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1.1 INTRODUCTION

Trace metal (element) analysis is utilized in a wide range of

applications, including medical diagnostics, medical and biological

research, pharmaceutical analysis, contamination of food and drinking

water, food content analysis, nutritional evaluation, geological,

environmental analysis and semiconductor quality control. Trace metals

can be detected in biological samples; such as blood or urine, foods and

food supplements, pharmaceuticals, chemical compounds, potable water,

along with several other matrices. Trace analysis begins with the raw

material stage. In spite of exercising maximum care, pharmaceutical raw

materials may be contaminated by numerous substances such as

environmental factors, selective use, or as a consequence of natural

processes. The heterogeneous physicochemical properties of the

substances, the diversity of the matrices and divergent statutory

requirements impose very high demands on the analytical laboratory.

Some inorganic impurities are toxic even at low levels, and these

impurities should be monitored to ensure safety. Sources of inorganic

impurities include those deliberately added to the process (e.g.,

catalysts), carried through a process that is conducted according to good

manufacturing practices (e.g., undetected contaminants from starting

materials or reagents), those coming from the process (e.g., leaching from

pipes and other equipments), and those occur naturally (e.g., from

naturally derived plant or mineral sources). Regardless of source, the

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control of these impurities may be certified by a vendor, but purchasers

also must confirm the absence of impurities before using these

manufactured materials.

United States Pharmacopoeia

The United States Pharmacopoeia (USP) classified impurities in

various sections;

- Impurities in Official Articles

- Ordinary Impurities

- Organic Volatile Impurities

For most drugs, the reactive species consists of;

• Water- that can hydrolyze some drugs or affect the dosage form

performance

• Small electrophiles- like aldehydes and carboxylic acid

derivatives

• Peroxides- that can oxidize some drugs

• Metals- which can catalyze oxidation of drugs and the

degradation pathway

• Leachable or Extractable- can come from glass, rubber stoppers,

and plastic packaging materials.

Metal oxides such as NaO2, SiO2, CaO, MgO, are the major

components leached/extracted from glass.

Generally most synthetic materials contain leachable

oligomers/monomers, vulcanizing agents, accelerators,

plasticizers, and antioxidants.

These impurities are needed to be analyzed by using different

analytical methods.

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Analytical Method Development for Impurity Analysis

New drug development requires meaningful and reliable analytical

data to be produced at various stages of the development.

a) Sample selection for analytical method development

b) Screening of Chromatographic conditions and Phases, typically

using either isocratic or linear solvent- strength mode of gradient

elution.

c) Optimization of the method to fine-tune parameters related to

ruggedness and robustness

The impurities can be identified predominantly by following

methods:

• Reference standard method

• Spectroscopic method

• Separation method

• Isolation method

• Characterization method

Reference standard method

The key objective of this is to provide clarity to the overall life cycle,

qualification and governance of reference standards used in development

and control of new drugs. Standards serve as the basis of evaluation of

both process and product performance and are the benchmarks for

assessment of drug safety for patient consumption. These standards are

needed, not only for the active ingredients in dosage forms but also for

impurities, degradation products, starting materials, process

intermediates, and excipients.

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Spectroscopic Methods

The Ultra Violet (UV), Infra Red (IR), Mass Spectral (MS), Nuclear

Magnetic Resonance (NMR) and Raman spectroscopic methods are

routinely being used for characterizing impurities.

Separation Methods

The Capillary electrophoresis, Chiral Separations, Gas

Chromatography, Supercritical Fluid Chromatography, Thin Layer

Chromatography (TLC), High Performance TLC, High Performance Liquid

Chromatography are regularly being used for separation of impurities

and degradation products.

Isolation methodsIt is often necessary to isolate impurities. The instrumental

methods are used for isolation of impurities as it directly characterizes

the impurities. Generally, chromatographic and non-chromatographic

techniques are used for isolation of impurities prior to its

characterization. The term ‘chromatographic reactor’ refers to the use of

an analytical-scale column as both a flow-through reactor, and

simultaneously, a separation medium for the reactant(s) and product(s).

