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Efficient Quality Control of Pharmaceutical Products

Closed vessel digestion procedure for elemental impurities in pharmaceuticals in compliance with USP <233>

Dr. Kerstin Dreblow

Metal contaminants do normally not have any therapeutic effect, but might lead to severe side-effects and affect the stability of drugs. Therefore, elemental impurities have to be monitored and controlled in drug substances, drug products and excipients.

Since almost 100years elemental impurities were determined by a colorimetric test which detects only metals precipitating by sulfide ions (Pb, Hg, Bi, As, Sb, Sn, Cd, Ag, Cu, Mo). To comply with the heavy metals limit, the colored precipitate had to be compared visually with a 100 ppm Pb standard. This test is not only inaccurate non-specific and insensitive, but also does not quantify the individual concentration of the elements. The new general chapters USP <232> and USP <233> describes new toxicity limits and modern procedures for reliable and robust determination of elemental impurities.

Limits specified in USP <232>

USP requires that all elemental impurities (catalyst and environmental contaminants) occurring in drug substances, drug product or excipients have to comply with the specified limits. Especially As, Cd, Pb, and Hg have to be controlled due to their bioavailability and toxic potential for humans. Permissible daily exposure (PDE) limits defined in general chapter <232> are valid for a larger number of elements (incl. PGE).

Table 1 depicts the allowed values for elemental impurities for drug products.

Elemental Impurities for Drug Products1

Elements

Oral

Daily Dose [µg/day)

Parental Daily Dose

[µg/day]

Inhalational Daily Dose [µg/day]

LVP Component Limit

[µg/day]

Cd

25

2.5

1.5

0.25

Pb

5

5

5

0.5

Inorg. As

1.5

1.5

1.5

0.15

Inorg. Hg

15

1.5

1.5

0.15

Ir

100

10

1.5

1.0

Os

100

10

1.5

1.0

Pd

100

10

1.5

1.0

Pt

100

10

1.5

1.0

Rh

100

10

1.5

1.0

Ru

100

10

1.5

1.0

Cr

*

*

25

*

Mo

100

10

10

1.0

Ni

500

50

1.5

5.0

V

100

10

30

1.0

Cu

1000

100

100

10

Procedures specified in USP <233>

General chapter <233> includes two analytical procedures (ICP-AES, ICP-MS) for determination of elemental impurities in pharmaceuticals.

However, due to the broad range of drug substances and products a single approach suitable for all sample types is not applicable. Sample pretreatment techniques should be individually chosen according to the substance. It is distinguished between:

  • Neat: suitable for liquids
  • Direct aqueous solution: sample soluble in aqueous solvent
  • Direct organic solution: sample soluble in organic solvent
  • Indirect solution: sample is not soluble neither in aqueous nor in organic solvent

Closed vessel digestion procedures

A wide range of drug samples show limited solubility in aqueous or organic solvents. In this case, USP <233> specifies the use of closed-vessel digestion with concentrated acids but does not mandate a specific methodology. Since the digestion success depends on the sample composition and matrix it is up to every individual laboratory to develop and validate a suitable closed-vessel digestion method (incl. acid mixture and digestion protocols).

Even if open vessel methods are widely-used in routine analysis with closed vessel methods the risk of contamination can be minimized. The advantage of the closed procedure lies in the significantly higher working temperatures which can be achieved.

While operating temperatures in open systems are limited by the boiling point of the acid solution, closed digestion vessels typically allow temperatures in the range of 200-260 °C to be reached. This results in a dramatic increase in the reaction kinetics, allowing digestions to be carried out in a matter of hours (pressure digestion) or, if microwave heating is employed, in 20-40 minutes.

Conventional pressure digestion systems

Fig. 1: Digestec – stainless steel pressure digestion vessels with PTFE inliner for most difficult digestion

More than 40 years ago Berghof introduced a product based on the pressure digestion method developed by Prof. Tölg. These stainless steel pressure digestion vessels with a TFM-PTFE liner are available in a variety of capacities ranging from 50 to 250 ml, a max. operating temperature of 260 °C, and a max. operating pressure of 200 bar. In any case, safety is assured by an appropriately dimensioned pressure relief device. For safety reasons, heating takes place in special heating blocks and not in a laboratory oven. This leads to a slow, gentle and therefore safe heating of the samples.

A decisive advantage lies in the ability of extending the digestion period nearly indefinitely. This allows even the hardest samples to be completely dissolved.

The digestec digestion system offers the highest possible level of flexibility and represents an economical alternative to microwave digestions or microwave decomposition, particularly for laboratories which only process a limited number of samples.

Microwave digestion

In recent years, heating digestion solutions with microwaves has become increasingly popular. In this process the digestions are carried out in closed containers made of chemically inert materials which are transparent to microwaves. Aside from acceleration of the reaction kinetics by employment of a closed vessel, directly heating the sample solution leads to a further decrease in digestion times. Thus, typical microwave digestions take merely 20-40 minutes.  However, since this rapid heating is accompanied by an equally rapid pressure increase and, possibly, spontaneously induced exothermic reactions, the temperature progression of each sample must be continuously recorded and the microwave power must be regulated accordingly. From a safety aspect, it is therefore most practical that the pressure progression is recorded in parallel with the temperature and that this measurement also is used to regulate power. In this way, an optimal process control can be achieved, particularly for safety reasons.

Fig. 2: The new microwave digestion system Speedwave Xpert with its unique temperature and pressure measurement system

It is on the basis Speedwave Xpert microwave digestion system was designed. With 2000Watt of power even challenging samples can be reliably digested. Furthermore, technologies specifically developed and patented to measure both temperature and pressure were implemented for this system. Here, thermometers measure contact-less and directly the temperature of the sample solution as well as the outer vessel wall.

The decisive advantage of this sensor combination lies in the fact that the heat radiated by the sample is directly measured inside the vessel while a second sensor measures the heat radiated by the vessel wall. The optical pressure monitoring permits the contact-free acquisition of the internal pressure of all vessels. These techniques do not require the measurement in a reference vessel. Combined, temperature and pressure monitoring offer optimal process control, particularly from the point of view of safety.

Beyond this, thanks to the top-loading design, together with TFM-PTFE vessels consisting of only a few components, handling is as simple as possible.

Recovery determination in pharmaceutical drugs

Digestion systems were tested for their applicability for drug substances and drug products according to new USP chapter. Analysis has been performed of As, Hg, Pb and Cd since these elements are of special importance. For doing so, a plant drug (Alchemillae vulg) was spiked with Pb, Cd, and Hg standard solution. A 500 mg sample was digested with HNO3:HCl:H2O2 (3.0 mL:0.5 mL:2.0 mL) in the speedwave microwave digestion system. The elements have been analyzed by ICP-MS.

Recovery of Pb, Cd, Hg in plant drugs

Element

Recovery [%]

Standard deviation [%]

Pb

84.5

1.74

Cd

94.9

1.94

Hg

104.7

1.44


USP chapter <233> defines acceptance criteria for spike recovery values of 70-150 % for the mean of three replicated preparations. All analyzed elements meet the given requirements with excellent accuracy. It was shown that Berghof digestion systems are suitable instruments for sample preparation of pharmaceuticals giving good results in accordance with USP general chapter <233>.

Facts, background information, dossiers
  • USP U.S. Pharmacopeia
  • impurities
  • pharmaceuticals
More about Berghof
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