Module 3 - Involves a part of CTD that is submitted to FDA for an NDA application PDF

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Involves a part of CTD that is submitted to FDA for an NDA application...

Description

Vilazodone hydrochloride 3.2.S.1.1 Nomenclature

TWIND Pharmaceuticals Pvt. Ltd. 12/11/2016

TABLE OF CONTENTS 3.2.S.1 GENERAL INFORMATION.................................................................................3 VILAZODONE HYDROCHLORIDE, TWIND PHARMACEUTICALS PVT. LTD.............3 3.2.S.1.1 NOMENCLATURE 3 3.2.S.1.2 Recommended INN 3 Table 1 Recommended INN 3 Vilazodonum (Latin) 3 3.2.S.2 STRUCTURE (VILAZODONE, TWIND PHARMACEUTICALS PVT. LTD.).5 3.2.S.2.1 Structural Formula (Relative Stereochemistry):

5 3.2.S.2.2

Structural Formula (Absolute Stereochemistry):

5 3.2.S.2.3 Molecular Formula: The molecular formula of Vilazodone hydrochloride is C26H27N5O2xHCl. 6 3.2.S.2.4 Molecular Weight: The molecular weight of Vilazodone hydrochloride is 477.99. The molecular weight of vilazodone is 441.2. (Merck KGAaA; FDA, 2016) 6 3.2.S.3 GENERAL PROPERTIES.....................................................................................7 VILAZODONE HYDROCHLORIDE, TWIND PHARMACEUTICALS PVT. LTD.............7 1 Confidential

Vilazodone hydrochloride 3.2.S.1.1 Nomenclature

TWIND Pharmaceuticals Pvt. Ltd. 12/11/2016

3.2.S.4

TWIND PHARMACEUTICALS PVT. LTD. , VILAZODONE HYDROCHLORIDE..............................................................................................8 3.2.S.5 ANALYTICAL PROCEDURES (VILAZODONE HCL, TWIND PHARMACEUTICALS)........................................................................................9 3.2.S.5.1 Description9 3.2.S.5.2 Identification 9 3.2.S.5.3 Assay 9 3.2.S.5.4 Dissolution10 3.2.S.5.5 Impurities 10 3.2.S.5.5.1

Organic Impurities.....................................................................................................10

3.2.S.5.5.2

Inorganic Impurities...................................................................................................10

3.2.S.5.5.3

Residual Solvents.......................................................................................................11

3.2.S.5.6

Tests

11

3.2.S.5.6.1

Physicochemical Properties........................................................................................11

3.2.S.5.6.2

Particle Size...............................................................................................................11

3.2.S.5.6.3

Polymorphic Forms....................................................................................................12

3.2.S.5.6.4

Chiral Purity...............................................................................................................12

3.2.S.5.6.5

Water Content............................................................................................................12

3.2.S.6

CONTAINER CLOSURE SYSTEM (VILAZODONE HYDROCHLORIDE, TWIND PHARMACEUTICALS PVT.LTD).......................................................12 3.2.P.1 DESCRIPTION AND COMPOSITION OF VILAZODONE HYDROCHLORIDE............................................................................................14 3.2.P.1.1 Dosage Form 14 3.2.P.5.2 ANALYTICAL PROCEDURES (VILAZODONE HYDROCHLORIDE, ORAL TABLETS)................................................................................................17 REFERENCES........................................................................................................................21

List of Tables Table 1 Recommended INN Table 2 Assay Table 3 Vilazodone hydrochloride Package Specifications Table 4 Composition

3 9 11 13

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Vilazodone hydrochloride 3.2.S.1.1 Nomenclature

3.2.S.1

TWIND Pharmaceuticals Pvt. Ltd. 12/11/2016

GENERAL INFORMATION

VILAZODONE HYDROCHLORIDE, TWIND PHARMACEUTICALS PVT. LTD. 3.2.S.1.1

NOMENCLATURE

Recommended Vilazodone [ CITATION WHO01 \l 1033 ] International Nonproprietary Name (INN): Compendial name: Chemical name(s)

2-benzofurancarboxamide, 5-[4-[4-(5-cyano-1H-indol-3-yl) butyl]1-piperazinyl]-, hydrochloride (1:1).[ CITATION Mer16 \l 1033 ]

Company or laboratory XXX code: Other non-proprietary name(s): Chemical Abstracts 163521-12-8 [ CITATION NIH16 \l 1033 ] Service (CAS) registry number: 3.2.S.1.2

Recommended INN

Table 1 Recommended INN Vilazodonum (Latin) vilazodone Vilazodone (French) Vilazodona (Spanish)

5-[4[4-(5-cyanoindol-3-yl)butyl]-1-piperazinyl]-2-benzofurancarboxamide 5-[4[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazin-1-yl]-benzofurane-2carboxamide 5-[4-[4-(5-cianoindol-3-il)butyl]-1-piperazinil]-2-benzofurancarboxamida

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Vilazodone Hydrochloride - Vilazodone 3.2.S.1.2 Structure

3.2.S.2

TWIND Pharmaceuticals Pvt. Ltd. 12/13/20

[ CITATION WHO01 \L 1033 ]STRUCTURE (VILAZODONE, TWIND PHARMACEUTICALS PVT. LTD.)