A list of methods that is used for isolation of impurities is given below.

• Solid-phase extraction methods

• Liquid-liquid extraction methods

• Accelerated solvent extraction methods

• Supercritical fluid extraction

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• Column chromatography

• Flash chromatography

Characterization Methods

Highly sophisticated instrumentation, such as MS attached to a

GC or HPLC, are inevitable tools in the identification of minor

components (drugs, impurities, degradation products, metabolites) in

various matrices. For characterization of impurities, different techniques

are used; which are as follows:

MSIt has an increasingly significant impact on the pharmaceutical

development process for several years. Advances in the design and

efficiency of the interfaces, that directly connect separation techniques

with Mass Spectrometers have afforded new opportunities for monitoring,

characterization, and quantification of drug-related substances in API

and pharmaceutical formulations. If single method fails to provide the

necessary selectivity, orthogonal coupling of chromatographic techniques

such as HPLC-TLC and HPLC-CE, or coupling of chromatographic

separations with information rich spectroscopic methods such as HPLC-

MS or HPLC-NMR may need to be contemplated, but hopefully as a

development tool only rather than a tool for routine QC use.

The LC-MS-MS systems are used for complex mixture analysis of

thermally unstable and biologically relevant molecules, viz.,mosapride, is

largely attributed to the “soft” nature of atmospheric pressure chemical

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ionization (APCI), and atmospheric pressure ionization (APPI). HPLC-

DAD-MS (HPLC coupled with a diode array UV detector and a mass

spectrometer) and such other techniques are almost routinely used. NMR

has now been added to this combination to provide HPLC-DAD-NMR-MS

capabilities in a commercial instrument. Numerous applications have

been sought in the areas of drug designing and in monitoring quality,

stability, and safety of pharmaceutical compounds, whether produced

synthetically, extracted from natural products or produced by

recombinant methods. The applications include alkaloids, amines, amino

acids, analgesics, antibacterial, anticonvulsants, antidepressant,

tranquilizers, antineoplastic agents, anesthetics, macromolecules,

steroids, miscellaneous.

The compendial method is based on the assumption that each

element present in the sample matrix will react with thioacetamide 100%

or to the exact extent as the Pb standard to form a sulfide species. The

insolubility of most sulfides has long been used in remediation efforts in

the environmental field, where heavy metals are precipitated to remove

them from soils, waters and other contaminated areas. In the same way,

the compendial method assumes that any sulfides generated in the

sample will form a precipitate which can then be compared to the

precipitate formed by the Pb standard. The compendial method also

assumes that the reaction kinetics for the formation of the potential

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sulfides is very similar to the reaction kinetics for the formation of lead

sulfide in the standard solution and that the reaction kinetics is not

impacted significantly by the sample matrix. Since many metal sulfides

can form colloids, the compendial method requires that the visual

sample comparison be performed in a relatively short amount of time

after the precipitate has formed (~ 5 min) to minimize any effects that

Ostwald ripening may cause. Lastly, since the compendial method relies

on a visual comparison, it assumes that the visual characteristics of the

potential sulfides formed are similar enough to the lead sulfide and

unaffected by the sample matrix to be considered essentially identical.

One crucial assumption that is not mentioned above is that the

heating and/or ashing step that the sample must undergo does not

result in the loss of any of the elements of interest and preclude them

from forming precipitates or colloids for comparison. For the volatile

elements, such as mercury and selenium, this assumption lacks

scientific merit, and given the known toxicological effects of these

elements, highlights the need for the development of a more reliable and

accurate method. A USP committee on the “Harmonization of the USP,

EP and JP Heavy Metals Testing Procedures” acknowledge several of the

shortcomings in the compendial methods.

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1.2 REVIEW OF EARLIER WORKS

1.2.1 Review of earlier works on trace metals analysis in organic

matrices

The inorganic impurities originates from various reaction vessels,

electrodes, catalysts, reagents, solvents, plumbing and raw materials and

other equipments used during the synthesis of pharmaceuticals. All

these are characteristic in synthetic route of a manufacturing process.

