by Reynhardt Klopper and Eric Fox


Pharmaceutical


A Novel Sample Preparation Method for Complete Digestion of Complex Pharmaceutical Matrices


or more than 100 years, the USP Gen- eral Chapter <231> concomitant visual test was the standard method for the determination and quantification of heavy metal impurities present in pharmaceutical products and raw materials. Based in principle upon the precipitation of insoluble metal sulfides, General Chapter <231> sample prepa- ration involves ashing the sample at 600–800 °C followed by acid digestion of the resultant resi- dues. Improvements in analytical equipment and techniques, however, have elucidated several known drawbacks of this technique. Considerable amounts of known volatile el- ements (As, Hg, etc.) may be lost during the ashing step, and the inability of some elements (As, Cd, Hg, etc.) to form colored complexes with sulfide ions can lead to under-recoveries of these heavy metal impurities. (Moreover, the time required for the ashing and digestion procedure can be in excess of 4 hr, slowing the acceptance of raw materials and shipment of finished products.) As a result of these frailties, USP recently approved General Chapters <232> and <233> to replace General Chapter <231>.1 Compliance with these two new chapters is re- quired by May 1, 2014.


F A brief summary of General


Chapters <232> and <233> Chapter <232> provides concentration limits of a number of metal impurities that may be present in pharmaceutical products and raw materials:


• Elements of Class 1: As, Hg, Cd, and Pb (the so-called “Big Four”) are known, or are strongly suspected to be, human toxicants and should be essentially absent (<2.5 μg/g for drug substances and excipients)


• Elements of Class 2: Cr, Cu, Mo, Ni, V, Pd, Pt, Os, Rh, Ru, and Ir are catalyst- and enviro- contaminants that are comparatively less toxic, but can affect the stability and shelf- life of products due to their catalytic nature.


Chapter <233> describes sample preparation procedures that can be employed prior to induc- tively coupled plasma (ICP) analysis. Dissolution of the sample in an aqueous or organic medium and closed-vessel (microwave) digestion are discussed in the chapter.


Challenges of acid digestion Although the closed-vessel sample preparation techniques proposed in Chapter <233> offer improved accuracy, sensitivity, and elemental specificity, the question of the broad applicabil- ity over a wide range of organic compounds used in the pharmaceutical industry remains. For example, many modern drugs have enteric coat- ings that consist of complex synthetic polymers or biopolymers. Using even the most aggressive acid mixtures in high-temperature and high- pressure environments, complete digestion of these complex components is not certain. Consequences of incomplete digestions include high residual carbon content; metal losses due to complexation; and high blank values, all of which can negatively impact the inductively coupled plasma-optical emission spectrometry/ mass spectrometry (ICP-OES/MS) analysis step.


Recently, a feasibility study with a variety of over-the-counter (OTC) aspirin samples was conducted by Evans Analytical Group (Liverpool, NY).2


The aim was to show efficacy of the com-


bined microwave-induced oxygen combustion technique coupled with ICP-MS analysis for pharmaceutical products.


Samples Four OTC aspirins with the same active pharmaceutical ingredient (API)—acetylsali- cylic acid—were examined. Thermogravimetric analyses revealed different mass loss patterns indicating different coating, buffering ingredi- ents, or formulation excipients. The major matrix component present in aspirin samples—car- bon—ranged from 30 wt% to 49 wt%.


AMERICAN LABORATORY • 23 • JUNE/JULY 2013


Instrumentation The Multiwave PRO microwave reaction system


(Anton Paar, Ashland, VA) (Figure 1) equipped with the Rotor 8NXQ80 was used for the sample preparation. The rotor is supplied with eight quartz glass vessels and has simultaneous pres- sure measurement capability on all digestion vessels. Simultaneous pressure measurement enables the rotor to proactively detect exother- mic reactions and take suitable action (such as reducing the microwave power) to keep it within safe temperature and pressure limits. Since the rotor has the ability to reach maximum reaction conditions of 300 °C and 80 bar, it is suitable for use with the most challenging samples.


Due to the enteric coatings on the aspirin samples, the microwave-induced oxygen com- bustion procedure was also used. This procedure combines the advantages of an ashing/combus- tion technique with closed-vessel acid digestion in a single preparation step. The method prevents analyte losses and matrix effects, while eliminat- ing the need for concentrated acids or solvents that may interfere with the analysis step.


Microwave-induced oxygen combustion was performed in the quartz vessels of the Rotor 8N configuration used with the Multiwave PRO microwave reaction system. A PerkinElmer


Figure 1 – Multiwave PRO microwave reaction system.


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