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Biopharmaceutics & pharmacokinetics

A validated UPLC/ESI-MS/MS
bioanalytical method for the
quantification of Perindopril
and Amlodipine in human
Kalaiyarasi. D
JNTU, Hyderabad
Scope of the Method Validation
Encompasses all possible well-characterized and fully validated bioanalytical method to yield reliable results that can be satisfactorily interpreted. A primary concern in biopharmaceutics is the bioavailability of drugs. refers to the measurement of the rate and extent of active drug that reaches the systemic circulation. means access to the bloodstream METHODOLOGY
Selection of drugs combination and collection based on literature survey Study of physicochemical properties of drug molecule. Find out solubility of combination in solvent Tuning of the molecule of interest, source parameters, MS scanning and optimization. Selection of chromatographic method (based on solubility study, retention of compound) Concentration range of compounds in sample of interest and Method validation Report the final results and discussion OPTIMIZED UPLC-ESI-MS/MS ACQUISITION
CONDITIONS FOR PERINDOPRIL & AMLODIPINE
UPLC Conditions
Mobile phase: Solvent A: 0.1% Formic acid in MilliQ water (V/V) Solvent B: 0.1% Formic acid in Acetonitrile (V/V) Injection Volume: 10 µL Parameters
Conditions
AQUITY UPLC BEHC18 , 2.1 x 100 mm, 1.7 µm Gradient Program Time (min)
OPTIMIZED UPLC-ESI-MS/MS ACQUISITION
CONDITIONS FOR PERINDOPRIL & AMLODIPINE
MS/MS Conditions
Ion polarity
Positive
Data storage
Source temperature (°C) 150 Gas flow (L/H) Desolvation temperature (°C) Capillary Voltage (KV) MRM
Compound Parent m/z Product m/z Cone (V) Collision (V)
PER 369.58 172 35 28
AMD 408.97 238 35 18
LID 612.79 280 35 16
Mass
Mass range Min range APE7 235 (3.526) Cm (232:236) 3: Daughters of 369ES+ PERINDOPRIL
APE7 249 (3.744) Cm (244:263) 5: Daughters of 409ES+ AMLODIPINE
Extraction Method-LLE
CALIBRATION STANDARDS AND QC SAMPLE CONCENTRATION
Final Conc. of
Final Conc. of
Final Conc. of
perindopril
amlodipine
Standard ID
(IS)(ng/mL)
Final Conc. of
Final Conc. of
Final Conc. of
QC Samples ID
perindopril
amlodipine
(IS)(ng/mL)
Bio Analytical Method validation Results
Methods used for quantitative measurement of analytes in any given
biological matrix must be
reliable and reproducible for the intended use…

Cmax (ULOQ) AUCt/AUC∞ 80% (LLOQ) Carry-over (LLOQ ≤5% Cmax)  Calibration curve 15–20% Bias / Precision  Accuracy & Precession  Recovery Matrix effect Dilution integrity Suitability for the assay Bio Analytical Method validation Results (contd.,)
Screening and Selectivity
Specificity : for an analyte Selectivity: for a matrix Experimental Design:
Matrix blanks: 8 lots, n=1 for each lot
Matrix blank fortified with IS: 8 lots, n=1 for each lot
LLOQ Selectivity Sample: 6 lots, fortified with analyte at LLOQ
level and IS. n=3 for each lot

Result: 7
out of the 8 lots meet the following criteria:
Response for the analyte in matrix blanks and matrix blank
fortified with IS were ≤20% of the mean analyte response in the
acceptable LLOQ.
 Selectivity LLOQ replicates for each lot meets accuracy
acceptance limit, and the mean accuracy was within ±20.0% of the
nominal concentration
Bio Analytical Method validation Results (contd.,)
2. ASCOT (AUTO SAMPLER CARRIES OVER TEST )
Sequence:
Aqueous blank (without spiked drug)-1
Highest aqueous concentration
Aqueous blank (without spiked drug)-2
Lowest aqueous concentration.
Blank matrix without drug-1
Extracted Highest concentration
Blank matrix without drug -2
Extracted Lowest concentration
%Carry Over for Aqueous samples={Area of Aq.Blank-2 - Aq.Blank-1/Area of Aq.LLOQ} * 100 %CarryOver for Extracted samples={Area of Ex.Blank-2 - Ex.Blank-1/Area of Ext STD8} * 100 Result: Calculated the % carryover at the RT of analyte/ISTD in both
unextracted and Extracted samples. The %Carry over for RT of analyte &
ISTD not more than 5% .
Bio Analytical Method validation Results (contd.,)
3. Linearity
Experimental Design: A calibration curve consist of
A blank sample (matrix sample processed without analyte or internal standard), A zero sample (matrix sample processed without analyte but with internal standard), and Six non-zero samples (matrix samples processed with analyte and internal standard) covering the expected range, including LLOQ. Four concentrations (including LLOQ, low, medium, and high), each concentration n=3 Results:
Standards were not more than 15% of nominal concentrations, except at
LLOQ where the standard was not more than 20%.
The analyte response at the LLOQ was five times the response compared
to blank response.
Correlation coefficient: r2 was 0.9889 to 0.9985 for both drugs .
Bio Analytical Method validation Results (contd.,)
4. Accuracy and precision
Experimental Design: For both the inter-run and intra-run
experiments, as followed and used the linearity data to calculate the
accuracy and precision
Result:
For Accuracy, the mean values for both PER and AMD were
within 15% of the nominal value, except at LLOQ, where it was not
more than 20%.
The precision determined at each concentration level and it were
not exceed 15% of the coefficient of variation (CV) except for the
LLOQ, where it showas not exceed 20% of the CV.
Bio Analytical Method validation Results (cond.,)
5. Recovery
Experimental Design: Analyte at LQC and HQC levels, and IS at the
level of use: pre extraction spiked samples (n=6) are compared with
mean response of post extraction spiked matrix samples (n=6)
Extracted sample Response % Recovery = ------------------------------------ x 100 Un-extracted sample response Result: Recovery of the analyte were not be 100%, but the
extent of recovery of an analyte and of the internal standard
was observed consistent, precise, and reproducible.
Bio Analytical Method validation Results (cond.,)
6. Dilution (Parallelism)
Dilution of samples should not affect the accuracy and precision. If applicable, dilution integrity should be demonstrated by spiking the matrix with an analyte concentration above the ULOQ and diluting this sample with blank matrix. Accuracy and precision should be within the set criteria, i.e. within ±15%.
Experimental Design: Two level at ULOQ concentration (2 fold and
4fold dilution); each dilution, n=6.
Result:
Mean accuracy was within ±15.0% RE of nominal; precision was
≤15.0% RSD.
Bio Analytical Method validation Results (cond.,)
7. Matrix Effect
Experimental Design: It was evaluated by processing post extracted
spiked samples at six replicates of LQC and HQC concentration and
analyzed with aqueous LQC and HQC concentration and difference of
response is calculated.

Calculation:
Matrix factor = B/A
% Matrix effect = [(B-A)/A] * 100
where, A, is the response of the aqueous sample and
B is response for the post extracted spiked samples.
Result:
Both QC samples MF was within 0.85 to 1.15 and %CV for each set of
LQC and HQC were not more than 15%.
References
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Thank you for your attention

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