The potential impurities of several drugs palladium and its compounds

are routinely monitored [1-6]. Catalysts containing Tungsten were

processed in synthesis of several pharmaceuticals. Important activity in

pharmaceutical industry is monitoring of heavy metals, final drug

substances and in-process intermediates not only because of the catalyze

decomposition but also for their potential toxicity. Serious health

hazards may occur even at very low doses with heavy metals like lead

and cadmium in pharmaceuticals [8,9]. Longer exposures to lead cause

adverse effects on behavioral and psychological activities in living beings.

0.06 mg of lead intake per day for one month is enough for chronic

poisoning. Osteomalacia, obstructive lung and kidney dysfunction

diseases are caused due to chronic toxicity. Cadmium accumulates into

human body and has half life of 30 years which is another human

carcinogen [9] and is a serious health hazard. It accumulates in the

human body and has a biological half-life of 30 years. The levels of heavy

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metals in pharmaceuticals are controlled by limit tests and usually

defined by regulatory agencies which are permissible with the tests,

make sure no inorganic based contaminants are introduced into drugs at

any of the steps in manufacturing process. The proposed limit of Pt in

calcium folinate is 20 µg g−1 by European Pharmacopoeia (EP) [10]. The

collective monitoring of total metal content in pharmaceutical products is

proposed by all Japanese Pharmacopoeia [JP], British Pharmacopoeia

[BP], European Pharmacopoeia [EP] and United States Pharmacopoeia

[USP]. The precipitation method of metal sulfides from an aqueous

solution and for visual comparison of the color, these methods involve to

that of similarly treated standard solution of lead. The methods

discussed are laborious in terms of less sensitive, non-specific, less

accurate and time consuming. In pharmaceuticals there is a great need

for the development of selective and highly sensitive technique for

determination of trace metals to ensure the safety and efficacy of drugs

for human consumption.

Detrimental effects of some of the heavy metals found in

medicinal products, European medicines agency [EMEA] has described

the guidelines on specification limits for residues [11]. For analysis of

trace elements atomic spectrometric techniques like ICP-AES, ICP-MS &

AAS are widely used for analysis of trace elements [12, 13]. When the

concentration of analyte is high, generally used technique is Flame-AAS

[F-AAS] or when analyte concentration is low, graphite furnace AAS [GF-

AAS] is Suitable. Their application is limited for the analysis of impurities

10

due to their relatively high detection limits. For determination of each

metal, highly specific hallow cathode lamps are used. In the analysis of

pharmaceutical Products, inductively coupled plasma plays a major

significant role [15,16]. ICP-MS is a multi-elemental technique but could

not be used for spectral interferences and accuracy at ultra trace levels.

For fast multi-elemental determination of heavy metals in different

sample matrices at ultra trace and trace concentrations is one of the

sensitive analytical technique [ICP-MS].Mass spectrometer coupled with

inductively coupled plasma ionization is emerged as a most suitable and

powerful technique for analysis of trace elements in pharmaceuticals and

bulk drugs [26-45].

In pharmaceutical industry ICP-MS provides a major service for

the analysis of heavy metals in drugs. Limitations of ICP-MS include non

availability of certified reference standard and high capital investment for

most of the pharmaceutical products [46-70]. ICP-MS method has been

developed and applied for the determination of Lead Isotope ratios in Port

wine. 24 port wine samples of different ages and characteristics are

tested by this method [71-80].

Lead isotope ratios in the analyzed samples were tested with

ICP-MS equipped with Nickel cones, peristaltic sample delivery pump

and nebulizer. Mass 208 was selected to maximize the ion intensity and

optimum instrumental conditions. Lead isotopic standard solution as

external correction and with TI as the internal standard chosen as mass

bias correction, because of constant natural isotope ratio and proximity

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in mass to the analyte of interest TI was selected as internal standard.

