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Improve the efficiency of your impurity testing

Last updated on

Nick Hauser, Product Manager Analytical Standards, nick.hauser@millliporesigma.com

1

To ensure the safety of pharmaceutical products, active pharmaceutical ingredients (APIs) need to be tested thoroughly. The accurate detection and control of impurities in drug substances and products is an essential element of ICH and GMP requirements. Reference Materials for these impurities are often hard to find, very expensive, or time consuming to make and maintain consistency. In pharmaceutical quality control (QC) laboratories, APIs and related substances are weighed daily or weekly to make multi-analyte stock or working level solutions. This cumbersome approach introduces the potential for inconsistencies and error, especially with difficult to handle materials.

Our new product range of pharmaceutical impurity solutions saves both cost and labor by providing all regulated impurities in one mix. These impurity solutions are manufactured as Certified Reference Materials (CRMs) according to ISO 17034 and ISO/IEC 17025 double accreditation. Accelerated stability studies are conducted under sub-freezer, freezer, refrigerated, room temperature and 40⁰C conditions over several weeks to determine any degradation or interaction of the individual analytes. If necessary, individual impurities will be removed from the mixtures and manufactured as single component solutions using conditions that will fortify stability. These single component solutions are manufactured at convenient concentrations to be easily combined with the existing mixtures with minimal sample handling. Also, storage in ampoules under argon protects the materials from air, light and changes in concentration.

Another unique and valuable aspect of these solutions is that the individual neat materials that are used as starting materials are Secondary Pharmaceutical Reference Standards. These Secondary Standards are manufactured as Certified Reference Materials and made traceable to a corresponding Primary Compendial Standard. The products are designed to be used as stocks and/or working level solutions.

Table 1​ shows the composition of the combination of Acetaminophen impurity mix A-134, 4′-Acetoxyacetanilide (Acetaminophen RC A) solution A-135, 4-Aminophenol (Acetaminophen RC K) solution A-136, and 4-Chloroacetanilide (Acetaminophen RC J) solution C-166 comprising the components required for analysis according to the monograph methods. See compound structures in Figure 1​.

Figure 2​ shows an example chromatogram of the Acetaminophen and Related Compound solutions (structures of components shown) combined as one sample solution.

Ready access to consistent, accurate, and reliable ISO manufactured impurity solutions is a significant improvement for the efficiency of pharmaceutical product QC testing.

A complete overview of all our available reference materials for pharmaceutical impurities (neats and solutions) listed by API can be found at SigmaAldrich.com/pharma-impurity-mixture​.

To see all our reference materials for Pharmacopoeias, please visit SigmaAldrich.com/standards-pharma​.

Table 1.​ Acetaminophen Impurity portfolio (combining cat.nos. A-134, A-135, and A-136).

Component

USP Related Compound (RC)

EP Impurity

Acetaminophen

-

-

4-Acetoxyacetanilde

A

H

N-(4-Hydroxy phenyl)propanamide

B

B

2-Acetamidophenol

C

A

Acetanilide

D

D

4-Nitrophenol

F

F

4-Chloroacetanilide

J

J

4-Aminophenol

-

K

Figure 1.​ Chemical structures of the Acetaminophen impurities

2

Figure 2.​ HPLC-UV Analysis of the combined Acetaminophen Impurities (Cat. Nos. A134, A135, A136).

Conditions

Column:

Ascentis®​ Express C8, 100 x 3.0 mm, 2.7 µm (53852-U ​)

Mobile Phase

[A]: Acetonitrile

[B]: 0.1 % Ammonium acetate in Water

Flow Rate:

0.6 mL/min

Column Temp:

35 ˚C

Detector

UV, 238 nm

Injection

10 µL

Sample

Mixture of Acetaminophen impurity mix (A-134), 4′-Acetoxyacetanilide (Acetaminophen RC A) solution (A-135), and 4-Aminophenol (Acetaminophen RC K) solution (A-136), 20.8 µg/mL each individual compound in final sample solution

 

Gradient

Time (min)

 %A

%B

0.0

5

95

8.0

60

40

1          0.0

60

40

10.1

5

95

16.0

5

95

3

Pharmaceutical Impurity CRM Mixes and Solutions Currently Available

Description (each offered in 1ML unit)

Concentration

 (μg/mL)

 Cat. No.

Acetaminophen (Paracetamol) Impurity Mix

25

A-134

   4′-Acetoxyacetanilide (Acetaminophen RCA)

250

A-135

   4-Aminophenol (Acetaminophen RCK)

250

A-136

   4-Chloroacetanilide (Acetaminophen RCJ)

250

C-166

Aspirin Impurity Mix

100

A-143

   Acetylsalicylic Anhydride (Aspirin Impurity F)

100

A-155

Bupropion Impurity Mix

100

B-082

Bupropion System Suitability Mix

12-20

B-069

Caffeine Impurity Mix

0.4-2.0

C-175

   6-Amino-1,3-dimethyl-5-(formylamino) uracil (Caffeine Impurity B)

40

C-194

   Caffeine Impurity E Nitrate

100

C-195

Chlorpheniramine Impurity Mix

50

C-193

   Chlorpheniramine Impurity C

50

C-197

Fluconazole Impurity Mix

10

F-051

Furosemide Impurity Mix

5

F-052

Fluticasone Impurity Mix

20

F-061

Guaifenesin Impurity Mix

500-1000

G-022

Ibuprofen Impurity Solution

25

I-036

   (2RS)-2-(4-butylphenyl)propanoic acid (Ibuprofen Impurity B)

100

I-037

Lidocaine Impurity Mix

20-200

L-048

Metformin Impurity Mix

50

M-195

    Cyanoguanidine (Metformin Related Compound A)

50

M-196

Nevirapine Impurity Mix

15-30

N-116

Omeprazole Impurity Mix

60

O-048

Parabens Impurity Mix

50

P-125

Pyridoxine Impurity Mix

50

P-126

Pramipexole Organic Impurity System Suitability Mix

15-37.5

P-141

    Pramipexole Chiral System Suitability Solution

10

P-140

Riboflavin Impurity Mix

90

R-029

Salicylic Acid Impurity Mix

10-500

S-100

Thiamine Impurity Mix

100

T-134

The content of a mix (compound listing) and the CRM’s solvent can be seen on the product detail page on our website.