couple of days as your body adjusts to it. Consult your doctor if any of the side effects persist or worry you.
Levocetirizine is an antihistamine used to relieve allergy symptoms such as watery eyes, runny nose, itching eyes /nose, and sneezing. It is also used to relieve itching and hives. It works by blocking a certain natural substance (histamine) that your body makes during an allergic reaction.
Before taking it, tell your doctor if you have any kidney problems or epilepsy (seizures). Your dose may need to be modified or Levocetirizine may not suit you. Some other medicines can interact with Levocetirizine so let your healthcare team know what else you are taking. You should also talk to your doctor before using Levocetirizine if you are pregnant or breastfeeding, although it is not thought to be harmful.
Mechanism of action:
Levocetirizine, the (R) enantiomer of cetirizine, is a potent and selective antagonist of peripheral H1-receptors.
Binding studies revealed that levocetirizine has a high affinity for human H1-receptors (Ki = 3.2 nmol/l). Levocetirizine has an affinity 2-fold higher than that of cetirizine (Ki = 6.3 nmol/l). Levocetirizine dissociates from H1-receptors with a half-life of 115 ± 38 min. After single administration, levocetirizine shows a receptor occupancy of 90% at 4 hours and 57% at 24 hours.
Pharmacodynamic studies in healthy volunteers demonstrate that, at half the dose, levocetirizine has comparable activity to cetirizine, both in the skin and in the nose.
Pharmacodynamic effects
The pharmacodynamic activity of levocetirizine has been studied in randomized, controlled trials:
In a study comparing the effects of levocetirizine 5mg, desloratadine 5mg, and placebo on histamine-induced wheal and flare, levocetirizine treatment resulted in significantly decreased wheal and flare formation which was highest in the first 12 hours and lasted for 24 hours, (p<0.001) compared with placebo and desloratadine.
The onset of action of levocetirizine 5 mg in controlling pollen-induced symptoms has been observed at 1-hour post-drug intake in placebo-controlled trials in the model of the allergen challenge chamber.
In vitro studies (Boyden chambers and cell layers techniques) show that levocetirizine inhibits eotaxin-induced eosinophil transendothelial migration through both dermal and lung cells. A pharmacodynamic experimental study in vivo (skin chamber technique) showed three main inhibitory effects of levocetirizine 5 mg in the first 6 hours of pollen-induced reaction, compared with placebo in 14 adult patients: inhibition of VCAM-1 release, modulation of vascular permeability and a decrease in eosinophil recruitment.
Manufacturing Procedure of Levocetirizine 5 mg Tablets IP
TABLE OF CONTENTS
- PRODUCT DETAILS
- MANUFACTURING FORMULA
- LIST OF EQUIPMENT
- GENERAL PRECAUTIONS
- MANUFACTURING INSTRUCTIONS
- MANUFACTURING PROCESS DETAILS
- GRANULATION
- COMPRESSION
- COATING
PRODUCT DETAILS:
Product Name: Levocetirizine Dihydrochloride Tablets IP
Product Description: White color round shape, biconvex, film-coated tablet having both sides plain.
Strength: 5 mg
Label claim: Each film-coated tablet contains: Levocetirizine Dihydrochloride IP – 5 mg
Average Weight: 102 mg (Film-coated tablets)
Shelf Life:24 months
Storage: Store in a cool, dry, and dark place below 25 0C
Drug Category: Anti-histamine Drug
MANUFACTURING FORMULA:
| Material Name | Category | Overages | Batch Qty.
