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Product Details
Active Ingredient: CRIZOTINIB
Proprietary Name: XALKORI
Dosage Form; Route of Administration: CAPSULE; ORAL
Strength: 200 MG and 250 MG
Reference Listed Drug: 200 MG and 250 MG
Reference Standard: 250 MG
TE Code: None
Application Number: N202570
Approval Date: Aug 26, 2011
Applicant Holder Full Name: PF PRISM CV
Marketing Status: Prescription
Regulatory
status:
Approval in different country:
US FDA: Aug 26, 2011
EMA: 23 October 2012
Health Canada: May 10, 2012
Australia: 13 December 2017
Note:
XALKORI has received approval for patients with ALK-positive NSCLC in more than 90 countries including Australia, Canada, China, Japan, South Korea and the European Union. XALKORI is also approved for ROS1-positive NSCLC in more than 60 countries.
Exclusivity Data
Exclusivity Code (Expiration): ODE-111 (03/11/2023)
OB
listed Patents Information
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Patent No |
Patent Expiration |
Drug Substance |
Drug Product |
Submission Date |
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08/26/2025 |
DS |
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05/12/2027 |
09/14/2011 |
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Claim 1: A method of reversing or inhibiting the progress of abnormal cell growth in a mammal comprising, administering to said mammal a therapeutically effective amount of (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine or a pharmaceutically acceptable salt thereof, wherein the abnormal cell growth is a cancer mediated by an anaplastic lymphoma kinase. |
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10/08/2029 |
DS |
DP |
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Claim 1: Compound as per figure mentioned in API information Claim 2: A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. |
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11/06/2029 |
DS |
DP |
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Claim 1:A crystalline form of free base of (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine having a powder X-ray diffraction pattern substantially. Claim 5. The crystalline form of claim 1, wherein the powder X-ray diffraction pattern has peaks at diffraction angles (2θ) of 15.7±0.1, 17.3±0.1, 19.7±0.1, and 26.8±0.1. Claim 10. The capsule of claim 7 comprising from 50 to 100 mg of the crystalline form of (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine. |
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03/01/2025 |
DS |
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API information
STRUCTURE
Chemical Name: (R)-3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine
Molecular Formula: C21H22Cl2FN5O
Molecular Weight: 450.34 daltons
Appearance: White to pale-yellow powder
Hygroscopic: non-hygroscopic
Solubility: The solubility of crizotinib in aqueous media decreases over the range pH 1.6 to pH 8.2 from greater than 10 mg/mL to less than 0.1 mg/mL. Crizotinib solubility in aqueous media decreases with increasing pH.
BCS Class:IV
Polymorphism: Only one crystalline form has been found, this is the thermodynamically stable form A, no other crystalline form has been found.
pKa: 9.4 (piperidinium cation) and 5.6 (pyridinium cation)
pKa (Strongest Basic): (Predicted) -0.25
Log P: The log of the distribution coefficient (octanol/water) at pH 7.4 is 1.65.
CAS No: 877399-52-5
Chiral center: The crizotinib structure contains one chiral center
Degradation and Stability: Stability results have been provided for up to 12 months at 25°C/60%RH and 6 months at 40°C/75%RH. They show a good stability for the active substance. The parameters tested were the same as those included in the release specification. Stress studies were performed at high temperatures and no significant degradation was observed after 14 days stored at 100°C. Minor degradation was observed when crizotinib was exposed to strongly acidic, strongly basic, intense light and oxidative conditions.