Under selected experimental conditions this method was found to be

suitable for mass bias correction. Lead isotope ratios of RSD values

associated to mean values found to be about 0.3% for 208Pb/206Pb and

207Pb/206Pb and 0.8% for 204Pb/206Pb. They analyzed all port wine

samples and observed the significant decrease of the lead concentration

with the age [81-90]. To eliminate sample carry over effects and to abate

size cyclonic chamber these methods was developed. To obtain freedom

from matrix effects isotope dilution technique was applied using the long

lived isotope 129I. To avoid loss of Iodine at initial stages sample pre

treatment and special care was taken. A High Pressure Asher Autoclave

concentrated nitric acid in closed vessel was used for sample digestion

and an optimized heating program was used for nitric acid digestion. To

alter the chemical form of potentially volatile species a lengthy sample

preparation is mandatory or additional oxidizing reagents were not added

such as perchloric acid. Proposed method results compared with neutron

activation analysis [NAA] [91-100]. The RSD of both methods were

comparable and author found that resulting to be 10% for NAA and 8%

for ICP-MS.ICP-MS techniques were applied by Caroli et al to assess the

feasibility of producing new certified reference material for trace elements

in honey [101-110]. The following list of elements was considered, they

are Fe, Ni, Mn, Sn, Pb, Zn, As, Cd, Cr and Cu. For the simultaneous

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multi-elemental analysis of essential and toxic elements the double

focusing ICP-MS was investigated as a powerful tool for number of

matrices by different groups [126-130]. Caroli et al carried out a ring test

to determine multi-elemental distribution pattern of honey collected from

two botanical origins and to evaluate a long term stability of honey

samples. Extensive studies conducted by many authors to determine Cu,

Cd, Pd, Fe and Zn in different food items, the extensive results obtained

were tested by different laboratories by ICP-MS or ICP method adopted

by AOAC International [111-120].

To investigate elemental concentration in vegetables such as

onions and peas, Gunderson et al has applied ICP-MS, produced in

conventional Danish agricultural crops and organic crops [121-125].

Under carefully controlled contamination free conditions sampling,

sample preparation and ICP-MS analysis were performed. Sixty three

trace and major elements were determined in Onion and Peas collected

from conventionally cultivated sites and fifty five elements from

organically cultivated sites by using High Resolution [HR] ICP-MS. To

characterize the analyzed samples with regard to geographic origin it is

possible by comparison of elemental concentration profiles by

multivariate analysis. For the simultaneous multi-elemental analysis of

essential and toxic elements the Double Focusing ICP-MS was

investigated as a powerful tool for number of matrices by different group

[126-130].

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1.2.2 Review of Earlier Works on Ion chromatographic analysis

There is a great amount of potentially interfering matrix

components usually trace level analytes and with measured one. This is

a common problem in most of the methods in field of analytical

chemistry in real samples. When the sample contains high concentration

of ionic species becomes a severe problem in ion chromatography [134-

149]. This method has not been widely studied for the simultaneous

determination of five common inorganic cations and seven common

inorganic anions. Xu et al [150-160] has made an approach to determine

common inorganic ions and also performed cation exchange

chromatography/ single column ion exclusion chromatography for

cations and ions separation and also used DL-malicacid-methanol-water

as eluent. For successful separation of only five common cations Ca2+, K+,

Mg2+, Na+ and NH4+ and four common anions Cl-, F-, NO3-, and SO42-.

This method was used in past years particular attention has been given

for the speciation and trace analysis in high ionic matrices of

environmental and biological samples [160-179].

The final chromatogram was influenced considerably by varying

the retention times of anlayte ions by means of different processes of

matrix components [180-209], by change of matrix ion content the

composition inside the column and self elution was effected.

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The high matrix anion concentrations with retention behaviour of

analyte anions in sample strongly count-on the relative affinities of mass

and eluent anions. The eluent anion has a significantly lesser affinity

than matrix components, matrix anions self elution effect prevents other

anions from being retained by shortens the retention time of solutes and

stationary phase, when the eluent was changed it predominates the

matrix anion and had an affinity for stationary phase less than eluent it

prolonged the retention time of anlaytes, eluent ions replace matrix

component in stationary phase, sample in the separator column was

followed by modified eluent which was very poor in eluent component but

enriched with matrix ion [210-216].In this method three anions SO42-,

Cl- and NO3- could be separated, are the anionic species have limited

selectivity [211-224]. To evaluate the real quality of natural waters by

the method described in US EPA 300.0, five cations determined together

with seven anions.