(In kg) |
|
| Dry Mixing | ||||
| Levocetirizine Dihydrochloride | API | 1 % | 2.525 kg | |
| MCCP PH-102 | Diluent | — | 5.075 kg | |
| Starch | Diluent | — | 2.500 kg | |
| Cross Carmillose Sodium | Disintegrants | — | 0.625 kg | |
| Binder | ||||
| Ethyl Cellulose | Binder | — | 0.010 kg | |
| Isopropyl Alcohol (IPA) | Solvent | — | 10.800 liter | |
| Lubricant | ||||
| Talcum | Anti-caking agent | — | 1.500 kg | |
| MCCP PH-102 | Diluent | — | 35.650 kg | |
| Cross Carmillose Sodium | Disintegrants | — | 0.625 kg | |
| Aerosil | Glidant | — | 0.500 kg | |
| Calcium Stearate | Anti-Adherent | — | 1.000 kg | |
LIST OF EQUIPMENT:
- Weighing Balance
- Vibro Sifter
- Mass Mixer with propeller
- Portable Stirrer
- Tray Dryer
- Double Cone Blender
- Halogen Moisture Balance
- Compression Machine
- SS Containers with lid
- Filter Cloth 100 #
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 products or a mixture of Active Ingredients and Excipients, wear gloves and a 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 from QA before starting the manufacturing operation during batch-to-batch and product-to-product changeover.
- Do not overwrite any entry. In case of a mistake, cancel the entry by a single line with a sign & date and make the correct entry.
MANUFACTURING PROCESS DETAILS:
GRANULATION:
STEP – I (SIFTING):
Check Sieve Integrity (before sifting and after sifting).
Set the Vibro Sifter and sieve the Dispensed Materials as per Sieve Sizes mentioned below:
| Material Name | Std. Qty. (kg) | Sieve No. |
| Dry Mixing | ||
| Levocetirizine Dihydrochloride IP | 2.525 kg | 40 # |
| MCCP PH-102 IP | 5.075 kg | 40 # |
| Starch IP | 2.500 kg | 100 # |
| Cross Carmillose Sodium IP | 0.625 kg | 40 # |
| Binder | ||
| Ethyl Cellulose IP | 0.010 kg | — |
| Isopropyl Alcohol IP ( IPA) | 10.800 liter | — |
| Lubricant | ||
| Talcum IP | 1.500 kg | 60 # |
| MCCP PH-102 IP | 35.650 kg | 40 # |
| Cross Carmillose Sodium IP | 0.625 kg | 40 # |
| Aerosil IP | 0.500 kg | 14 # |
| Calcium Stearate IP | 1.000 kg | 60 # |
Collect the sifted Levocetirizine Dihydrochloride IP (2.525 kg), MCCP PH-102 IP (5.075 kg), Starch IP (2.500 kg), and Cross Carmillose Sodium IP (0.625 kg) in one Polybag (capacity: 20 kg).
Collect the sifted Talcum IP (1.500 kg), MCCP PH-102 IP (35.650 kg), Cross Carmillose Sodium IP (0.625 kg) and Aerosil IP (0.500 kg) in one Polybag (capacity: 50 kg).
Collect the sifted Calcium Stearate IP (1.000 kg) in one Polybag (capacity: 2.0 kg).
STEP – II (BINDER PREPARATION):
Take Isopropyl Alcohol IP (10.800 liters) in SS Container (capacity: 20 liters) and add Ethyl Cellulose IP (0.010 kg) to it. Mix together by Portable Stirrer continuously stirring till Ethyl Cellulose IP is dissolved properly in IPA.
Mixing Time: 10 minutes.
Filter it with filter cloth 100 # in an SS container (capacity: 20 liters).
STEP – III (DRY MIXING):
Transfer the sifted material Levocetirizine Dihydrochloride IP, MCCP PH-102 IP, Starch IP, and Cross Carmillose Sodium IP in Mass Mixer ( capacity: 100 liters) and dry mix the materials till uniform mixing.
Mixing Time: 10 minutes.
Mixing Speed: 36 RPM
Paddle (Blades) Timing: 5 minutes in a clockwise direction and 5 minutes in the anti-clockwise direction.
STEP –IV (BINDING OF DRY MIX MATERIAL):
Slowly add the binder of Step-II to the dry mix material of Step-III and mix for 10 minutes till uniform binding after binding, collect the wet mass in four Trays (capacity: 3.000 kg each).
