Certificate of Analysis – Certified Reference Material

CANDESARTAN CILEXETIL
Product no.: PHR1854-200MG
Lot no.: LRAD7905
Description of CRM: White Powder
Expiry date: 31 July 2028
Storage: 2°C to 8°C /Protect from Light
Certificate version: LRAD7905.1 (Note: Certificates may be updated due to
Pharmacopeial Lot Changes or the availability of new data.
Check our website at: www.sigma-aldrich.com for the most
current version.)

Chemical formula: C33H34N6O6

Molecular mass: 610.7
CAS No.: 145040-37-5

Certified Purity ± associated uncertainty U, U=k . u (k=) (Mass Balance/

Analyte
basis)

Candesartan Cilexetil 99.7 % Ucrm = ± 0.2 %, k = 2.0 (as is basis)

Metrological traceability: Traceable to the SI and higher order standards from NIST through an unbroken
chain of comparisons. Additional traceability to Primary Standards is established
through comparative assay determinations. See “Details on metrological
traceability” on page 2.
Measurement method: Where applicable, the certified value is based on a purity determination by mass
balance. See “Certification process details” on page 3.
Intended use: Intended for R&D and Analytical Use only. Not for drug, household or other uses.
Minimum sample size: 20 mg
Instructions for handling Do not dry, use on the as is basis. The internal pressure of the container may be
and correct use: slightly different from the atmospheric pressure at the user’s location. Open
slowly and carefully to avoid dispersion of the material. Attachment of a 20 mm
aluminum crimp seal recommended for unused portions.
Health and safety All chemical reference materials should be considered potentially hazardous and
information: should be used only by qualified laboratory personnel. Please refer to the Safety
Data Sheet for detailed information about the nature of any hazard and appropriate
precautions to be taken.
Accreditation: Sigma-Aldrich RTC is accredited by the US accreditation authority ANAB as a
registered reference material producer AR-1470 in accordance with ISO 17034.
Certificate issue date: 28 July 2024

ISO 17034
AR-1470 Andy Ommen - QC Authority Christopher Rucinski - QA Authority

Sigma-Aldrich RTC, 2931 Soldier Springs Rd. Laramie, WY 82070, USA;

Tel. 1 307-742-5452; Fax 1 307-855-831-9211; www.sigmaaldrich.com
Sigma-Aldrich RTC is a subsidiary of Merck KGaA, Darmstadt, Germany.

Certificate Page 1 of 7 Certificate version 01

 Packaging: 200 mg in amber vial
Details on metrological This standard has been gravimetrically prepared using balances that have been
traceability: fully qualified and calibrated to ISO 17025 requirements. All calibrations utilize
NIST traceable weights which are calibrated externally by a qualified ISO 17025
accredited calibration laboratory to NIST standards. Qualification of each balance
includes the assignment of a minimum weighing by a qualified and ISO 17025
accredited calibration vendor taking into consideration the balance and installed
environmental conditions to ensure compliance with USP tolerances of NMT
0.10% relative error. Fill volume to predetermined specifications is
gravimetrically verified throughout the dispensing process using qualified and
calibrated balances. Further traceability to a corresponding Primary Standard
may be achieved through a direct comparison assay. Where a Primary Standard
is available, the assay value will be included in the specified section of the COA.
Associated uncertainty: Uncertainty values in this document are expressed as Expanded Uncertainty
(UCRM) corresponding to the 95% confidence interval. UCRM is derived from the
combined standard uncertainty multiplied by the coverage factor k, which is
obtained from a t-distribution and degrees of freedom. The components of
combined standard uncertainty include the uncertainties due to characterization,
homogeneity, long term stability, and short term stability (transport). The
components due to stability are generally considered to be negligible unless
otherwise indicated by stability studies.

2 2 2
𝑈𝑐𝑟𝑚 = (√𝑢𝑐ℎ𝑎𝑟𝑎𝑐𝑡𝑒𝑟𝑖𝑧𝑎𝑡𝑖𝑜𝑛 + 𝑢ℎ𝑜𝑚𝑜𝑔𝑒𝑛𝑒𝑖𝑡𝑦 + 𝑢𝑠𝑡𝑎𝑏𝑖𝑙𝑖𝑡𝑦 ) × 𝑘

Traceability Assay:
Comparative assay demonstrates direct traceability to Pharmacopeial Standards

ASSAY vs. USP REFERENCE STANDARD (1087803) (as is basis)

ASSAY VALUE vs. USP LOT
99.3 % R14510
Labeled Content = 0.997 mg/mg

ASSAY vs. EP CRS (Y0001388) (as is basis)

ASSAY VALUE vs. EP BATCH
99.4 % 2.0
Labeled Content = None
Assigned Content = 99.7 % *
*The assigned content of the EP CRS was determined by assay against the USP Reference Standard

ASSAY vs. BP REFERENCE STANDARD (1248) (as is basis)

ASSAY VALUE vs. USP LOT
99.5 % 4187
Labeled Content = 99.6 %

Method: HPLC (ref.: Candesartan Cilexetil, Current Compendial Monographs)

Column: Ascentis Express C8, 150 mm x 4.6mm, 5µm particle size
Mobile Phase: (Acetonitrile:Water:TFA)
Mobile Phase Ratio: (550:450:1)
Flow Rate: 1.5 mL/min
Column Temperature: 30 °C
Injection Volume: 5 µL
Detector: DAD, Wavelength: 282 nm