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1.3 PRESENT WORK

There are two main objectives in the present thesis,

a) Method developments for trace heavy metals analysis in Proton pump

inhibitor compounds and its intermediates using ICP-MS.

b) Ion chromatographic determination of inorganic anions in Proton

Pump Inhibitors

The goal of this work was to develop a quick and sensitive

screening method for the analysis of trace heavy metals by using

Inductively Coupled Plasma Mass Spectrometry Dynamic Reaction Cell

(DRC), elements like Cd, Co, Cu, Cr, Fe, Mn, Ni, Pt, Pb, Pd, Sn, Se, Sb, V

and Zn in rabeprazole, omeprazole, pantoprazole (PPIs) and their

intermediates [51, 78, 87]. Histamine receptor blockers are inferior to

that of gastric acid suppression by PPIs. For various disorders like acid

peptic disorders, peptic ulcer diseases, non steroidal anti-inflammatory

drug induced gastropathy and gastro esophageal reflux disease. PPIs

have been proved as improved treatment. The side effects of PPIs have

been found to be minimal and few drug interactions are significant.

These are generally considered safe for long term treatment. Proton

pump inhibitor has shown great success to treat acid- related gastro-

intestinal disease.

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The DRC ICP-MS method have been developed & investigated in

every step of synthesis in order to establish source of the heavy metal

contamination for the monitoring of trace metals during the synthesis to

meet rigorous standard limit requirements. In many ways heavy metal

contamination may be carried to intermediates and bulk drug

substances by solvents, reagents, electrodes and raw materials used in

synthesis. A quadrupole ICP-MS equipped with DRC was employed for

the determination of 15 elements Zn, V, Sn, Se, Sb, Cd, Cr, Cu, Co, Mn,

Fe, Ni, Pd, Pb and Pt. The ammonia gas (NH3) is used as a reaction gas in

DRC mode and the effectiveness of NH3 gas in reducing or eliminating

polyatomic ions and studying effect of carbon interference in the analysis

are also reported.

ICP-MS has been selected as one of the basic alternative methods,

because it has good sensitivity, optimal sample size, reasonable

elemental interferences and self controlled multi-elemental analysis with

selection of suitable range of elements. For many of the elements of

interest detection limits (DL) at ppb and sub ppb levels are commonly

achieved with ICP-MS. ICP-MS detection limits are sensitive and permits

the analyst to utilize less concentrated sample solutions, minimizing

potential effects of sample matrix, eliminating minimum quantity of

sample size and consisting of wide variety of organic molecules which

include bases, free acids and salts in developing a method, by sample

17

dilution it is desirable to minimize the sample matrix effects to less

extent.

Objective of this work is the development of a procedure for the ion

chromatographic determination of fluoride, chloride, bromide, nitrate,

phosphate and sulfate in aqueous solutions of Rabeprazole sodium,

Pantoprazole sodium and Omeprazole sodium (PPIs). The clear solutions

of PPI were analyzed for the inorganic anions content by estimation on

ion chromatograph equipped with a conductivity detector [150-160]. The

eluents used for separation of anions are sodium carbonate, and sodium

bicarbonate using the Metrosep Anion Dual 1 anion-exchange column. In

the absence of matrix standards, the separation efficiency has been

investigated by spiking samples with varying amounts of anionic

standards with spike recoveries obtained between 102 to 120 %. The

sample organic matrix strongly interferes in analytical procedures. It was

observed that presence of matrix increased the conductance of

monovalent anions. The matrix enhancement factor was calculated for

each anion in the matrix.

To determine inorganic anions with a single eluent in a single run this

analytical method provides better operating conditions. The equipment

consists of anion exchange column, one pump, one injection valve, with

conductivity detector.

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