3.2.S.2.1

Structural

Formula

(Relative

Stereochemistry):

Formula

(Absolute

Stereochemistry):

[CITATION Buc14 \l 1033 ]

3.2.S.2.2

Structural

[ CITATION DrA15 \l 1033 ]

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Vilazodone Hydrochloride - Vilazodone 3.2.S.1.2 Structure

3.2.S.2.3

TWIND Pharmaceuticals Pvt. Ltd. 12/13/20

Molecular Formula: The molecular formula of Vilazodone hydrochloride is C26H27N5O2xHCl.

3.2.S.2.4

Molecular Weight: The molecular weight of Vilazodone hydrochloride is 477.99. The molecular weight of vilazodone is 441.2.[ CITATION Mer16 \l 1033 ]

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3.2.S.3

TWIND PHARMACEUTICALS

General Properties Vilazodone hydrochloride, TWIND Pharmaceuticals Pvt. ltd.

Appearance: Odor:

Odorless[ CITATION Mer16 \l 1033 ]

pH:

3.54

Melting/boiling range:

Melting point – 2700C[ CITATION Mer16 \l 1033 ]

Dissociation (pKa):

constant 7.1[ CITATION CDR11 \l 1033 ]

Specific rotation:

+39.5 to +41.5[ CITATION Loo11 \l 1033 ]

Solubility Profile:

Aqueous solubility – 0.32mg/ml.[CITATION CDR11 \l 1033 ]

Hygroscopicity:

Slightly hygroscopic[CITATION CDR11 \l 1033 ]

Crystallinity:

Vilazodone hydrochloride is available in both amorphous and crystalline forms. Crystalline forms have to be synthesized. [ CITATION Moh15 \l 1033 ]

Polymorphs:

Polymorphic, 15 forms. Classified from I-XI and XIII-XVI[ CITATION Zen14 \l 1033 ]

Particle size:

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TWIND PHARMACEUTICALS

[CITATION Moh15 \l 1033 ] Chiral centers:

3.2.S.4

0[ CITATION Che11 \l 1033 ]

TWIND PHARMACEUTICALS PVT. LTD. , VILAZODONE HYDROCHLORIDE

Vilazodone Hydrochloride is manufactured by: Manufacturer: Address: Responsibility:

TWIND Pharmaceuticals Pvt. Ltd. 102 Chestnut Road, Cambridge, MA 02115 Responsible for whole manufacturing and testing process.

Name of Contact Person: Akshay Kulkarni Telephone Number for (857)-666-9086 Contact Person:

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3.2.S.5

3.2.S.5.1

TWIND PHARMACEUTICALS

ANALYTICAL PROCEDURES (VILAZODONE TWIND PHARMACEUTICALS)

HCL,

Description

Vilazodone Hcl drug substance is a solid substance that is cream or white in color. Chemical name: 163521-12-8; benzofuran-2-carboxamide.

5-(4-(4-(5-Cyano-1H-indol-3-yl)

butyl)

piperazin-1-yl)

Molecular weight: 441.524 g/mol

3.2.S.5.2

Identification

Various compounds have been detected as same as that of Vilazodone Hcl., with differences in their molecular formula. The placing of hydrogen atoms and oxygen atoms are different in these compunds and can be detected by NMR spectrum and UV spectroscopy*. Liquid chromatography and mass spectrometry (LC-MS) is used to for the purification of the API Vilazodone Hcl. For Eg: Vilazodone with two molecular formulas (C26H27N5O2) and (C26H28N5O2+), the presence of extra H-atom can be detected by that of NMR spectroscopy.

3.2.S.5.3

Assay

20 tablets each containing 20 mg of vilazodone hydrochloride was weighed and finely powdered, powdered quantity containing 20 mg of vilazodone hydrochloride was weighed and transferred to a Standard flask (10 ml). The drug is then dissolved in methanol and sonicated for 15 minutes. Mobile phase is used to make up the volume i.e. upto 10 ml. the solution is then passed through the membrane filter of 0.2µm. The final concentration of 6µg/ml of Vilazodone Hcl is achieved by diluting the 0.6 ml solution to 6 ml by using the mobile phase. The choromatogram is then recorded by injecting 20µl of this solution into the chromatogram column. Area of the sample drug is compared with that of the standard drug which further calculates the concentration of vilazodone Hcl in each tablet. The HPLC method also detects other impurities present in the test drug substance.

