Meeting the USP <232>/<233> Regulation for Elemental Impurities in Pharmaceutical Products with ICP-OES

APPLICATION NOTE
ICP-Optical Emission Spectroscopy
Authors:
Lori Foglio
Lee Davidowski
Ken Neubauer
PerkinElmer, Inc.
Shelton, CT
Meeting the USP <232>/<233>
Regulation for Elemental
Introduction
Impurities in Pharmaceutical
The U.S. Pharmocopeia is in the
process of revising the analytical
Products with ICP-OES
protocols for the analysis of metals
in pharmaceutical products. A detailed summary of the methodology and the changes is
available1, so only a brief description will be given here.
The new methods that will be enacted are USP Chapters <232> and <233>,
which deal with inorganic content in pharmaceutical products that enters the body
through consumption, inhalation, or injection directly into the blood stream. With the
exception of large volume parenterals, the upper concentration limits of inorganic
elements which can enter the body are based on a maximum permissible daily
exposure (PDE) – these are defined in Chapter <232> and shown in Table 1 for
orally consumed medications.
Table 1. USP <232> Oral Permissible Daily Exposure of Inorganic Elements
in Drug Products
Element
Oral PDE (µg/day)
Cadmium (Cd)
5
Lead (Pb)
5
Inorganic Arsenic (As)
15
Inorganic Mercury (Hg)
15
Iridium (Ir)
100
Osmium (Os)
100
Palladium (Pd)
100
Platinum (Pt)
100
Rhodium (Rh)
100
Ruthenium (Ru)
100
Molybdenum (Mo)
180
Nickel (Ni)
600
Vanadium (V)
120
Copper (Cu)
1300
However, ICP-OES is also an appropriate analytical technique for
medications with low daily doses, such as allergy, blood pressure,
and sleep-aid medicines. In addition, since ICP-OES can handle
higher levels of dissolved solids than ICP-MS, samples do not need
to be diluted as much. This combination of low daily doses and
smaller dilutions allows ICP-OES to meet the USP <232>/<233>
criteria for a variety of medications.
To analytically determine a person’s exposure to the elements in
Table 1, the maximum dose of the medication must be taken into
account, as well as the dilution factor used in sample preparation
prior to analysis. USP <232>/<233> defines this level as the “J”
value, which is determined with the following formula:
J=
PDE
Maxium Daily Dose * Dilution Factor
where:
PDE = maximum permissible daily exposure in µg/g
Since ICP-MS has very high sensitivity, it is the most applicable
technique to meet the requirements of USP <232>/<233> as it can
measure the low concentrations from medications with high daily
doses and large dilution factors, which result in lower J values.
Maximum Daily Dose = the maximum dose of the
medicine, in grams
Dilution Factor = the dilution factor used in sample
preparation for analysis
From this equation, it is evident that the J value will vary by
medication, with larger daily doses (such as analgesics and
cold remedies) having much smaller J values than medications
with smaller daily doses (such as allergy and blood pressure
medications).
When considering an appropriate analytical technique to meet
the requirements of USP <232>/<233>, the medication must
be considered.
This work demonstrates that the PerkinElmer Optima® 8300
ICP-OES can meet the USP <232>/<233> requirements for
medicines with low daily doses, focusing on over-the-counter
allergy and antacid medications. Although a wide variety of
prescription medications would also be appropriate for ICP-OES,
these were not analyzed due to difficulty in attaining samples. It
should also be noted that analyses for osmium were not
performed due to safety concerns regarding the formation of OsO4
gas and its safe disposal.
Experimental
Samples and Sample Preparation
All medications in this work were purchased at local stores and
selected for their low maximum daily doses: 1-2 tablets/day. All
sample digestions were done in a PerkinElmer Titan MPS™
Microwave Sample Preparation System using low-pressure vessels.