API MSDS:
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API DMF and supplier Information
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Formulation
information
Composition
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200 mg |
Capsule Fill: colloidal silicon dioxide (2mg), microcrystalline cellulose (83mg), anhydrous dibasic calcium phosphate (83mg), sodium starch glycolate (20mg), magnesium stearate (12mg) Capsule shells: The pink opaque hard
gelatin capsule shell components contain gelatin, titanium dioxide, and red
iron oxide. The white opaque hard gelatin capsule shell components contain
gelatin and titanium dioxide. |
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250 mg |
Capsule Fill: colloidal silicon dioxide (2.5mg), microcrystalline cellulose (103.75mg), anhydrous dibasic calcium phosphate (103.75mg), sodium starch glycolate (25mg), magnesium stearate (15mg) Capsule shells: The pink opaque
hard gelatin capsule shell components contain gelatin, titanium dioxide, and
red iron oxide. The white opaque hard gelatin capsule shell components
contain gelatin and titanium dioxide. |
Manufacturing process details:
Development Background:
The aim of the development was to obtain an immediate release hard gelatin capsule to deliver 200 mg and 250 mg crizotinib as a single unit dose. The initial dosage form used during early Phase 1 clinical studies was a powder in capsule (PIC), consisting of crizotinib in a hard gelatin capsule shell. Then a tablet dosage form was developed containing 50 mg and 100 mg crizotinib (drug substance loading of 12.5%), to meet increased clinical demand for Phase 3 clinical studies. In vitro dissolution profiles for both the clinical tablet and PIC dosage forms demonstrated rapid release within 30 minutes in 0.1N HCl. In vivo performance was subsequently shown to be bioequivalent between the clinical tablet and PIC. However for manufacturability reasons, the crizotinib capsule form was developed and it was designed to be qualitatively similar to the clinical tablet formulation. The pharmaceutical development was based on the Quality by Design concept. No design space has been claimed by the applicant in the manufacturing process of the finished product.
Manufacturing Process:
The manufacturing process is considered
as standard, and adequate information has been provided.
The main critical steps have been studied in detail and the critical process
parameters (CPPs) have been described adequately. The target normal operating
ranges and proven for these CPPs are considered acceptable. A satisfactory
validation protocol was filed.
Capsule Details
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Parameters |
200 mg |
250 mg |
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Description |
Hard gelatin capsule, size 1, white opaque body and pink opaque cap, printed with black ink “Pfizer” on the cap and “CRZ 200” on the body |
hard gelatin capsule, size 0, pink opaque cap and body, printed with black ink “Pfizer” on the cap and “CRZ 250” on the body |
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Capsule Dimension |
Size 1 |
Size 0 |
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Capsule image |
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OGD Details:
Apparatus: I (Basket)
Speed: 60 RPM
Volume: 900 mL
Medium: 0.1N HCl (degassed)
Time point (min): 5, 10, 15, 30 and 45
Updated date: 04/14/2016
Packaging details
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Market |
200 mg |
250 mg |
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US |
Bottles of 60 capsules: NDC 0069-8140-20 |
Bottles of 60 capsules: NDC 0069-8141-20 |
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EU |
HDPE bottles with a polypropylene closure containing 60 hard capsules. PVC-foil blisters containing 10 hard capsules. Each carton contains 60 hard capsules. |
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Australia |
Blister pack (ARTG: 190964 ) Bottle (ARTG: 190966) |
Blister pack (ARTG: 190965) Bottle (ARTG: 190963) |
Drug Product stability and Shelf life:
For Blister Pack (EU)
· Results are provided for up to 12 months at 25°C/60%RH and 30°C/75%RH and 6 months at 40°C/75%RH in both packaging systems.
· Samples stored in PVC/aluminium foil blisters showed some caking of the capsule contents at the 6 month time point at 30°C/75%RH and from the 2 month time point onwards at 40°C/75%RH.
· Brittleness of the capsule shells was also seen at the 6 month time point at 40°C/75%RH.
· These observations were not associated with changes in degradation product levels, assay or dissolution results.
· Also, they were not been observed through 9 months at the 25°C/60%RH or 30°C/75%RH storage conditions. For samples stored in PVC/aluminium foil blisters, the water content increased by about 0.5% at 25°C/60%RH and by about 1.5% at 30°C/75%RH and 40°C/75%RH through 6 months.
· The water content did not increase at the 9 month time point. This increased water content has not led to any changes in degradation product levels, assay or dissolution results
· The capsules are also stable to light. Also in use stability of capsules packed in the HDPE bottle has been demonstrated.
For US (Bottle)
· Based on the stability data provided, the Agency grants a fifteen (15) month expiry for the drug product, as packaged in the commercial configuration and when stored at USP controlled room temperature.
Shelf life:
· EU: 4 years
· US: 15 Months
Drug product assessment reports
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FDA Label |
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Dailymed |
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Summary of product characteristic |
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Patient leaflet |
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FDA chemistry review |
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FDA Pharmacology Review(s) |
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FDA Clinical Pharmacology Biopharmaceutics Review(s) |
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FDA BE Recommendation |
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European Public Assessment Report |
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Australia Public Assessment Report |
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