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TWIND PHARMACEUTICALS

Table 2 Assay Tablet Formulation T1 T2

3.2.S.5.4

Drug Vilazodone HCl Vilazodone HCl

Amount (mg/tab) 20 mg 20 mg

Present

Amount (mg/tab) 9.861 20.032

found

% Label claim 99.30% 100.66%

Dissolution

Vilazodone Hcl is administered orally and exhibits poor aqueous solubility and also poor bioavailability; particle size along with surface area plays a major role in solubility. When particle size is reduced and surface area of individual particle increases the therapeutic efficacy of the drug is enhanced due to increased solubility. Twind pharmaceuticals have been using the micronized polymorphic form of vilazodone hydrochloride which enhances the dissolution and absorption characteristics of the drug. Dissolution profile of the tablets is compared to micronized Vilazodone Hcl to unmicronized vilazodone Hcl From the above information it is clear that micronized drug particles show increased drug release as compared to the unmicronized drug particles. 3.2.S.5.5

Impurities

3.2.S.5.5.1

Organic Impurities

During the storage of the drug two organic impurities are found in Vilazodone hydrochloride 1) Vilazodone N-oxide 2) Oxo Vilazodone These are the degradation products of the drug. 3.2.S.5.5.2

Inorganic Impurities

Inorganic impurities may be detected in the drug substance or in the end product. They are mainly formed during the manufacturing process. The salts include: 1) Vilazodone succinate 9 Confidential

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TWIND PHARMACEUTICALS

2) Vilazodone phosphate 3.2.S.5.5.2.1

Catalysts

Air acts as a catalyst and may lead to the formation of explosive peroxides, Strong oxidizing agents also acts as a catalyst leading to the degradation of drug. 3.2.S.5.5.2.2

Residue on Ignition

The residue left after ignition of Vilazodone hydrochloride is ≤ 0.2%. 3.2.S.5.5.2.3

Heavy Metals

The heavy metal contents in the drug is ≤ 20 ppm. 3.2.S.5.5.3

Residual Solvents

Various residual solvents are used in the preparation of vilazodone hcl, they include mixtures like water/ethanol and solvents like methanol, isopropanol and methylene chloride. These are organic volatile substances that is used in the manufacturing process and should be removed to meet the product specifications. GC/FID Headspace is used to detect the content of residual solvents in the drug substance vilazodone hcl. 3.2.S.5.6 3.2.S.5.6.1 3.2.S.5.6.1.1

Tests Physicochemical Properties pH

The solubility of vilazodone is tested in the acidic pH and it is found to be greatest. (pK a1=7.1) 3.2.S.5.6.1.2

Melting Point/Range

The melting point range is 203-205oC. 3.2.S.5.6.1.3

Refractive Index

The refractive index is around 1.3675-1.3695. 3.2.S.5.6.2

Particle Size

Highly pure and stable Vilazodone Hydrochloride Crystalline Form IV which id free from other solid state forms id used by Twind Pharmaceuticals which has a D (90) particle size of less than or equal to 100 microns. Centrifugal collectors and Electrostatic precipitators are used to measure the particle size and particle size distribution. 10 Confidential

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3.2.S.5.6.3

TWIND PHARMACEUTICALS

Polymorphic Forms

Vilazodone exists in various polymorphic forms, they are as follows polymorph I II, III, IV, V, VI, VII, VIII, IX, X, XI, XIII, XIV, XV and XVI respectively. 3.2.S.5.6.4

Chiral Purity

The chiral purity of vilazodone was assessed using the HPLC method. 3.2.S.5.6.5

Water Content

Vilazodone exists in different crystalline and polymorphic forms and the moisture content found in the drug is 2.02% as detected by Karl Fischer titration.

3.2.S.6

CONTAINER CLOSURE SYSTEM (VILAZODONE HYDROCHLORIDE, TWIND PHARMACEUTICALS PVT.LTD)

Vilazodone Hydrochloride is solid substance manufactured by TWIND Pharmaceuticals Pvt. Ltd. It is stored in a HDPE – High Density Polyethylene drums which gives protection from light and mechanical strength, which is the secondary packaging with double LDPE – Low Density Polyethylene liners that are heat sealed with a twist tie which gives protection from air and moisture. These drums are filled with bags containing active pharmaceutical ingredient which is known as primary package Table 3: Vilazodone hydrochloride Package Specifications Specification Primary package Secondary Package Lining of the drums

Material Polyethylene bags containing the Active Pharmaceutical Ingredient. HDPE (High Density Polyethylene) drums LDPE (Low Density Polyethylene)

[ CITATION Gui991 \l 1033 ].