A single tablet of each medication (0.1 – 0.3 g) was added to a
digestion vessel, followed by 5 mL of concentrated nitric acid, 2 mL
of 30% H2O2, and analyte spikes, as required. The vessels sat
uncapped in a fume hood for ten minutes and were then placed
into the microwave and digested according to the program in Table
2. After completion, the contents of the digestion vessels were
transferred to autosampler tubes and diluted to the appropriate
volume with 18 MΩ deionized water. The appropriate dilution
factor depended on the medication being analyzed. An advantage
of ICP-OES compared to ICP-MS is its ability to handle high levels
of total dissolved solids, which allow for smaller dilutions.
The internal standard (Y, 100 μg/L) was added to all standards and
samples, post-digestion. Calibration standards were made in 15%
(v/v) nitric acid to match the acid content of the samples.
Table 2. Titan MPS Microwave Digestion Program
2
Step
Temperature (°C)
Pressure (bar)
Ramp (min)
Hold (min)
Power (%)
1
140
30
5
10
70
2
190
30
5
20
90
3
50
30
1
10
0
Instrumental Parameters
All analyses were done on an Optima 8300 ICP-OES operating in
axial view mode. The instrumental parameters used are displayed
in Table 3, while the elements and wavelengths are shown in
Table 4. To aid with method development, Universal Data
Acquisition2 was used to help identify interferences.
Table 3. Instrumental Parameters
Results and Discussion
Table 5 shows the medications evaluated in this work and their
associated J values.
Table 5. Elements and Associated J Values for the Medicines Studied
Element
Allergy Relief-1*
(µg/L)
Allergy Relief-2*
(µg/L)
Acid Reducer
(µg/L)
67
Cd
170
170
Parameter
Value
Pb
170
170
67
Instrument
Optima 8300 ICP-OES
As
500
500
200
Nebulizer
SeaSpray
Hg
500
500
200
3300
3300
1300
Glass cyclonic, unbaffled
Ir
Sample Uptake Rate
1.5 mL/min
Pd
3300
3300
1300
Nebulizer Gas Flow
0.55 L/min
Pt
3300
3300
1300
Plasma Gas Flow
10 L/min
Rh
3300
3300
1300
Auxiliary Gas Flow
0.2 L/min
Ru
3300
3300
1300
1500 W
Mo
6000
6000
2400
Axial
Ni
20000
20000
7900
V
4000
4000
1600
Cu
43000
43000
17000
Spray Chamber
RF Power
Plasma View Mode
Table 4. Elements and Wavelengths
Element
Wavelength (nm)
Cd
226.502
Pb
220.353
As
188.979
Hg
194.168
Ir
224.268
Pd
340.458
Pt
265.945
Rh
343.489
Ru
240.272
Mo
202.031
Ni
221.648
V
290.880
Cu
327.393
* Two different formulations of the same allergy relief medicine were studied.
Both contained the same level of active ingredient and daily dosage – only the inactive
ingredients and tablet size differed.
Calibration curves were constructed with a blank and two
calibration standards with concentrations of 0.5J and 2J, as
specified in USP Chapter <233>. All calibration curves gave linear
regressions > 0.9999.
To meet the repeatability requirements of USP <233>, six separate
tablets of the same medication were digested with a spike at the
J value. Tables 6 and 7 show the results for the allergy and acid
reducer medicines; all have relative standard deviations significantly
less than the 20% criteria defined in the method. (It should be
noted that none of the elements in the method were detected in
any of the unspiked tablets.)
