Method Development And Validation Protocol

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Method Development for Dissolution Test of Delayed Release Aspirin Tablet 300mg : 

Method Development for Dissolution Test of Delayed Release Aspirin Tablet 300mg QAA303 Group 2, QA06-4

Aspirin: 

Aspirin Aspirin is an odourless, colourless, white crystalline powder

Delayed Release Aspirin Tablet 300mg : 

Delayed Release Aspirin Tablet 300mg Generic name: Aspirin (ASA) Brand name: Bayer aspirin, Ecotrin Chemical name: Acetyl salicylic acid Systematic name: 2-acetoxybenzoic acid Dosage form: tablet Coating preparation: enteric-coated Release type: delayed–release

Delayed Release Aspirin Tablet 300mg: 

Delayed Release Aspirin Tablet 300mg Molecular formula: CH3COOC6H4COOH Molecular weight: 180.16 Chemical structure:

3D Still Image and Flash: 

3D Still Image and Flash

Physical and Chemical Properties: 

Physical and Chemical Properties Density: 1.40 g/cm³ Melting point: 136 °C Boiling point: 140 °C (decomposes) Solubility in water: 1 mg/ml (20 °C) Specific gravity: 1.35 pKa: 3.48

Pharmacokinetic Properties: 

Pharmacokinetic Properties Bioavailability: rapid and complete Protein binding: 99.6% Toxicity: Oral rat LD50: 200 mg/kg Derivation: 2-Hydroxy-Benzoic Acid i.e.Salicylic acid (SA) {Aspirin is rapidly hydrolyzed to salicylic acid}

Salicylic Acid(Degradation Product) : 

Salicylic Acid(Degradation Product) Chemical name: 2-Hydroxybenzoic acid Molecular formula: HOC6H4COOH Molecular mass: 138.123 g/mol Chemical structure:

Salicylic Acid(Degradation Product): 

Salicylic Acid(Degradation Product) SA structural image is as follows: Melting point: 159 °C Boiling point: 211 °C (2666 Pa) Density: 1.44 g/cm³ (at 20 °C) pKa: 2.97

Strategy in Method Development : 

Strategy in Method Development method and apparatus choice assay method pre-validation consideration of media parameters test on different agitation speeds test on sampling time points determination of the isosbestic points linearity/range verification Precision verification deaeration temperature volume pH value start runs of dissolution test

Assay Method Prevalidation : 

Assay Method Prevalidation Determination of the isosbestic points Linearity/range verification Precision verification Instrumental calibration Repeatability Ruggedness

Determination of Isosbestic Points: 

Determination of Isosbestic Points In spectroscopy, an isosbestic point is a specific wavelength at which two (or more) chemical species have the same absorptivity An isosbestic point may be attained by drawing an isosbestic plot at which the absorption spectra of two species cross each other when two print-outs of isosbestic plots are put together and overridden

Determination of Isosbestic Points: 

Determination of Isosbestic Points According to USP 29,Aspirin RS.Salicylic Acid RS, the isosbestic point of ASA and SA is about 280nm in the acid stage,and about 265nm in the buffer stage Verification needs to be made if the isosbestic point falls within 280+3nm in the acid stage,and within 265 +3nm in the buffer stage If not,the validation has to be done

Linearity/Range Verification: 

Linearity/Range Verification Linearity is the ability of the method to elicit test results that are directly proportional to analyte concentration within a given range Range is the interval between the upper and lower levels of analyte concentration (inclusive) over which the method shows acceptable linearity, accuracy and precision

Linearity/Range Verification : 

Linearity/Range Verification Range: from 0% to 120% The working concentrations of Aspirin at both acid stage and buffer stage are pre-set as: 1. 40ppm at the acid stage (300mg10%÷750ml) 2. 300ppm at the buffer stage (300mg÷1000ml) Calibration Curves of Aspirin RS in 0.1 N HCl solution and the premixed buffer solution to be drawn after the following tests:

Calibration Curve of Aspirin RS in 0.1 N HCl Solution: 

Calibration Curve of Aspirin RS in 0.1 N HCl Solution

Calibration Curve at the Acid Stage : 

Calibration Curve at the Acid Stage Make a series of dilutions of the Aspirin RS stock solution into 20ppm, 25ppm, 30ppm, 35ppm, 40ppm, 45ppm and 50ppm Measure absorbances with a UV/Visible spectrophotometer at the confirmed wavelength of the isosbestic point of ASA and SA Do statistical analysis with linear regression and plot the asymptote of calibration curve Calculate R2 to verify the linearity/range