Certificate Page 2 of 7 Certificate version 01

 Representative Chromatogram from Lot: LRAD7905 Analysis

Certification process details:

The certified purity is determined by mass balance and calculated as

𝟏𝟎𝟎 − 𝑻𝑪𝑰
% 𝑃𝑢𝑟𝑖𝑡𝑦 = (𝟏𝟎𝟎 − 𝐑𝐎𝐈 − 𝐋𝐎𝐃 − 𝐇𝟐 𝐎 − 𝐑𝐒) ∗ ( )
𝟏𝟎𝟎
• TCI = Total Chromatographic Impurities
• LOD = Loss on Drying
• H2O = Water content determined by Karl Fischer analysis
• ROI = Residue on Ignition
• RS = Residual Solvents

Methods for impurity determination may be added or deleted as required. The following techniques are applied:

CHROMATOGRAPHIC IMPURITY ANALYSIS

METHOD: HPLC (ref.: Candesartan Cilexetil, Current Compendial Monographs)
Column: Zorbax Eclipse Plus C18, 4.6 x 100mm, 3.5µm particle size
Mobile Phase A: (Water:Acetonitrile:TFA) (900:100:1)
Mobile Phase B: (Water:Acetonitrile:TFA) (100:900:1)
Gradient:
Time (min) %A %B
0-30 65-5 35-95
30-45 5 95
45-50 5-65 95-35
50-55 65 35
Flow Rate: 1.0 mL/min
Column Temperature: 30 °C
Injection Volume: 10 µL
Detector: DAD, Wavelength: 254 nm
Impurities Detected:

Impurity 1: 0.026 % Impurity 2: 0.019 %

Impurity 3: 0.014 % Impurity 4: 0.023 %
Impurity 5: 0.0081% Impurity 6: 0.033 %
RCA: 0.043 % RCB: 0.076 %
RCD: 0.012 % RCF: 0.087 %

Total Impurities: 0.34 %

Certificate Page 3 of 7 Certificate version 01

 Representative Chromatogram from Lot: LRAD7905 Impurity Analysis

RESIDUAL SOLVENTS
Method: GC-MS Headspace (ref.: Adapted from Residual Solvents USP <467>)
Column: SPB-624, 30 m x 0.25 mm x 1.4 µm
Carrier gas: He
Flow: 1.0 mL/min
Split Ratio: 5:1
Injection/Temperature: 1 mL/180 °C
Temperature Program: 40 °C for 5 min, 8 °C/min to 200 °C, hold 5 min

Solvents Detected: None

WATER DETERMINATION
Method: Karl Fischer (ref.: Current Compendial Monographs)
Mean of three measurements, Water Content = None

RESIDUE ANALYSIS
Method: Sulfated Ash (ref.: Current Compendial Monographs)
Sample Size: ~ 300 mg
Mean of three measurements, Residue = NONE

CERTIFIED PURITY BY MASS BALANCE

99.7 % Ucrm = ± 0.2 %, k = 2.0

(as is basis)

Homogeneity assessment: Homogeneity was assessed in accordance with ISO Guide 35. Completed units
were sampled using a random stratified sampling protocol. The results of
chemical analysis were then compared by Single Factor Analysis of Variance
(ANOVA). The uncertainty due to homogeneity was derived from the ANOVA.
Heterogeneity was not detected under the conditions of the ANOVA.
Analytical method: HPLC
Sample size: 20 mg

Stability assessment: Significance of the stability assessment will be demonstrated if the analytical
result of the study and the range of values represented by the Expanded
Uncertainty do not overlap the result of the original assay and the range of its
values represented by the Expanded Uncertainty. The method employed will
usually be the same method used to characterize the assay value in the initial
evaluation.

Certificate Page 4 of 7 Certificate version 01

 Long Term Stability Evaluation - An assessment, or re-test, versus a
Compendial Reference Standard may be scheduled, within the 3 year
anniversary date of a release of a Secondary Standard. The re-test interval will
be determined on a case-by-case basis. Short Term Stability Study - It is useful
to assess stability under reasonably anticipated, short term transport conditions
by simulating exposure of the product to humidity and temperature stress. This
type of study is conducted under controlled conditions of elevated temperature
and humidity.

Identification Test:
INFRARED SPECTROPHOTOMETRY (Comparative identification analysis demonstrates direct traceability to
Pharmacopeial standards)

Candesartan Cilexetil PHR1854 LRAD7905 vs. USP Lot R14510 / BP Batch 4187 / EP Batch 2.0

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 MASS SPECTRUM

Method: HR-QTOF; 4.0 kV ESI+; temperature: 325 °C

Theoretical value: 611.2618 m/z

The signal of the MS spectrum is consistent with the theoretical value and its interpretation is consistent with the
structural formula.

1H NMR

Consistent with structure

Certificate Page 6 of 7 Certificate version 01

 Certificate of analysis revision history:
Certificate version Date Reason for version
LRAD7905.1 28 July 2024 Original Release

Disclaimer:
The purchaser is required to determine the suitability of this product for any particular
application. Sigma-Aldrich RTC makes no warranty of any kind, express or implied, other than
its products meet all quality control standards set by Sigma-Aldrich RTC. We do not guarantee
that the product can be used for any particular application.

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Certificate Page 7 of 7 Certificate version 01