Table 6. Results for Analysis of Six Separate Acid Reducer Tablets
Element
Tablet 1 (µg/L)
Tablet 2 (µg/L)
Tablet 3 (µg/L)
Tablet 4 (µg/L)
Tablet 5 (µg/L)
Tablet 6 (µg/L)
%RSD
Cd
70.8
69.7
70.5
69.6
69.2
69.8
0.9
Pb
68.7
71.3
64.7
66.7
66.6
69.4
3.5
As
203
203
204
200
199
203
1.0
Hg
181
188
182
183
185
185
1.2
Ir
1450
1450
1440
1450
1450
1450
0.5
Pd
1380
1300
1320
1290
1300
1300
2.6
Pt
1270
1260
1260
1270
1270
1270
0.5
Rh
1290
1280
1280
1300
1280
1290
0.5
Ru
1290
1280
1270
1290
1290
1280
0.4
Mo
2380
2350
2350
2350
2360
2360
0.6
Ni
8170
8160
8080
8160
8200
8180
0.5
V
1660
1660
1650
1660
1670
1670
0.4
Cu
19200
19700
19000
19300
19500
1950
1.3
3
Table 7. Results for Analysis of Six Separate Allergy Relief Tablets
Element
Tablet 1 (µg/L)
Tablet 2 (µg/L)
Tablet 3 (µg/L)
Tablet 4 (µg/L)
Tablet 5 (µg/L)
Tablet 6 (µg/L)
%RSD
Cd
171
172
170
170
168
172
0.9
Pb
167
165
168
169
164
168
1.2
As
497
508
501
496
490
502
1.3
Hg
498
508
500
498
494
507
1.1
Ir
3390
3390
3420
3380
3360
3430
0.7
Pd
3510
3470
3430
3420
3390
3500
1.4
Pt
3310
3300
3260
3260
3240
3300
0.9
Rh
3230
3230
3200
3170
3160
3240
1.0
Ru
3300
3290
3270
3260
3230
3310
0.9
Mo
6330
6340
6290
6270
6200
6330
0.8
Ni
20000
20100
20200
20000
19900
20300
0.7
V
4030
4040
4070
4020
4000
4070
0.7
Cu
44900
45100
44800
44500
44000
45000
0.9
To determine the ruggedness of the method, samples were
analyzed on three separate days, and the results compared. Table 8
shows the relative standard deviations from a three-day analysis of
both the acid reducer and allergy relief medications, all of which
are well below the USP <233> requirement of 25% RSD over
three days.
Table 8. RSDs for Acid Reducer and Allergy Relief Tablets Over Three Days
Element
Acid Reducer
% RSD over
Three Days
Allergy Relief
% RSD over
Three Days
Cd
1.1
0.4
Pb
1.4
0.2
As
1.6
1.1
Hg
3.2
0.8
Ir
1.7
0.8
Pd
7.7
1.2
Pt
1.2
0.5
Rh
2.3
3.7
Ru
0.3
0.8
Mo
0.5
0.2
Ni
1.2
0.5
V
1.5
0.4
Cu
0.9
0.9
The accuracy of the method was assessed by determining
pre-digestion spike recoveries of 0.5J and 1.5J, as specified in the
method. Table 9 shows the recoveries for the acid reducer and
allergy medicines, all well within the 70-150% window specified
in the method.
Table 9. Spike Recoveries (%) for Acid Reducer and Allergy Medicines
Acid Reducer
0.5J
1.5J
Allergy Relief
0.5J
1.5J
Cd
100
99.2
98.3
92.3
Pb
98.0
100
101
97.6
As
104
97
96.4
95.5
Hg
92.4
93.5
104
97.8
Ir
108
112
105
95.8
Pd
91.7
96.6
102
98.0
Pt
101
97.5
100
99.2
Rh
94.9
96.9
101
98.0
Ru
94.3
98.9
106
108
Mo
94.3
97.1
103
96.3
Ni
99.2
99.0
99.1
94.0
V
99.7
99.3
98.3
94.8
Cu
108
110
101
95.0
Element
Conclusion
This work has demonstrated that the Optima 8300 ICP-OES
from PerkinElmer can meet and exceed the requirements of USP
Chapters <232>/<233> for medications with low daily doses, as
demonstrated with allergy relief and acid reducer tablets. The
ability of ICP-OES to handle high levels of dissolved solids allows
for minimal dilution of the samples. These low dilution factors,
combined with low daily doses, allow ICP-OES to meet the USP
<232>/<233> criteria for a variety of medications.
References
1. “Implementation of USP New Chapters <232> and <233>
on Elemental Impurities in Pharmaceutical Products”,
PerkinElmer Inc., 2014
2. “Universal Data Acquisition on the Optima ICP-OES”,
PerkinElmer Inc., 2009-2014
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