Calibration Curve of Aspirin RS in the Premixed Buffer: 

Calibration Curve of Aspirin RS in the Premixed Buffer

Calibration Curve at the Buffer Stage: 

Calibration Curve at the Buffer Stage Make a series of dilutions of the Aspirin RS stock solution into 60ppm, 110ppm, 160ppm, 210ppm, 260ppm, 310ppm and 360ppm Measure absorbances with a UV/Visible spectrophotometer at the confirmed wavelength of the isosbestic point of ASA and SA Do statistical analysis with linear regression and plot the asymptote of calibration curve Calculate R2 to verify the linearity/range

Acceptance Criteria of the Calibration Curves: 

Acceptance Criteria of the Calibration Curves The Coefficient of Determination is greater than 0.999 (i.e.R2  0.999 ) The slope is significantly different from zero (i.e.S  0 ) The intercept is not significantly different from zero (i.e.k close to 0 )

Precision Verification: 

Precision Verification System Precision The UV/Vis spectrophotometer used in this project (e.g.Pharmacia Biotech®Ultraspec 3000 or 2000) needs to be calibrated before daily measurement Repeatability (inter-assay precision) Ruggedness (intermediate precision)

Inter-assay Precision at Acid Stage: 

Inter-assay Precision at Acid Stage

Repeatability at Acid Stage: 

Repeatability at Acid Stage Make 6 replicates of 40ppm Aspirin artificial mixture in 0.1 N HCl solution Measure the absorbances at the plotted wavelength of the isosbestic point Do statistical analysis to verify the inter-assay precision at acid stage

Inter-assay Precision at Buffer Stage: 

Inter-assay Precision at Buffer Stage

Repeatability at buffer stage : 

Repeatability at buffer stage Make 6 replicates of 300ppm Aspirin artificial mixture in the premixed buffer Measure the absorbances at the plotted wavelength of the isosbestic point Do statistical analysis to verify the inter-assay precision at buffer stage

Acceptance Criteria of the Inter-assay Precisions: 

Acceptance Criteria of the Inter-assay Precisions RSD should be varied within 2%, after statistical calculation and analysis

Ruggedness: 

Ruggedness Intermediate precision (Ruggedness) is the ability of the method to withstand changes external to the method It expresses within laboratory variations: different analysts, different equipments, different days, etc.

Samples used in Ruggedness: 

Samples used in Ruggedness Acid stage: 40ppm spiked Aspirin RS solution triplicates (Rep.1, Rep.2, Rep.3) Buffer stage: 300ppm spiked Aspirin RS solution triplicates (Rep.1, Rep.2, Rep.3)

Intermediate Precision at Acid Stage: 

Intermediate Precision at Acid Stage

Intermediate Precision at Buffer Stage: 

Intermediate Precision at Buffer Stage

Acceptance Criteria of the Intermediate Precisions: 

Acceptance Criteria of the Intermediate Precisions Acid stage: hypothesis tests with two-factor ANOVA would be used to justify if there are significant differences between Analyst 1 and Analyst 2, And between Pharmacia Biotech® Ultraspec3000 and Ultraspec2000 Buffer stage: hypothesis tests with two-factor ANOVA would be used to justify if there are significant differences between Analyst 1 and Analyst 2, And between Pharmacia Biotech® Ultraspec3000 and Ultraspec2000

Dissolution Method Development : 

Dissolution Method Development Method and apparatus selection Suitability of dissolution testers Tests on deaerated and non-deaerated media Tests on different agitation speeds Study design on sampling time points Design on the dissolution tests

Method and Apparatus Selection: 

Method and Apparatus Selection Apparatus choice (paddle/basket) Method A of USP chapter <724> Volumes of media in Method A 750ml of 0.1N hydrochloric acid is poured into each vessel at acid stage 250ml of 0.2M tribasic sodium phosphate is replenished into every vessel at buffer stage

Test on Degassed and Gassed Media: 

Test on Degassed and Gassed Media

Test on Different Agitation Speeds: 

Test on Different Agitation Speeds

Study Design on Time Points: 

Study Design on Time Points

Acceptance Criteria at Acid Stage : 

Acceptance Criteria at Acid Stage

Acceptance Criteria at Buffer Stage: 

Acceptance Criteria at Buffer Stage

Specifications to Be Set up: 

Specifications to Be Set up Apparatus 2: ____ rpm Q≥75% in ____ minutes

THANK YOU: 

THANK YOU