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TWIND PHARMACEUTICALS

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3.2.P.1

TWIND PHARMACEUTICALS

DESCRIPTION AND COMPOSITION OF VILAZODONE HYDROCHLORIDE

3.2.P.1.1

Dosage Form

The dosage form of vilazodone hydrochloride is oral tablets.

3.2.P.1.2

Composition

Table 4 Composition Active ingredient Ingredient Name Vilazodone hydrochloride Inactive ingredient Ingredient Name Lactose monohydrate Cellulose, microcrystalline Magnesium stearate Colloidal silicon dioxide Polyvinyl alcohol Titanium dioxide Polyethylene glycol Talc

3.2.P.1.3

Strength 20 mg Strength 106 mg 107 mg 1.25 mg 1.25 mg 2% 5 mg 2.5 %w/v 2.5mg

Type of Container and Closure for Dosage Form

The container system for vilazodone hydrochloride tablets is aluminum blister package. The blister consists of aluminum foil blister lidding and blister film which is supplied by ACG Pharma Ltd.2

3.2.P.1.4 •

NA

3.2.P.1.5 •

Diluent Description and Composition

Type of Container and Closure for Reconstitution Diluent

NA

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Vilazodone Hydrochloride 3.2.S.4.2 Analytical Procedures

3.2.P.3.1

TWIND Pharmaceuticals 12/16/2016

TWIND PHARMACEUTICALS PVT. LTD. VILAZODONE HYDROCHLORIDE, TABLET TWIND Pharmaceuticals Pvt. Ltd. 102 Chestnut Road, Cambridge, MA 02115

Manufacturer: Address: Responsibility:

To oversee the process of manufacturing, production and testing of Vilazodone hydrochloride. Contact Akshay Kulkarni, MSc, PhD

Name of Person: Telephone Number for (857)-666-9086 Contact Person: Contractor: N/A Address: Responsibility: Name of Contact Person:

Telephone Number for Contact Person: Production Site: TWIND Pharmaceuticals Pvt. Ltd. Address: 102 Chestnut Road, Cambridge, MA 02115 Responsibility: To produce Vilazodone hydrochloride for clinical testing. Name of Contact Akshay Kulkarni, MSc., PhD. Person: Telephone Number for (857)-666-9086 Contact Person: Manufacturing and TWIND Pharmaceuticals Pvt. Ltd. Testing Site: Address: 102 Chestnut Road Cambridge, MA 02115 Responsibility:

To manufacture and test Vilazodone hydrochloride, which will be used for clinical testing.

Name of Contact Akshay Kulkarni, MSc., PhD. Person: Telephone Number for (857)-666-9086 Contact Person:

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Vilazodone Hydrochloride 3.2.S.4.2 Analytical Procedures

3.2.P.5.2

TWIND Pharmaceuticals 12/16/2016

ANALYTICAL PROCEDURES (VILAZODONE HYDROCHLORIDE, ORAL TABLETS)

The summary of analytical procedures including the validation characteristics and acceptance criteria is shown in Table 1. Validation characteristics

Acceptance criteria

Specificity

1. Peaks from injections of the diluent and placebo solution shall have no significant interference with the analysis of Vilazodone Hydrochloride. 2. Any peak eluting at the retention time of the Vilazodone Hydrochloride peak shall have a %interference should be less than 0.1 of the average area of the Vilazodone Hydrochloride peak from five injections of the standard solution for system suitability. 1. The correlation coefficient from the regression line (r2) ≧0.995. 2. The % y-intercept from the regression line ≦± 5.0% of the response of the analytical concentration from the regression equation. Report the upper and lower concentrations (from linearity) where acceptable linearity, accuracy and precision are demonstrated. 1. The individual and average % recoveries are 95.0%~105.0%. 2. The %RSD of the % recoveries for three injections of each of the sample at each level are ≦5.0%. 3. The %RSD of the overall % recoveries for the nine samples≦15.0%.

Linearity

Range Accuracy

Precision— Repeatability

The %RSD of the results from six sample preparations are not more than 2.0.

Precision— Intermediate precision

1. The %RSD of the results from six sample preparations are not more than 2.0. 2. The %difference of the average result between analyst 1 and analyst 2 are not more than 2.0.

Identification

The %difference between the retention time of the major peak in the chromatogram of the sample solution and the mean retention time of the Vilazodone Hydrochloride peak in the bracketing reference chromatograms shall be less than 3.0.

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Vilazodone Hydrochloride 3.2.S.4....