Mixing Time: 10 minutes.
Mixing Speed: 36 RPM.
Paddle (Blades) Timing: 5 minutes in a clockwise direction and 5 minutes in an anti-clockwise direction.
STEP –V (DRYING):
Dry the wet material of Step IV as follows:
Load these four Trays in a 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 1.0 to 1.5 % at 105°C checking by Halogen Moisture Balance.
Drying Temperature: 35°C (After Air Drying)
Drying Time: 03 hours (To be validated in the next batch).
Raking Frequency: After every 20 minutes.
STEP-VI (SIZING/MILLING):
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 granules in one Poly-lined HDPE Container (capacity: 30 liters).
STEP – VII (PRE –LUBRICATION):
Load the sized granules of Step-VI in Double Cone Blender (capacity: 200 liters) and add sifted Talcum IP, MCCP PH-102 IP, Cross Carmillose Sodium IP, and Aerosil IP, mix properly till uniform mixing of sized material with Pre-Lubricating Materials.
Mixing Time: 40 minutes (20 minutes clockwise direction and 20 minutes anti-clockwise direction).
Mixing Speed: 10 RPM.
STEP – VIII (LUBRICATION):
Add the sifted Calcium Stearate IP in Pre- Lubricated Materials of Step-VII in a Double Cone Blender and mix properly till uniform mixing of materials with Calcium Stearate IP.
Mixing Time: 05 minutes (clockwise direction).
Mixing Speed: 10 RPM.
STEP- IX (BLEND SAMPLE ANALYSIS):
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
The appearance of the blend -White free-flowing granular powder
Blend Uniformity: 90 % to 110 %
Blend Assay:98 % to 103 %
LOD: 1.0 % to 1.5 %
STEP – X:
Take the Tare Weight of two Poly-lined HDPE Containers (capacity: 30 liters each), record the Tare Weight in BMR and unload the above-blended material from Double Cone Blender in Poly-lined HDPE Containers (capacity: 30 liters 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 the 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: 50.000 kg (100 %)
Actual Batch Yield Limit: 49.500 kg (NLT 99 %) (To be established in next batch).
STEP – XI:
Clean all equipment used in the granulation as per respective equipment cleaning SOP.
COMPRESSION:
STEP – I:
After receiving QC approval for the blend, verify the Net Weight of the received blend as per the status label in Granules Day Store.
Set the 35 stations (B-Tooling) Compression Machine. Compress the blend as per the below parameters and In Process checks and take a sample for Dissolution (Qty. 20 tablets) and send it to QC Department for Dissolution Analysis.
After confirmation of the Dissolution result continue the compression with the blend as per the following parameters and In Process checks under controlled environmental conditions.
| Parameters | Standard | In-Process Frequency |
| Feed frame alignment and adjustment | Should be satisfactory | —– |
| Lower Weight Assembly | Should be satisfactory | —– |
| Hydraulic Pressure | 5-6 Tones | —– |
| Machine Speed | 18 RPM to 22 RPM | —– |
| Upper Punch Size | 6.5 mm | —– |
| Lower Punch Size | 6.5 mm | —– |
| Die | 6.5 mm | —– |
| Diameter | 6.5 mm | 2 hours |
| Thickness of Tablets | 2.5 mm ± 0.2 mm | 2 hours |
| Weight of 20 Tablets | 2.00 gm ± 2 % | 30 minutes |
| Tablets for Dissolution | 100 mg ± 2 % | Before starting the Compression |
| Dissolution | NLT 80 % | —- |
| Product Description | White color, round shape, biconvex, uncoated tablet having both sides plain. | 30 minutes |
| 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 % | 01 hour |
| Standard Average Weight of Tablets | 100 mg ± 2 % | 30 minutes |
| Hardness | NLT 3.0 kg/cm2 | 30 minutes |
| Disintegration Time | NMT 15 min (IHS NLT 03 minutes) | 01 hour |
| Friability | NMT 1% | 01 hour |
Collect the compressed tablets in SS Container (capacity: 20 liters each on both sides), when SS containers are filled with tablets, transfer the tablets to two Poly-lined HDPE Containers as given in below Step-III.
