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jbladon 1 Second Order Terms in Purity Calculations of Pharmaceutical Reference Standards

2nd Order Terms in Purity Calculations of Reference Standards

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2nd order terms cannot be excluded in purity calculations of pharmaceutical reference standards.

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Page 1: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 1!

Second Order Terms in Purity Calculations of

Pharmaceutical Reference Standards!

Page 2: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 2!

CASE I!

%Purity = 100% − %Water − %HPLC Impurities

Protocol requires using HPLC purity and! the water content to determine analyte purity!

?!

Page 3: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 3!

CASE I!

%Purity = F

1F

2100%

Protocol requires using HPLC purity and! the water content to determine analyte purity!

F1 is the fraction of entire sample that is not water.

F2 is the fraction of sample excluding water that is analyte.

Page 4: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 4!

Let,

A = Analyte*

Im = Impurities*

W = Water

Then,

F1 =A + Im

A + Im+W

⎛⎝⎜

⎞⎠⎟

, F2 =A

A + Im

⎛⎝⎜

⎞⎠⎟

F1F2 =A + Im

A + Im+W

⎛⎝⎜

⎞⎠⎟

A

A + Im

⎛⎝⎜

⎞⎠⎟=

A

A + Im+W

⎛⎝⎜

⎞⎠⎟

____________________ • Where each response factor is known or it is assumed they are identical

Page 5: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 5!

%HPLC Impurities

100%=

Im

A + Im

⎛⎝⎜

⎞⎠⎟

Rearrange F2

F2 =A

A + Im

⎛⎝⎜

⎞⎠⎟=

A + Im− Im

A + Im

⎛⎝⎜

⎞⎠⎟= 1−

Im

A + Im

⎛⎝⎜

⎞⎠⎟

F2 = 1−%HPLC Impurities

100%

⎛⎝⎜

⎞⎠⎟

Page 6: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 6!

%Water

100%=

W

A + Im+W

Rearrange F1

F1 =A + Im

A + Im+W

⎛⎝⎜

⎞⎠⎟=

A + Im+W −WA + Im+W

⎛⎝⎜

⎞⎠⎟

=A + Im+W

A + Im+W−

W

A + Im+W

⎛⎝⎜

⎞⎠⎟

F1 = 1−%Water

100%

⎛⎝⎜

⎞⎠⎟

Page 7: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 7!

Page 8: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 8!

%Purity = 1−%Water

100%

⎛⎝⎜

⎞⎠⎟

1−%HPLC Impurities

100%

⎛⎝⎜

⎞⎠⎟

100%

%Purity = 1−%Water

100%−

%HPLC Impurities

100%+

%Water

100%

⎛⎝⎜

⎞⎠⎟

%HPLC Impurities

100%

⎛⎝⎜

⎞⎠⎟

⎧⎨⎪

⎩⎪

⎫⎬⎪

⎭⎪100%

The Second Order Term

Page 9: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 9!

Example

Let %Water = 2.5%

%HPLC Impurities = 5.0%

Then %Purity = {1- 0.025 - 0.050 + (0.025)(0.050)}100%

%Purity = 92.6%

If the second order term is omitted, %Purity = 92.5%

Page 10: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 10!

CASE II

Protocol requires using the HPLC purity,!the water and solvent content, and!

the inorganic ion content !to determine analyte purity!

Page 11: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 11!

1. Water Content by TGA!2. Solvent Content by Gas

Chromatography!3.  Inorganic Ions by Ion Chromatography!4. Fraction of what is left by HPLC Purity!

Page 12: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 12!

%Purity = 100% − %Water − %Solvent

− %Inorganic − %HPLC Impurities

?!

Page 13: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 13!

%Purity = F

1F

2100%

F1 is the fraction of sample that is

not water/solvent/inorganic

F2 is the fraction of sample

excluding water/solvent/inorganic

that is analyte.

Page 14: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 14!

Let,

A = Analyte*

IMP = Impurities*

W = Water

S = Solvent

IN = Inorganic

Then,

F1 =A + IMP

A + IMP + IN +W + S

⎛⎝⎜

⎞⎠⎟

, F2 =A

A + IMP

⎛⎝⎜

⎞⎠⎟

____________________ • Where each response factor is known or it is assumed they are identical

Page 15: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 15!

F1F2=

A + IMP

A + IMP +W + S + IN

⎛⎝⎜

⎞⎠⎟

A

A + IMP

⎛⎝⎜

⎞⎠⎟

F1F2=

A

A + IMP +W + S + IN

⎛⎝⎜

⎞⎠⎟

Page 16: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 16!

%HPLC Impurities

100%=

IMP

A + IMP

Rearrange F2

F2 =A

A + IMP

⎛⎝⎜

⎞⎠⎟=

A + IMP − IMPA + IMP

⎛⎝⎜

⎞⎠⎟

F2 =A + IMP

A + IMP−

IMP

A + IMP

⎛⎝⎜

⎞⎠⎟

F2 = 1−%HPLC Impurities

100%

Page 17: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 17!

%Water / Solvent

100%=

W + S

A + IMP +W + S + IN

%IN

100%=

IN

A + IMP +W + S + IN

Rearrange F1

F1 =A + IMP

A + IMP +W + S + IN

⎛⎝⎜

⎞⎠⎟=

F1 =A + IMP +W + S + IN −W − S − IN

A + IMP +W + S + IN

⎛⎝⎜

⎞⎠⎟

F1 =

A + IMP +W + S + IN

A + IMP +W + S + IN−

W + S

A + IMP +W + S + IN

−IN

A + IMP +W + S + IN

⎜⎜⎜

⎟⎟⎟

F1 = 1−%Water / Solvent

100%−

%IN

100%

Page 18: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 18!

%Purity = 1−%Water / Solvent

100%−

%IN

100%

⎛⎝⎜

⎞⎠⎟

x 1−%HPLC Impurities

100%

⎛⎝⎜

⎞⎠⎟

100%

Page 19: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 19!

%Purity =

1−%Water/Solvents

100%−

%IN

100%−

%HPLC Impurities

100%

+%Water/Solvents

100%

⎛⎝⎜

⎞⎠⎟

%HPLC Impurities

100%

⎛⎝⎜

⎞⎠⎟

+%IN

100%

⎛⎝⎜

⎞⎠⎟

%HPLC Impurities

100%

⎛⎝⎜

⎞⎠⎟

⎪⎪⎪⎪

⎪⎪⎪⎪

⎪⎪⎪⎪

⎪⎪⎪⎪

100%

The Second Order Terms

Page 20: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 20!

Example

Let %Water/Solvent = 2.5%

%Inorganic = 5.0% %HPLC Impurities = 5.0%

Then

%Purity = {1- 0.025 - 0.050 - 0.050 + (0.025)(0.050) + (0.050)(0.050)}100%

%Purity = 87.9%

If both second order terms are omitted, %Purity = 87.5%

Page 21: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 21!

Dr. Wiley and the Division of Chemistry Staff in 1883.

Wiley, third from right, was 37. Courtesy Wallace F. Janssen FDA Historian

Meet the Boys of the FDA

Page 22: 2nd Order Terms in Purity Calculations of Reference Standards

jbladon! 22!

If you have a question about an equation to calculate the purity of a reference standard in a protocol or method, see your supervisor and

bring my handouts for this presentation