STEP – II:
Send the sample of compressed tablets (Qty. 30 tablets) to the QC department for analysis.
STEP – III:
Take the Tare Weight of two Poly-lined HDPE Containers (capacity: 30 liters each), record the Tare Weight in BMR and transfer the compressed tablets to Poly-lined HDPE Containers (capacity: 30 liters 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 the 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 Compressed Tablets:
Theoretical Batch Yield: 50.000 kg (100 %).
Actual Batch Yield Limit: 49.500 kg (NLT 99 %) (To be established in next batch).
STEP – IV:
After completion of the compression of tablets, clean the Compression Machine as per cleaning SOP.
COATING:
Verify the Net Weight of the received compressed tablets for coating as per the status label and after confirmation continues for tablet coating.
STEP – I (COATING MATERIALS DETAILS):
| Material Name | Batch Quantity |
| Instacoat White Aq.III | 1.000 kg. |
| Purified Water IP | 6.000 liter |
STEP-II (LIST OF EQUIPMENT FOR COATING):
- Coating Machine and Coating Pan
- Spray Gun
- Filter Cloth 100 #
- Portable Stirrer
- SS Container
- Poly-lined HDPE Containers with lid
STEP – III (PREPARATION OF COATING SOLUTION):
Take Purified Water IP (6.000 liters at room temperature) in SS Container (capacity: 10 liters) and add Instacoat White Aq.III (1.000 kg) and mix together with Portable Stirrer continuously stirring till uniform mixing is achieved.
Speed of Stirrer: Constant.
Mixing Time: 15 minutes.
Filter the coating solution with Filter Cloth 100 # in SS Container (capacity: 10 liters).
Keep the solution for 15 minutes to let it the foam settle down. Thereafter proceed with the coating process.
STEP – IV (COATING PROCEDURE):
Coating will be done in one lot, take total compressed tablets for coating (50.000 kg).
Load the tablets in the coating pan (Capacity: 36″), start the hot air blower, set the inlet air temperature at 60°C to 65°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 a coating pan | 03 |
| No. of Guns | 01 |
| Inlet Temperature | 60°C to 65°C |
| Peristaltic Pump Speed | 2 – 4 RPM |
| Atomization | 2.5 to 3.0 kg/cm2 |
| Gun to Tablet Bed Distance | 10 inch |
| BED Temperature | 400C to 45 0C |
| Pan RPM | 13 to 15 RPM |
| % Weight Gain | 1.5 to 2.0 % |
| Coating Time | 01 Hour |
STEP – V (COATING IN-PROCESS CHECK PARAMETERS):
| S.No. | Parameters | Standard | In-Process Frequency |
| 1 | Product Description | White color, round shape, biconvex, film-coated tablet having both side plain |
After batch completion |
| 2 | Weight of 20 Tablets after coating | 2.040 gm. ± 2 % | |
| 3 | Standard Average Weight after coating | 102 ± 2 % | |
| 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 % | |
| 5 | Thickness | 2.6 mm ± 0.2 mm | |
| 6 | Disintegration | NMT 30 min. |
STEP – VI:
Send the composite sample of coated tablets (Qty. 30 tablets) to the QC department for analysis.
STEP – VII:
Take the Tare Weight of two Poly-lined HDPE Containers (capacity: 30 liters each), record the Tare Weight in BMR and transfer the coated tablets to Poly-lined HDPE Containers (capacity: 30 liters 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 the 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: 51.000 kg (100 %)
Actual Batch Yield Limit NLT 50.490 kg (NLT 99 %) (To be established in next batch).
Reference: Levocetirizine 5 mg film-coated tablets